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Sample records for neonatal rat ventricular

  1. Calcium-sensing receptor induces rat neonatal ventricular cardiomyocyte apoptosis

    SciTech Connect

    Sun Yihua; Liu Meina; Li Hong; Shi Sa; Zhao Yajun; Wang Rui; Xu Changqing . E-mail: syh200415@yahoo.com.cn

    2006-12-01

    The calcium-sensing receptor (CaSR) exists in many tissues, and its expression has been identified in rat cardiac tissue. However, Physiological importance and pathophysiological involvement of CaSR in homeostatic regulation of cardiac function are unclear. To investigate the relation of CaSR and apoptosis in cardiomyocytes, we examined the role of the CaSR activator gadolinium chloride (GdCl{sub 3}) in rat neonatal ventricular cardiomyocytes. Expression of the CaSR protein was observed by Western blot. The apoptotic ratio of rat neonatal ventricular cardiomyocytes was measured with flow cytometry and immunofluorescence techniques. A laser scan confocal microscope was used to detect the intracellular concentration of calcium ([Ca{sup 2+}]{sub i}) in rat neonatal ventricular cardiomyocytes using the acetoxymethyl ester of fluo-3 (fluo-3/(AM)) as a fluorescent dye. The results showed that GdCl{sub 3} increased the phosphorylation of extracellular signal-regulated protein kinase (ERK), c-Jun NH{sub 2}-terminal protein kinases (JNK), and p38. GdCl{sub 3} also activated caspase 9 and increased apoptosis in myocyte by increasing [Ca{sup 2+}]{sub i}. In conclusion, these results suggest that CaSR promotes cardiomyocyte apoptosis in rat neonatal ventricular cardiomyocytes through activation of mitogen-activated protein kinases and caspase 9 signaling pathways.

  2. Calcium current in isolated neonatal rat ventricular myocytes.

    PubMed Central

    Cohen, N M; Lederer, W J

    1987-01-01

    1. Calcium currents (ICa) from neonatal rat ventricular heart muscle cells grown in primary culture were examined using the 'whole-cell' voltage-clamp technique (Hamill, Marty, Neher, Sakmann & Sigworth, 1981). Examination of ICa was limited to one calcium channel type, 'L' type (Nilius, Hess, Lansman & Tsien, 1985), by appropriate voltage protocols. 2. We measured transient and steady-state components of ICa, and could generally describe ICa in terms of the steady-state activation (d infinity) and inactivation (f infinity) parameters. 3. We observed that the reduction of ICa by the calcium channel antagonist D600 can be explained by both a shift of d infinity to more positive potentials as well as a slight reduction of ICa conductance. D600 did not significantly alter either the rate of inactivation of ICa or the voltage dependence of f infinity. 4. The calcium channel modulator BAY K8644 shifted both d infinity and f infinity to more negative potentials. Additionally, BAY K8644 increased the rate of inactivation at potentials between +5 and +55 mV. Furthermore, BAY K8644 also increased ICa conductance, a change consistent with a promotion of 'mode 2' calcium channel activity (Hess, Lansman & Tsien, 1984). 5. We conclude that, as predicted by d infinity and f infinity, there is a significant steady-state component of ICa ('window current') at plateau potentials in neonatal rat heart cells. Modulation of the steady-state and transient components of ICa by various agents can be attributed both to specific alterations in d infinity and f infinity and to more complicated alterations in the mode of calcium channel activity. PMID:2451004

  3. Heat stress activates AKT via focal adhesion kinase-mediated pathway in neonatal rat ventricular myocytes.

    PubMed

    Wei, Hongguang; Vander Heide, Richard S

    2008-08-01

    Heat stress (HS)-induced cardioprotection is associated with increased paxillin localization to the membrane fraction of neonatal rat ventricular myocytes (NRVM). The purpose of this study was 1) to examine the subcellular signaling pathways activated by HS; 2) to determine whether myocardial stress organizes and activates an integrated survival pathway; and 3) to investigate potential downstream cytoprotective proteins activated by HS. After HS, NRVM were subjected to chemical inhibitors (CI) designed to simulate ischemia by inhibiting both glycolysis and mitochondrial respiration. Protein kinase B (AKT) expression (wild type) was increased selectively with an adenoviral vector. Cell signaling was analyzed with Western blot analysis, while oncosis/apoptosis was assayed by measuring Trypan blue exclusion and/or terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) staining, respectively. HS increased phosphorylation of focal adhesion kinase (FAK) at tyrosine 397 but did not adversely affect the viability of NRVM before CI. HS increased association between FAK and phosphatidylinositol 3-kinase as well as causing a significant increase in AKT activity. Increased expression of wild-type AKT protected myocytes from both oncotic and apoptotic cell death. Increased expression of a FAK inhibitor, FRNK, reduced AKT phosphorylation in response to HS both at time 0 and after 10 min of CI compared with myocytes expressing empty virus. We conclude that myocardial stress activates cytoskeleton-based signaling pathways that are associated with protection from lethal cell injury.

  4. Effects of the venom of the spider Ornithoctonus hainana on neonatal rat ventricular myocytes cellular and ionic electrophysiology.

    PubMed

    Zhang, Yiya; Liu, Jinyan; Liu, Zhonghua; Wang, Meichi; Wang, Jing; Lu, Shanshan; Zhu, Li; Zeng, Xiongzhi; Liang, Songping

    2014-09-01

    Cardiac ion channels are membrane-spanning proteins that allow the passive movement of ions across the cell membrane along its electrochemical gradient, which regulates the resting membrane potential as well as the shape and duration of the cardiac action potential. Additionally, they have been recognized as potential targets for the actions of neurotransmitters, hormones and drugs of cardiac diseases. Spider venoms contain high abundant of toxins that target diverse ion channels and have been considered as a potential resource of new constituents with specific pharmacological properties. However, few peptides from spider venoms were detected as cardiac channel antagonists. In order to explore the effects of the venom of Ornithoctonus hainana on the action potential and ionic currents of neonatal rat ventricular myocytes (NRVMs), whole cell patch clamp technique was used to record action potential duration (APD), sodium current (INa), L calcium current (ICaL), rapidly activating and inactivating transient outward currents (Ito1), rapid (IKr) and slow (IKs) components of the delayed rectifier currents and the inward rectifier currents (IK1). Our results showed that 100 μg/mL venom obviously prolonged APDs. Significantly, the venom could inhibit INa and ICaL effectively, while no evident inhibitory effects on cardiac K(+) channels (Ito1, Iks, Ikr and Ik1) were observed, suggesting that the venom represented a multifaceted pharmacological profile. The effect of venom on Na(+) and Ca(2+) currents of ventricular myocytes revealed that the hainan venom as a rich resource of cardiac channel antagonists might be valuable tools for the investigation of both channels and drug development.

  5. The GSTM2 C-Terminal Domain Depresses Contractility and Ca2+ Transients in Neonatal Rat Ventricular Cardiomyocytes.

    PubMed

    Hewawasam, Ruwani P; Liu, Dan; Casarotto, Marco G; Board, Philip G; Dulhunty, Angela F

    2016-01-01

    The cardiac ryanodine receptor (RyR2) is an intracellular ion channel that regulates Ca2+ release from the sarcoplasmic reticulum (SR) during excitation-contraction coupling in the heart. The glutathione transferases (GSTs) are a family of phase II detoxification enzymes with additional functions including the selective inhibition of RyR2, with therapeutic implications. The C-terminal half of GSTM2 (GSTM2C) is essential for RyR2 inhibition, and mutations F157A and Y160A within GSTM2C prevent the inhibitory action. Our objective in this investigation was to determine whether GSTM2C can enter cultured rat neonatal ventricular cardiomyocytes and influence contractility. We show that oregon green-tagged GSTM2C (at 1 μM) is internalized into the myocytes and it reduces spontaneous contraction frequency and myocyte shortening. Field stimulation of myocytes evoked contraction in the same percentage of myocytes treated either with media alone or media plus 15 μM GSTM2C. Myocyte shortening during contraction was significantly reduced by exposure to 15 μM GSTM2C, but not 5 and 10 μM GSTM2C and was unaffected by exposure to 15 μM of the mutants Y160A or F157A. The amplitude of the Ca2+ transient in the 15 μM GSTM2C - treated myocytes was significantly decreased, the rise time was significantly longer and the decay time was significantly shorter than in control myocytes. The Ca2+ transient was not altered by exposure to Y160A or F157A. The results are consistent with GSTM2C entering the myocytes and inhibiting RyR2, in a manner that indicates a possible therapeutic potential for treatment of arrhythmia in the neonatal heart. PMID:27612301

  6. The GSTM2 C-Terminal Domain Depresses Contractility and Ca2+ Transients in Neonatal Rat Ventricular Cardiomyocytes

    PubMed Central

    Hewawasam, Ruwani P.; Liu, Dan; Casarotto, Marco G.; Board, Philip G.; Dulhunty, Angela F.

    2016-01-01

    The cardiac ryanodine receptor (RyR2) is an intracellular ion channel that regulates Ca2+ release from the sarcoplasmic reticulum (SR) during excitation–contraction coupling in the heart. The glutathione transferases (GSTs) are a family of phase II detoxification enzymes with additional functions including the selective inhibition of RyR2, with therapeutic implications. The C-terminal half of GSTM2 (GSTM2C) is essential for RyR2 inhibition, and mutations F157A and Y160A within GSTM2C prevent the inhibitory action. Our objective in this investigation was to determine whether GSTM2C can enter cultured rat neonatal ventricular cardiomyocytes and influence contractility. We show that oregon green-tagged GSTM2C (at 1 μM) is internalized into the myocytes and it reduces spontaneous contraction frequency and myocyte shortening. Field stimulation of myocytes evoked contraction in the same percentage of myocytes treated either with media alone or media plus 15 μM GSTM2C. Myocyte shortening during contraction was significantly reduced by exposure to 15 μM GSTM2C, but not 5 and 10 μM GSTM2C and was unaffected by exposure to 15 μM of the mutants Y160A or F157A. The amplitude of the Ca2+ transient in the 15 μM GSTM2C - treated myocytes was significantly decreased, the rise time was significantly longer and the decay time was significantly shorter than in control myocytes. The Ca2+ transient was not altered by exposure to Y160A or F157A. The results are consistent with GSTM2C entering the myocytes and inhibiting RyR2, in a manner that indicates a possible therapeutic potential for treatment of arrhythmia in the neonatal heart. PMID:27612301

  7. Role of inositol-1,4,5-trisphosphate receptor in the regulation of calcium transients in neonatal rat ventricular myocytes.

    PubMed

    Zeng, Zheng; Zhang, Heping; Lin, Na; Kang, Man; Zheng, Yuanyuan; Li, Chen; Xu, Pingxiang; Wu, Yongquan; Luo, Dali

    2014-01-01

    This study determined the regulatory effect of inositol 1,4,5-trisphosphate receptors (IP3Rs) on the basal Ca(2+) transients in cardiomyocytes. In cultured neonatal rat ventricular myocytes (NRVMs) at different densities, we used confocal microscopy to assess the effect of IP3Rs on the endogenous spontaneous Ca(2+) oscillations through specific activation of IP3Rs with myo-IP3 hexakis (butyryloxymethyl) ester (IP3BM), a membrane permeable IP3, and interference of IP3R expression with shRNA. We found that NRVMs at the monolayer state displayed coordinated Ca(2+) transients with less rate, shorter duration, and higher amplitude compared to single NRVMs. In addition, monolayer NRVMs exhibited 4 or 10 times more increased Ca(2+) transients in response to phenylephrine, an α-adrenergic receptor agonist, or IP3BM than single NRVMs did, while the transient pattern remained unaltered, suggesting that the sensitivity of intracellular Ca(2+) response to IP3R activation is different between single and monolayer NRVMs. However, interference of IP3R expression with shRNA reduced the frequency and amplitude of the spontaneous Ca(2+) fluctuates similarly in both densities of NRVMs, resembling the effects of ryanodine receptor inhibition by ryanodine or tetracaine. Our findings suggest that IP3Rs are involved, in part, in the regulation of native Ca(2+) transients, in profiles of their initiation and Ca(2+) release extent, in developing cardiomyocytes. In addition, caution should be paid in evaluating the behavior of Ca(2+) signaling in primary cultured cardiomyocytes at different densities. PMID:25242084

  8. Calcium-sensing receptor activation contributed to apoptosis stimulates TRPC6 channel in rat neonatal ventricular myocytes

    SciTech Connect

    Sun, Yi-hua; Li, Yong-quan; Feng, Shan-li; Li, Bao-xin; Pan, Zhen-wei; Xu, Chang-qing; Li, Ting-ting; Yang, Bao-feng

    2010-04-16

    Capacitative calcium entry (CCE) refers to the influx of calcium through plasma membrane channels activated on depletion of endoplasmic sarcoplasmic/reticulum (ER/SR) Ca{sup 2+} stores, which is performed mainly by the transient receptor potential (TRP) channels. TRP channels are expressed in cardiomyocytes. Calcium-sensing receptor (CaR) is also expressed in rat cardiac tissue and plays an important role in mediating cardiomyocyte apoptosis. However, there are no data regarding the link between CaR and TRP channels in rat heart. In this study, in rat neonatal myocytes, by Ca{sup 2+} imaging, we found that the depletion of ER/SR Ca{sup 2+} stores by thapsigargin (TG) elicited a transient rise in cytoplasmic Ca{sup 2+} ([Ca{sup 2+}]{sub i}), followed by sustained increase depending on extracellular Ca{sup 2+}. But, TRP channels inhibitor (SKF96365), not L-type channels or the Na{sup +}/Ca{sup 2+} exchanger inhibitors, inhibited [Ca{sup 2+}]{sub i} relatively high. Then, we found that the stimulation of CaR with its activator gadolinium chloride (GdCl{sub 3}) or by an increased extracellular Ca{sup 2+}([Ca{sup 2+}]{sub o}) increased the concentration of intracelluar Ca{sup 2+}, whereas, the sustained elevation of [Ca{sup 2+}]{sub i} was reduced in the presence of SKF96365. Similarly, the duration of [Ca{sup 2+}]{sub i} increase was also shortened in the absence of extracellular Ca{sup 2+}. Western blot analysis showed that GdCl{sub 3} increased the expression of TRPC6, which was reversed by SKF96365. Additionally, SKF96365 reduced cardiomyocyte apoptosis induced by GdCl{sub 3}. Our results suggested that CCE exhibited in rat neonatal myocytes and CaR activation induced Ca{sup 2+}-permeable cationic channels TRPCs to gate the CCE, for which TRPC6 was one of the most likely candidates. TRPC6 channel was functionally coupled with CaR to enhance the cardiomyocyte apoptosis.

  9. Carbon Nanohorns Promote Maturation of Neonatal Rat Ventricular Myocytes and Inhibit Proliferation of Cardiac Fibroblasts: a Promising Scaffold for Cardiac Tissue Engineering.

    PubMed

    Wu, Yujing; Shi, Xiaoli; Li, Yi; Tian, Lei; Bai, Rui; Wei, Yujie; Han, Dong; Liu, Huiliang; Xu, Jianxun

    2016-12-01

    Cardiac tissue engineering (CTE) has developed rapidly, but a great challenge remains in finding practical scaffold materials for the construction of engineered cardiac tissues. Carbon nanohorns (CNHs) may be a potential candidate due to their special structure and properties. The purpose of this study was to assess the effect of CNHs on the biological behavior of neonatal rat ventricular myocytes (NRVMs) for CTE applications. CNHs were incorporated into collagen to form growth substrates for NRVMs. Transmission electron microscopy (TEM) observations demonstrated that CNHs exhibited a good affinity to collagen. Moreover, it was found that CNH-embedded substrates enhanced adhesion and proliferation of NRVMs. Immunohistochemical staining, western blot analysis, and intracellular calcium transient measurements indicated that the addition of CNHs significantly increased the expression and maturation of electrical and mechanical proteins (connexin-43 and N-cadherin). Bromodeoxyuridine staining and a Cell Counting Kit-8 assay showed that CNHs have the ability to inhibit the proliferation of cardiac fibroblasts. These findings suggest that CNHs can have a valuable effect on the construction of engineered cardiac tissues and may be a promising scaffold for CTE. PMID:27263018

  10. Carbon Nanohorns Promote Maturation of Neonatal Rat Ventricular Myocytes and Inhibit Proliferation of Cardiac Fibroblasts: a Promising Scaffold for Cardiac Tissue Engineering

    NASA Astrophysics Data System (ADS)

    Wu, Yujing; Shi, Xiaoli; Li, Yi; Tian, Lei; Bai, Rui; Wei, Yujie; Han, Dong; Liu, Huiliang; Xu, Jianxun

    2016-06-01

    Cardiac tissue engineering (CTE) has developed rapidly, but a great challenge remains in finding practical scaffold materials for the construction of engineered cardiac tissues. Carbon nanohorns (CNHs) may be a potential candidate due to their special structure and properties. The purpose of this study was to assess the effect of CNHs on the biological behavior of neonatal rat ventricular myocytes (NRVMs) for CTE applications. CNHs were incorporated into collagen to form growth substrates for NRVMs. Transmission electron microscopy (TEM) observations demonstrated that CNHs exhibited a good affinity to collagen. Moreover, it was found that CNH-embedded substrates enhanced adhesion and proliferation of NRVMs. Immunohistochemical staining, western blot analysis, and intracellular calcium transient measurements indicated that the addition of CNHs significantly increased the expression and maturation of electrical and mechanical proteins (connexin-43 and N-cadherin). Bromodeoxyuridine staining and a Cell Counting Kit-8 assay showed that CNHs have the ability to inhibit the proliferation of cardiac fibroblasts. These findings suggest that CNHs can have a valuable effect on the construction of engineered cardiac tissues and may be a promising scaffold for CTE.

  11. Signaling responses after exposure to 5 alpha-dihydrotestosterone or 17 beta-estradiol in norepinephrine-induced hypertrophy of neonatal rat ventricular myocytes.

    PubMed

    Koshman, Yevgeniya E; Piano, Mariann R; Russell, Brenda; Schwertz, Dorie W

    2010-03-01

    Androgens appear to enhance, whereas estrogens mitigate, cardiac hypertrophy. However, signaling pathways in cells for short (3 min) and longer term (48 h) treatment with 17beta-estradiol (E2) or 5 alpha-dihydrotestosterone (DHT) are understudied. We compared the effect of adrenergic stimulation by norepinephrine (NE; 1 microM) alone or in combination with DHT (10 nM) or E2 (10 nM) treatment in neonatal rat ventricular myocytes (NRVMs) by cell area, protein synthesis, sarcomeric structure, gene expression, phosphorylation of extracellular signal-regulated (ERK), and focal adhesion kinases (FAK), and phospho-FAK nuclear localization. NE alone elicited the expected hypertrophy and strong sarcomeric organization, and DHT alone gave a similar but more modest response, whereas E2 did not alter cell size. Effects of NE dominated when used with either E2 or DHT with all combinations. Both sex hormones alone rapidly activated FAK but not ERK. Long-term or brief exposure to E2 attenuated NE-induced FAK phosphorylation, whereas DHT had no effect. Neither hormone altered NE-elicited ERK activation. Longer term exposure to E2 alone reduced FAK phosphorylation and reduced nuclear phospho-FAK, whereas its elevation was seen in the presence of NE with both sex hormones. The mitigating effects of E2 on the NE-elicited increase in cell size and the hypertrophic effect of DHT in NRVMs are in accordance with results observed in whole animal models. This is the first report of rapid, nongenomic sex hormone signaling via FAK activation and altered FAK trafficking to the nucleus in heart cells. PMID:20044473

  12. Thyroid hormone regulation of transmembrane signalling in neonatal rat ventricular myocytes by selective alteration of the expression and coupling of G-protein alpha-subunits.

    PubMed Central

    Bahouth, S W

    1995-01-01

    Thyroid hormone exerts profound effects on the activity of the hormone-sensitive adenylate cyclase system in the heart. Distinct guanine nucleotide-binding regulatory proteins (G-proteins) mediate stimulatory and inhibitory influences on adenylate cyclase activity. To examine whether the effects of thyroid hormone on adenylate cyclase involve specific changes in G-protein subunit expression, the influence of tri-iodothyronine (T3) on the biosynthesis and activity of G-proteins in neonatal rat ventricular myocytes was determined. In myocytes challenged with T3 for 5 days, Gs alpha levels increased by 4 +/- 0.5-fold, whereas Gi2 alpha levels declined by more than 80%. T3 down-regulated Gi2 alpha mRNA by 60% within 3 days, but had no effect on Gs alpha mRNA. The basis for the decline in Gi2 alpha mRNA was the T3-mediated suppression of Gi2 alpha gene transcription by 80 +/- 9% within 4 h. The decline in Gi2 alpha mRNA in response to T3 produced a 2-fold decrease in relative rate of synthesis of Gi2 alpha but not in its half-life (46 +/- 7 h). Gs alpha synthesis was not altered by T3, but the half-life of Gs alpha increased from 50 +/- 6 h in control cells to 72 +/- 8 h in T3-treated cells. In addition, T3 provoked the translocation of Gs alpha from the cytoplasmic to the membranous compartment. Membranous Gs alpha increased from 30 +/- 6% to 61 +/- 7% of total cellular Gs alpha, whereas cytoplasmic Gs alpha declined from 68 +/- 6% to 33 +/- 8% within 1 day of exposure to T3. T3-mediated up-regulation of Gs alpha enhanced the activation of myocardial adenylate cyclase by the stimulatory pathway whereas the down-regulation of Gi2 alpha attenuated the deactivation of myocardial adenylate cyclase by the inhibitory pathway. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:7741715

  13. Abnormal ventricular development in preterm neonates with visually normal MRIs

    NASA Astrophysics Data System (ADS)

    Shi, Jie; Wang, Yalin; Lao, Yi; Ceschin, Rafael; Mi, Liang; Nelson, Marvin D.; Panigrahy, Ashok; Leporé, Natasha

    2015-12-01

    Children born preterm are at risk for a wide range of neurocognitive and neurobehavioral disorders. Some of these may stem from early brain abnormalities at the neonatal age. Hence, a precise characterization of neonatal neuroanatomy may help inform treatment strategies. In particular, the ventricles are often enlarged in neurocognitive disorders, due to atrophy of surrounding tissues. Here we present a new pipeline for the detection of morphological and relative pose differences in the ventricles of premature neonates compared to controls. To this end, we use a new hyperbolic Ricci flow based mapping of the ventricular surfaces of each subjects to the Poincaré disk. Resulting surfaces are then registered to a template, and a between group comparison is performed using multivariate tensor-based morphometry. We also statistically compare the relative pose of the ventricles within the brain between the two groups, by performing a Procrustes alignment between each subject's ventricles and an average shape. For both types of analyses, differences were found in the left ventricles between the two groups.

  14. Exendin-4 enhances the migration of adipose-derived stem cells to neonatal rat ventricular cardiomyocyte-derived conditioned medium via the phosphoinositide 3-kinase/Akt-stromal cell-derived factor-1α/CXC chemokine receptor 4 pathway

    PubMed Central

    ZHOU, HAO; YANG, JUNJIE; XIN, TING; ZHANG, TAO; HU, SHUNYIN; ZHOU, SHANSHAN; CHEN, GUANGHUI; CHEN, YUNDAI

    2015-01-01

    Adipose-derived stem cells (ADSCs) are considered a suitable source of cells for the repair of tissue following acute myocardial infarction (AMI); however, the transplantation efficiency of ADSCs remains low. Therefore, identification of an efficient method to enhance the migration of engrafted cells to the target site is required. The present study used exendin-4 (Ex-4), a glucagon-like peptide-1 receptor agonist, to optimize the migratory capacity of ADSCs. The aim was to determine the effect and mechanisms of Ex-4 on the migration of ADSCs to neonatal rat ventricular cardiomyocyte-derived conditioned medium (NRVC-CM). The ADSCs and cardiomyocytes were cultured in vitro. Following incubation of the ADSCs with Ex-4, cell proliferation was measured using an MTT assay and the expression levels of CXC chemokine receptor 4 (CXCR4) were investigated by reverse transctiption quantitative polymerase chain reaction (RT-qPCR), western blot analysis and flow cytometry. In addition, the expression levels of stromal cell-derived factor-1α (SDF-1α) were evaluated in the NRVC-CM treated with Ex-4 by ELISA, RT-qPCR and western blot analysis. The migration of the ADSCs to the NRVC-CM was examined using a Transwell assay. Changes in the protein expression levels of phosphorylated (p−)Akt were examined in the two types of cell by western blot analysis. The results suggested that Ex-4 promoted the proliferation and expression of CXCR4 in the ADSCs, increased the secretion of SDF-1α in the cardiomyocytes and increased the expression levels of p-Akt in both cells. However, the alterations to the SDF-1α/C XC R4 cascade in the cells were abrogated following pretreatment with LY-294002, a phosphoinositide 3-kinase(PI3K) inhibitor. Furthermore, a Transwell migration assay revealed marked translocation of the ADSCs through the membranes, towards the NRVC-CM, following treatment with Ex-4. However, these effects were reduced significantly by pretreatment of the cells with the SDF-1

  15. Stenting of the right ventricular outflow tract in symptomatic neonatal tetralogy of Fallot.

    PubMed

    Haas, Nikolaus A; Laser, Thorsten K; Moysich, Axel; Blanz, Ute; Sandica, Eugen

    2014-04-01

    There is ongoing debate regarding the initial management of symptomatic neonates with tetralogy of Fallot. Although neonatal repair can be performed with low mortality, it is associated with increased morbidity and long-term impact on right ventricular performance. Traditionally, the modified Blalock-Taussig shunt remains the palliative procedure of choice. Differential pulmonary artery flow may occur and subsequently result in underdevelopment and distortion of pulmonary vessels. Transcatheter therapy was previously limited to balloon valvulotomy when the obstruction is predominantly at the pulmonary valve level. Stenting of the right ventricular outflow tract can enable adequate forward flow; however, pulmonary regurgitation may impact on right ventricular performance and cardiac output. Stenting of the right ventricular outflow tract with valve sparing placement of the stent thus treating the underlying pathophysiology of the hypercyanotic spells provides a safe and effective management strategy, improving arterial oxygen saturation, avoiding pulmonary regurgitation and encouraging pulmonary artery growth. PMID:23534437

  16. Right ventricular cavity near obliteration in neonatal severe biventricular hypertrophic cardiomyopathy

    PubMed Central

    Jivanji, Salim GM; Daubeney, Piers; Franklin, Rodney; Sheppard, Mary

    2014-01-01

    A newborn presenting with cyanosis at day 9 of life was admitted to the local hospital. Initial local echocardiography confirmed a cardiac issue and the patient was transferred to a tertiary cardiac hospital. Further imaging confirmed a rare presentation of cardiomyopathy with severe right ventricular outflow tract obstruction. Surgery was performed but with postoperative haemodynamic instability complicated by incessant ventricular tachycardia. Following discussion with the family, care was withdrawn. Postmortem demonstrated a rare form of hypertrophic cardiomyopathy with right ventricular outflow tract obstruction not previously described in a neonate. PMID:25336549

  17. Impaired acclimatization to chronic hypoxia in adult male and female rats following neonatal hypoxia.

    PubMed

    Lumbroso, Delphine; Joseph, Vincent

    2009-08-01

    We tested the hypothesis that neonatal exposure to hypoxia alters acclimatization to chronic hypoxia later in life. Rat pups were exposed to normobaric hypoxia (12% O(2); nHx group) in a sealed chamber, or to normoxia (21% O(2); nNx group) from the day before birth to postnatal day 10. The animals were then raised in normal conditions until reaching 12 wk of age. At this age, we assessed ventilatory and hematological acclimatization to chronic hypoxia by exposing male and female nHx and nNx rats for 2 wk to 10% O(2). Minute ventilation, metabolic rate, hypoxic ventilatory response, hematocrit, and hemoglobin levels were measured both before and after acclimatization. We also quantified right ventricular hypertrophy as an index of pulmonary hypertension both before and after acclimatization. There was a significant effect of neonatal hypoxia that decreases ventilatory response (relative to metabolic rate, VE/VCO(2)) to acute hypoxia before acclimatization in males but not in females. nHx rats had an impaired acclimatization to chronic hypoxia characterized by altered respiratory pattern and elevated hematocrit and hemoglobin levels after acclimatization, in both males and females. Right ventricular hypertrophy was present before and after acclimatization in nHx rats, indicating that neonatal hypoxia results in pulmonary hypertension in adults. We conclude that neonatal hypoxia impairs acclimatization to chronic hypoxia in adults and may be a factor contributing to the establishment of chronic mountain sickness in humans living at high altitude.

  18. Mathematical model of the neonatal mouse ventricular action potential

    PubMed Central

    Wang, Linda J.; Sobie, Eric A.

    2008-01-01

    Therapies for heart disease are based largely on our understanding of the adult myocardium. The dramatic differences in action potential (AP) shape between neonatal and adult cardiac myocytes, however, indicate that a different set of molecular interactions in neonatal myocytes necessitates different treatment for newborns. Computational modeling is useful for synthesizing data to determine how interactions between components lead to systems-level behavior, but this technique has not been used extensively to study neonatal heart cell function. We created a mathematical model of the neonatal (day 1) mouse myocyte by modifying, based on experimental data, the densities and/or formulations of ion transport mechanisms in an adult cell model. The new model reproduces the characteristic AP shape of neonatal cells, with a brief plateau phase and longer duration than the adult (APD80=60.1 vs. 12.6 ms). The simulation results are consistent with experimental data, including: 1) decreased density, and altered inactivation, of transient outward K+ currents, 2) increased delayed rectifier K+ currents, 3) Ca2+ entry through T-type as well as L-type Ca2+ channels, 4) increased Ca2+ influx through Na+-Ca2+ exchange, and 5) Ca2+ transients resulting from transmembrane Ca2+ entry rather than release from the sarcoplasmic reticulum (SR). Simulations performed with the model generated novel predictions, including increased SR Ca2+ leak and elevated intracellular [Na+] in neonatal compared with adult myocytes. This new model can therefore be used for testing hypotheses and obtaining a better quantitative understanding of differences between neonatal and adult physiology. PMID:18408122

  19. Metformin attenuates hyperoxia-induced lung injury in neonatal rats by reducing the inflammatory response

    PubMed Central

    Chen, Xueyu; Walther, Frans J.; Sengers, Rozemarijn M. A.; Laghmani, El Houari; Salam, Asma; Folkerts, Gert; Pera, Tonio

    2015-01-01

    Because therapeutic options are lacking for bronchopulmonary dysplasia (BPD), there is an urgent medical need to discover novel targets/drugs to treat this neonatal chronic lung disease. Metformin, a drug commonly used to lower blood glucose in type 2 diabetes patients, may be a novel therapeutic option for BPD by reducing pulmonary inflammation and fibrosis and improving vascularization. We investigated the therapeutic potential of daily treatment with 25 and 100 mg/kg metformin, injected subcutaneously in neonatal Wistar rats with severe experimental BPD, induced by continuous exposure to 100% oxygen for 10 days. Parameters investigated included survival, lung and heart histopathology, pulmonary fibrin and collagen deposition, vascular leakage, right ventricular hypertrophy, and differential mRNA expression in the lungs of key genes involved in BPD pathogenesis, including inflammation, coagulation, and alveolar development. After daily metformin treatment rat pups with experimental BPD had reduced mortality, alveolar septum thickness, lung inflammation, and fibrosis, demonstrated by a reduced influx of macrophages and neutrophils and hyperoxia-induced collagen III and fibrin deposition (25 mg/kg), as well as improved vascularization (100 mg/kg) compared with control treatment. However, metformin did not ameliorate alveolar enlargement, small arteriole wall thickening, vascular alveolar leakage, and right ventricular hypertrophy. In conclusion metformin prolongs survival and attenuates pulmonary injury by reducing pulmonary inflammation, coagulation, and fibrosis but does not affect alveolar development or prevent pulmonary arterial hypertension and right ventricular hypertrophy in neonatal rats with severe hyperoxia-induced experimental BPD. PMID:26047641

  20. Ventricular repolarization in a rat model of global heart failure.

    PubMed

    Krandycheva, Valeria; Kharin, Sergey; Strelkova, Marina; Shumikhin, Konstantin; Sobolev, Aleksey; Shmakov, Dmitry

    2013-07-01

    Isoproterenol in high doses induces infarction-like myocardial damage and structural and functional remodelling of the ventricular myocardium. The purpose of the present study was to investigate ventricular repolarization in a rat model of isoproterenol-induced heart failure. Isoproterenol was administered twice to female Wistar rats (170 mg/kg, s.c., 24 h apart). Four weeks after the injections, cardiac output was measured and unipolar epicardial ventricular electrograms were recorded in situ. Activation-recovery intervals were calculated to assess repolarization. Histological examination of the heart ventricles was also performed. Heart failure in rats treated with isoproterenol was indicated by myocardial histopathological damage and reduced cardiac output. In rats with heart failure, the regional differences in activation-recovery interval prolongation over the ventricular epicardium resulted in increasing heterogeneity in the activation-recovery interval distribution and increasing repolarization heterogeneity of the ventricular subepicardium. Myocardial damage and haemodynamic changes in heart failure induced by isoproterenol were accompanied by significant changes in ventricular repolarization, which were not associated with myocardial hypertrophy.

  1. Hair growth in neonatally undernourished rats.

    PubMed

    Salas, M; Pulido, S; Torrero, C; Regalado, M; Loranca, A

    1995-01-01

    Interaction between neonatal undernutrition and the increased self-grooming activity upon hair growth of several body areas was analyzed in rats of 10, 20 and 30 days of age. Light microscopic observations on methylene blue impregnated hairs showed that these perinatal influences delayed the growth of hair follicles and thickness and length of hair measurements of the head and thoracic areas. The hair growth of lateral abdominal regions was less affected. Data suggest that hair alterations are primarily related to food deprivation since hair follicle measures of all skin areas were more affected than the distal hair measurements. Moreover, the distribution of impaired hair growth on different body areas correlates well with the increased self-grooming components associated to neonatal undernourishment. PMID:8914627

  2. Neonatal ventricular fibrillation and an elusive ALCAPA: things are not always as they seem.

    PubMed

    Walker, Tracie C; Renno, Markus S; Parra, David A; Guthrie, Scott O

    2016-01-01

    An anomalous left coronary artery from the pulmonary artery (ALCAPA) is a rare congenital cardiac condition that typically presents with poor feeding and failure to thrive from progressive myocardial ischaemia. Previous reports of ALCAPA presenting with ventricular fibrillation (VF) have suggested a causative relationship. In this case, we present a neonate with VF without apparent cause after an extensive evaluation. Following implantable cardioverter-defibrillator placement for presumed idiopathic VF, at which time she also underwent surgical ligation of a patent ductus arteriosus (PDA), the neonate developed haemodynamic instability that ultimately was found to be due to ALCAPA. Numerous echocardiograms had missed the ALCAPA in the setting of mildly elevated pulmonary artery pressure. We discuss the limitations of current ultrasound technology in diagnosing ALCAPA in the setting of pulmonary hypertension and explain why the relationship between this patient's diagnosis of ALCAPA and her episode of VF is not clearly causative. PMID:27033289

  3. Computational tool for morphological analysis of cultured neonatal rat cardiomyocytes.

    PubMed

    Leite, Maria Ruth C R; Cestari, Idágene A; Cestari, Ismar N

    2015-08-01

    This study describes the development and evaluation of a semiautomatic myocyte edge-detector using digital image processing. The algorithm was developed in Matlab 6.0 using the SDC Morphology Toolbox. Its conceptual basis is the mathematical morphology theory together with the watershed and Euclidean distance transformations. The algorithm enables the user to select cells within an image for automatic detection of their borders and calculation of their surface areas; these areas are determined by adding the pixels within each myocyte's boundaries. The algorithm was applied to images of cultured ventricular myocytes from neonatal rats. The edge-detector allowed the identification and quantification of morphometric alterations in cultured isolated myocytes induced by 72 hours of exposure to a hypertrophic agent (50 μM phenylephrine). There was a significant increase in the mean surface area of the phenylephrine-treated cells compared with the control cells (p<;0.05), corresponding to cellular hypertrophy of approximately 50%. In conclusion, this edge-detector provides a rapid, repeatable and accurate measurement of cell surface areas in a standardized manner. Other possible applications include morphologic measurement of other types of cultured cells and analysis of time-related morphometric changes in adult cardiac myocytes.

  4. One-stage neonatal corrective repair for d-transposition of the great arteries and complete atrio-ventricular canal.

    PubMed

    Bautista-Hernandez, Victor; Marx, Gerald R; del Nido, Pedro J

    2007-01-01

    Association of d-transposition of the great arteries and complete atrio-ventricular canal constitutes an uncommon and complex cardiac anomaly usually associated with poor prognosis. We report our experience on one-stage neonatal repair for d-transposition of the great arteries and complete atrio-ventricular canal. Between August 1997 and 2005, four patients (two males and two females) underwent anatomical correction for d-transposition of the great arteries and complete atrio-ventricular canal using an arterial switch procedure and two-patch repair. Mean age and weight at operation were 20 days (range from 3 to 28 days) and 3.2kg (range from 2.7 to 3.5kg), respectively. None of the patients received preoperative palliative procedure. Associated lesions were left outflow tract obstruction in three patients and multiple muscular ventricular septal defects in two patients. All four patients survived the operation. There was one in-hospitality death due to fungal sepsis. One patient required late re-operation for left ventricular outflow tract obstruction and left atrio-ventricular valve regurgitation. For a mean follow-up of 67 months (range from 51 to 90 months) all patients are asymptomatic and with no residual defects. Corrective repair of d-transposition of the great arteries and complete atrio-ventricular canal can be successfully achieved in this very challenging population during the neonatal period. PMID:17110123

  5. Maternal hypoxia alters matrix metalloproteinase expression patterns and causes cardiac remodeling in fetal and neonatal rats.

    PubMed

    Tong, Wenni; Xue, Qin; Li, Yong; Zhang, Lubo

    2011-11-01

    Fetal hypoxia leads to progressive cardiac remodeling in rat offspring. The present study tested the hypothesis that maternal hypoxia results in reprogramming of matrix metalloproteinase (MMP) expression patterns and fibrillar collagen matrix in the developing heart. Pregnant rats were treated with normoxia or hypoxia (10.5% O(2)) from day 15 to 21 of gestation. Hearts were isolated from 21-day fetuses (E21) and postnatal day 7 pups (PD7). Maternal hypoxia caused a decrease in the body weight of both E21 and PD7. The heart-to-body weight ratio was increased in E21 but not in PD7. Left ventricular myocardium wall thickness and cardiomyocyte proliferation were significantly decreased in both fetal and neonatal hearts. Hypoxia had no effect on fibrillar collagen content in the fetal heart, but significantly increased the collagen content in the neonatal heart. Western blotting revealed that maternal hypoxia significantly increased collagen I, but not collagen III, levels in the neonatal heart. Maternal hypoxia decreased MMP-1 but increased MMP-13 and membrane type (MT)1-MMP in the fetal heart. In the neonatal heart, MMP-1 and MMP-13 were significantly increased. Active MMP-2 and MMP-9 levels and activities were not altered in either fetal or neonatal hearts. Hypoxia significantly increased tissue inhibitors of metalloproteinase (TIMP)-3 and TIMP-4 in both fetal and neonatal hearts. In contrast, TIMP-1 and TIMP-2 were not affected. The results demonstrate that in utero hypoxia reprograms the expression patterns of MMPs and TIMPs and causes cardiac tissue remodeling with the increased collagen deposition in the developing heart.

  6. The neurological effects of brevetoxin on neonatal rats

    SciTech Connect

    Tapley, S.R.; Ramsdell, J.S.; Xi, D.

    1994-12-31

    We have investigated the neuroexcitatory and neurodegenerative effects of brevetoxin on neonatal rats. Brevetoxin, a marine-biotoxin that has been implicated in several seafood poisoning incidents, is produced by the dinoflagellate Gymnodinium brevis. Four studies were done: dose response, northern analysis, immunohistochemistry and neurodegeneration. We found that neonatal rats are much more sensitive to brevetoxin than adult rats. The effectiveness of c-fos as a biomarker is being investigated, because of the high basal expression in young animals. The neurodegeneration, although not available yet, should provide valuable information.

  7. Cardiac Muscle Studies with Rat Ventricular Strips

    ERIC Educational Resources Information Center

    Whitten, Bert K.; Faleschini, Richard J.

    1977-01-01

    Details undergraduate physiology laboratory experiments that demonstrate mechanical properties of cardiac muscle, using strips from the ventricle of a rat heart. Includes procedures for obtaining length-tension curves, demonstrating the role of calcium in excitation-contraction coupling, and showing effects of several cardiovascular drugs…

  8. Mitochondrial integrity in a neonatal bovine model of right ventricular dysfunction.

    PubMed

    Bruns, Danielle R; Brown, R Dale; Stenmark, Kurt R; Buttrick, Peter M; Walker, Lori A

    2015-01-15

    Right ventricular (RV) function is a key determinant of survival in patients with both RV and left ventricular (LV) failure, yet the mechanisms of RV failure are poorly understood. Recent studies suggest cardiac metabolism is altered in RV failure in pulmonary hypertension (PH). Accordingly, we assessed mitochondrial content, dynamics, and function in hearts from neonatal calves exposed to hypobaric hypoxia (HH). This model develops severe PH with concomitant RV hypertrophy, dilation, and dysfunction. After 2 wk of HH, pieces of RV and LV were obtained along with samples from age-matched controls. Comparison with control assesses the effect of hypoxia, whereas comparison between the LV and RV in HH assesses the additional impact of RV overload. Mitochondrial DNA was unchanged in HH, as was mitochondrial content as assessed by electron microscopy. Immunoblotting for electron transport chain subunits revealed a small increase in mitochondrial content in HH in both ventricles. Mitochondrial dynamics were largely unchanged. Activity of individual respiratory chain complexes was reduced (complex I) or unchanged (complex V) in HH. Key enzymes in the glycolysis pathway were upregulated in both HH ventricles, alongside upregulation of hypoxia-inducible factor-1α protein. Importantly, none of the changes in expression or activity were different between ventricles, suggesting the changes are in response to HH and not RV overload. Upregulation of glycolytic modulators without chamber-specific mitochondrial dysfunction suggests that mitochondrial capacity and activity are maintained at the onset of PH, and the early RV dysfunction in this model results from mechanisms independent of the mitochondria.

  9. Androgen deficiency in male rats with prolonged neonatal streptozotocin diabetes.

    PubMed

    Derkach, K V; Moyseyuk, I V; Chistyakova, O V; Shpakov, A O

    2013-07-01

    We studied the diurnal dynamics of testosterone concentration in male rats with 240-day neonatal streptozotocin-induced diabetes mellitus, which is similar to human type 2 diabetes mellitus. We also studied the effects of intranasal administration of luliberin on testosterone level and the regulation of activities of adenylate cyclase and stimulatory G-proteins in the testicles of diabetic and intact animals by human chorionic gonadotropin. In rats with neonatal diabetes, a decrease in the mean diurnal level of testosterone and its morning rise were observed. The increase in testosterone level 30 min after luliberin administration was significantly reduced in diabetic animals, but no differences in the response to luliberin were observed in intact and diabetic rats 2-6 h after the treatment. The stimulatory effects of human chorionic gonadotropin on adenylate cyclase activity and binding of guanosine triphosphate by stimulatory G-proteins were reduced in the plasma membranes from the testicles of rats with neonatal diabetes in comparison with control specimens. Therefore, rats with neonatal diabetes were characterized by androgen deficiency, which can be related to the impairment of hypothalamic-pituitary-gonadal axis and reduced sensitivity of the adenylate cyclase system in the testicles of diabetic rats to human chorionic gonadotropin.

  10. Resveratrol reduces intracellular free calcium concentration in rat ventricular myocytes.

    PubMed

    Liu, Zheng; Zhang, Li-Ping; Ma, Hui-Jie; Wang, Chuan; Li, Ming; Wang, Qing-Shan

    2005-10-25

    Resveratrol (trans-3, 4', 5-trihydroxy stilbene), a phytoalexin found in grape skins and red wine, has been reported to have a wide range of biological and pharmacological properties. It has been speculated that resveratrol may have cardioprotective activity. The objective of our study was to investigate the effects of resveratrol on intracellular calcium concentration ([Ca(2+)](i)) in rat ventricular myocytes. [Ca(2+)](i) was detected by laser scanning confocal microscopy. The results showed that resveratrol (15~60 mumol/L) reduced [Ca(2+)](i) in normal and Ca(2+)-free Tyrode's solution in a concentration-dependent manner. The effects of resveratrol on [Ca(2+)](i) in normal Tyrode's solution was partially inhibited by pretreatment with sodium orthovanadate (Na3VO4, 1.0 mmol/L, P<0.01), an inhibitor of protein tyrosine phosphatase, or L-type Ca(2+) channel agonist Bay K8644 (10 mumol/L, P<0.05), but could not be antagonized by NO synthase inhibitor L-NAME (1.0 mmol/L). Resveratrol also markedly inhibited the ryanodine-induced [Ca(2+)](i) increase in Ca(2+)-free Tyrode's solution (P<0.01). When Ca(2+) waves were produced by increasing extracellular Ca(2+) concentration from 1 to 10 mmol/L, resveratrol (60 mumol/L) could reduce the velocity and duration of propagating waves, and block the propagating waves of elevated [Ca(2+)](i). These results suggest that resveratrol may reduce the [Ca(2+)](i) in isolated rat ventricular myocytes. The inhibition of voltage-dependent Ca(2+) channel and tyrosine kinase, and alleviation of Ca(2+) release from sarcoplasmic reticulum (SR) are possibly involved in the effects of resveratrol on rat ventricular myocytes. These findings could help explain the protective activity of resveratrol against cardiovascular disease. PMID:16220198

  11. Dioxin (TCDD) enhances triggered-afterdepolarizations in rat ventricular myocytes

    PubMed Central

    Xie, An; Walker, Nigel J.; Wang, Desuo

    2007-01-01

    The effects of TCDD (2,3,7,8-Tetrachlorodibenzo-p-dioxin) on action potential and afterdepolarizations were studied in rat ventricular myocytes using nystatin-perforated whole-cell patch-clamp technique. TCDD treatment, in the concentration range of 1 to 100 nM, significantly prolonged action potential duration measured at 90% of repolarization (APD90). The triggered delayed-afterdepolarizations (DADs) was observed in 6 out of 8 cells after exposure of TCDD (10 nM). In the presence of isoproterenol (ISO, 10 nM) or Bay K 8644 (1 μM), TCDD (10 nM) markedly augmented the amplitude and frequency of the arrhythmogenic DADs and triggered sustained spontaneous firings in ventricular myocytes. Voltage-clamp data indicated that TCDD (10 nM) exposure significantly enhanced the transient inward current (Iti). The triggered early-afterdepolarizations (EADs) were evoked only in cells simultaneously exposed to TCDD (10 nM) and ISO (or Bay K 8644). Further study indicated that TCDD treatment increased L-type Ca2+ current. These results indicate that activation of TCDD signaling pathway can prolong action potential duration and cause abnormal triggered afterdepolarizations. These effects may lead to clinically relevant ventricular arrhythmia especially when susceptible individuals are under elevated sympathetic stress or suffering from other myocardiopathies coincided with Ca2+-overload. PMID:17303918

  12. Dietary salt restriction in hyperthyroid rats. Differential influence on left and right ventricular mass

    PubMed Central

    Wangensteen, Rosemary; Rodríguez-Gómez, Isabel; Perez-Abud, Rocío; Quesada, Andrés; Montoro-Molina, Sebastián; Osuna, Antonio

    2015-01-01

    This study assessed the impact of salt restriction on cardiac morphology and biochemistry and its effects on hemodynamic and renal variables in experimental hyperthyroidism. Four groups of male Wistar rats were used: control, hyperthyroid, and the same groups under low salt intake. Body weight, blood pressure (BP), and heart rate (HR) were recorded weekly for 4 weeks. Morphologic, metabolic, plasma, cardiac, and renal variables were also measured. Low salt intake decreased BP in T4-treated rats but not in controls. Low salt intake reduced relative left ventricular mass but increased absolute right ventricular weight and right ventricular weight/BW ratio in both control and hyperthyroid groups. Low salt intake increased Na+/H+ exchanger-1 (NHE-1) protein abundance in both ventricles in normal rats but not in hyperthyroid rats, independently of its effect on ventricular mass. Mammalian target of rapamycin (mTOR) protein abundance was not related to left or right ventricular mass in hyperthyroid or controls rats under normal or low salt conditions. Proteinuria was increased in hyperthyroid rats and attenuated by low salt intake. In this study, low salt intake produced an increase in right ventricular mass in normal and hyperthyroid rats. Changes in the left or right ventricular mass of control and hyperthyroid rats under low salt intake were not explained by the NHE-1 or mTOR protein abundance values observed. In hyperthyroid rats, low salt intake also slightly reduced BP and decreased HR, proteinuria, and water and sodium balances. PMID:25030483

  13. Functional characteristics of neonatal rat β cells with distinct markers.

    PubMed

    Martens, G A; Motté, E; Kramer, G; Stangé, G; Gaarn, L W; Hellemans, K; Nielsen, J H; Aerts, J M; Ling, Z; Pipeleers, D

    2014-02-01

    Neonatal β cells are considered developmentally immature and hence less glucose responsive. To study the acquisition of mature glucose responsiveness, we compared glucose-regulated redox state, insulin synthesis, and secretion of β cells purified from neonatal or 10-week-old rats with their transcriptomes and proteomes measured by oligonucleotide and LC-MS/MS profiling. Lower glucose responsiveness of neonatal β cells was explained by two distinct properties: higher activity at low glucose and lower activity at high glucose. Basal hyperactivity was associated with higher NAD(P)H, a higher fraction of neonatal β cells actively incorporating (3)H-tyrosine, and persistently increased insulin secretion below 5 mM glucose. Neonatal β cells lacked the steep glucose-responsive NAD(P)H rise between 5 and 10 mM glucose characteristic for adult β cells and accumulated less NAD(P)H at high glucose. They had twofold lower expression of malate/aspartate-NADH shuttle and most glycolytic enzymes. Genome-wide profiling situated neonatal β cells at a developmental crossroad: they showed advanced endocrine differentiation when specifically analyzed for their mRNA/protein level of classical neuroendocrine markers. On the other hand, discrete neonatal β cell subpopulations still expressed mRNAs/proteins typical for developing/proliferating tissues. One example, delta-like 1 homolog (DLK1) was used to investigate whether neonatal β cells with basal hyperactivity corresponded to a more immature subset with high DLK1, but no association was found. In conclusion, the current study supports the importance of glycolytic NADH-shuttling in stimulus function coupling, presents basal hyperactivity as novel property of neonatal β cells, and provides potential markers to recognize intercellular developmental differences in the endocrine pancreas. PMID:24049066

  14. A Neonate with Susceptibility to Long QT Syndrome Type 6 who Presented with Ventricular Fibrillation and Sudden Unexpected Infant Death

    PubMed Central

    Sauer, Charles W.; Marc-Aurele, Krishelle L.

    2016-01-01

    Patient: Female, 19-day Final Diagnosis: 19 day old neonate with susceptibility to Long QT syndrome • ventricular fibrillation Symptoms: Cardiac arrest • cardiac arrhythmia • encephalopathy Medication: — Clinical Procedure: Cardioversion Specialty: Pediatrics and Neonatology Objective: Rare disease Background: This is a case of a neonate with susceptibility to long QT syndrome (LQTS) who presented with a sudden unexpected infant death. Experts continue to debate whether universal electrocardiogram (ECG) screening of all newborns is feasible, practical, and cost-effective. Case Report: A 19-day-old neonate was found unresponsive by her mother. ECG showed ventricular fibrillation and a combination of a lidocaine drip plus multiple defibrillations converted the rhythm to normal sinus. Unfortunately, MRI brain imaging showed multiple infarcts and EEG showed burst suppression pattern with frequent seizures; life supportive treatment was stopped and the infant died. Genetic testing revealed two mutations in the KCNE2 gene consistent with susceptibility to LQTS type 6. Conclusions: We believe this case is the first to demonstrate both a precipitating electrocardiographic and genetic cause of death for an infant with LQTS, showing a cause-and-effect relationship between LQTS mutation, ventricular arrhythmia, and death. We wonder whether universal ECG newborn screening to prevent LQTS death could have saved this baby. PMID:27465075

  15. Right ventricular cyclic nucleotide signaling is decreased in hyperoxia-induced pulmonary hypertension in neonatal mice.

    PubMed

    Heilman, Rachel P; Lagoski, Megan B; Lee, Keng Jin; Taylor, Joann M; Kim, Gina A; Berkelhamer, Sara K; Steinhorn, Robin H; Farrow, Kathryn N

    2015-06-15

    Pulmonary hypertension (PH) and right ventricular hypertrophy (RVH) affect 25-35% of premature infants with significant bronchopulmonary dysplasia (BPD), increasing morbidity and mortality. We sought to determine the role of phosphodiesterase 5 (PDE5) in the right ventricle (RV) and left ventricle (LV) in a hyperoxia-induced neonatal mouse model of PH and RVH. After birth, C57BL/6 mice were placed in room air (RA) or 75% O2 (CH) for 14 days to induce PH and RVH. Mice were euthanized at 14 days or recovered in RA for 14 days or 42 days prior to euthanasia at 28 or 56 days of age. Some pups received sildenafil or vehicle (3 mg·kg(-1)·dose(-1) sc) every other day from P0. RVH was assessed by Fulton's index [RV wt/(LV + septum) wt]. PDE5 protein expression was analyzed via Western blot, PDE5 activity was measured by commercially available assay, and cGMP was measured by enzyme-linked immunoassay. Hyperoxia induced RVH in mice after 14 days, and RVH did not resolve until 56 days of age. Hyperoxia increased PDE5 expression and activity in RV, but not LV + S, after 14 days. PDE5 expression normalized by 28 days of age, but PDE5 activity did not normalize until 56 days of age. Sildenafil given during hyperoxia prevented RVH, decreased RV PDE5 activity, and increased RV cGMP levels. Mice with cardiac-specific overexpression of PDE5 had increased RVH in RA. These findings suggest normal RV PDE5 function is disrupted by hyperoxia, and elevated PDE5 contributes to RVH and remodeling. Therefore, in addition to impacting the pulmonary vasculature, sildenafil also targets PDE5 in the neonatal mouse RV and decreases RVH.

  16. Neonatal hyperoxic lung injury favorably alters adult right ventricular remodeling response to chronic hypoxia exposure

    PubMed Central

    Goss, Kara N.; Cucci, Anthony R.; Fisher, Amanda J.; Albrecht, Marjorie; Frump, Andrea; Tursunova, Roziya; Gao, Yong; Brown, Mary Beth; Petrache, Irina; Tepper, Robert S.; Ahlfeld, Shawn K.

    2015-01-01

    The development of pulmonary hypertension (PH) requires multiple pulmonary vascular insults, yet the role of early oxygen therapy as an initial pulmonary vascular insult remains poorly defined. Here, we employ a two-hit model of PH, utilizing postnatal hyperoxia followed by adult hypoxia exposure, to evaluate the role of early hyperoxic lung injury in the development of later PH. Sprague-Dawley pups were exposed to 90% oxygen during postnatal days 0–4 or 0–10 or to room air. All pups were then allowed to mature in room air. At 10 wk of age, a subset of rats from each group was exposed to 2 wk of hypoxia (Patm = 362 mmHg). Physiological, structural, and biochemical endpoints were assessed at 12 wk. Prolonged (10 days) postnatal hyperoxia was independently associated with elevated right ventricular (RV) systolic pressure, which worsened after hypoxia exposure later in life. These findings were only partially explained by decreases in lung microvascular density. Surprisingly, postnatal hyperoxia resulted in robust RV hypertrophy and more preserved RV function and exercise capacity following adult hypoxia compared with nonhyperoxic rats. Biochemically, RVs from animals exposed to postnatal hyperoxia and adult hypoxia demonstrated increased capillarization and a switch to a fetal gene pattern, suggesting an RV more adept to handle adult hypoxia following postnatal hyperoxia exposure. We concluded that, despite negative impacts on pulmonary artery pressures, postnatal hyperoxia exposure may render a more adaptive RV phenotype to tolerate late pulmonary vascular insults. PMID:25659904

  17. Right ventricular noncompaction in a neonate with complex congenital heart disease.

    PubMed

    Alehan, Dursun; Dogan, Omer Faruk

    2005-08-01

    Ventricular noncompaction is a rare unclassified cardiomyopathy occurring because of arrest of the normal intrauterine compaction of the loose luminal component of the ventricular myocardium. There is limited data regarding its diagnosis and outcome in children. It is recognised, however, that right ventricular involvement is extremely rare. We report a case in which only the right ventricular myocardium was noncompacted, a situation which led to heart failure soon after birth.

  18. Evidence of ventricular contamination of the optical signal in preterm neonates with post hemorrhagic ventricle dilation

    NASA Astrophysics Data System (ADS)

    Kishimoto, J.; Diop, M.; McLachlan, P.; de Ribaupierre, S.; Lee, D. S. C.; St. Lawrence, K.

    2015-03-01

    Dilation of the cerebral ventricles is a common condition in preterm neonates with intraventricular hemorrhage (IVH). This post hemorrhagic ventricle dilation (PHVD) can lead to lifelong neurological impairment through ischemic injury due to increased intracranial pressure (ICP). Interventions, such as ventricular tapping to remove cerebrospinal fluid (CSF), are used to prevent injury, but determining the optimal time for treatment is difficult as clinical signs of increased ICP lack sensitivity. There is a growing interest in using near-infrared spectroscopy (NIRS) because of its ability to monitor cerebral oxygen saturation (StO2) at the bedside. However, the accuracy of NIRS may be affected by signal contamination from enlarged ventricles, especially if there are blood breakdown products (bbp) in CSF following IVH. To investigate this, serial NIR spectra from the head and from CSF samples were acquired over a month from seven IVH patients undergoing treatment for PHVD. Over time, the visual appearance of the CSF samples progressed from dark brown ("tea color") to clear yellow, reflecting the reduction in bbp concentration as confirmed by the stronger absorption around 760 nm at the earlier time points. All CSF samples contained strong absorption at 960 nm due to water. More importantly the same trend in these absorption features was observed in the in vivo spectra, and Monte Carlo simulations confirmed the potential for signal contamination from enlarged ventricles. These findings highlight the challenges of accurately measuring StO2 in this patient population and the necessity of using a hyperspectral NIRS system to resolve the additional chromophores.

  19. Homeostatic control of manganese excretion in the neonatal rat

    SciTech Connect

    Ballatori, N.; Miles, E.; Clarkson, T.W.

    1987-05-01

    Previous studies in neonatal and suckling animals showed that immature animals have a greatly diminished capacity to excrete manganese and therefore were considered to be unable to regulate tissue manganese concentrations. In contrast, the present studies indicate that suckling rats have the capacity to excrete excess manganese at rates nearly comparable to those of adults. Eight- to 10-day-old rats given a tracer dose of /sup 54/MnCl/sub 2/ (essentially carrier free), either via gavage or by intraperitoneal injection showed little elimination of the /sup 54/Mn until the 18-19th day of life, when there was an abrupt increase in the rate of the metal's excretion. However, when manganese was given in doses of 1 and 10 mg/kg, the young animals excreted from 30-70% of the dose in only 4 days, at which time a new rate of excretion was achieved. This enhanced rate of excretion remained constant until the 18-19th day of life, when it was again accelerated. Biliary excretion of manganese, the primary route for the elimination of the metal, was only 30-60% lower in 14-day-old rats compared with adults at doses ranging from tracer to 10 mg /sup 54/Mn/kg. For both the 14-day-old and adult rats, an apparent biliary transport maximum was reached at a dose of 10 mg Mn/kg. These studies indicate that the excretory pathways for manganese are well developed in the neonatal rat. The avid retention of tracer quantities of manganese by the neonate may be a consequence of the scarcity of this essential trace metal in its diet.

  20. Physiological pathway of magnesium influx in rat ventricular myocytes.

    PubMed

    Tashiro, Michiko; Inoue, Hana; Konishi, Masato

    2014-11-01

    Cytoplasmic free Mg(2+) concentration ([Mg(2+)]i) was measured in rat ventricular myocytes with a fluorescent indicator furaptra (mag-fura-2) introduced by AM-loading. By incubation of the cells in a high-K(+) (Ca(2+)- and Mg(2+)-free) solution, [Mg(2+)]i decreased from ? 0.9 mM to 0.2 to 0.5 mM. The lowered [Mg(2+)]i was recovered by perfusion with Ca(2+)-free Tyrode's solution containing 1 mM Mg(2+). The time course of the [Mg(2+)]i recovery was fitted by a single exponential function, and the first derivative at time 0 was analyzed as being proportional to the initial Mg(2+) influx rate. The Mg(2+) influx rate was inversely related to [Mg(2+)]i, being higher at low [Mg(2+)]i. The Mg(2+) influx rate was augmented by the high extracellular Mg(2+) concentration (5 mM), whereas it was greatly reduced by cell membrane depolarization caused by high K(+). Known inhibitors of TRPM7 channels, 2-aminoethoxydiphenyl borate (2-APB), NS8593, and spermine reduced the Mg(2+) influx rate with half inhibitory concentrations (IC50) of, respectively, 17 ?M, 2.0 ?M, and 22 ?M. We also studied Ni(2+) influx by fluorescence quenching of intracellular furaptra by Ni(2+). The Ni(2+) influx was activated by lowering intra- and extracellular Mg(2+) concentrations, and it was inhibited by 2-APB and NS8593 with IC50 values comparable with those for the Mg(2+) influx. Intracellular alkalization (caused by pulse application of NH4Cl) enhanced, whereas intracellular acidification (induced after the removal of NH4Cl) slowed the Mg(2+) influx. Under the whole-cell patch-clamp configuration, the removal of intracellular and extracellular divalent cations induced large inward and outward currents, MIC (Mg-inhibited cation) currents or IMIC, carried by monovalent cations likely via TRPM7 channels. IMIC measured at -120 mV was diminished to ? 50% by 100 ?M 2-APB or 10 ?M NS8593. These results suggest that TRPM7/MIC channels serve as a major physiological pathway of Mg(2+) influx in rat

  1. Neural regulation of acetylcholine receptors in rat neonatal muscle.

    PubMed Central

    Bambrick, L L; Gordon, T

    1992-01-01

    1. The neuronal regulation of the developmental decline in skeletal muscle acetylcholine (ACh) receptors was studied by comparing the effects of sciatic nerve section or of neuromuscular blockade with botulinum toxin (BoTX) on this decline in neonatal and adult rats, using 125I-alpha-bungarotoxin (125I-BTX) as a ligand for the receptor alpha-subunit. 2. The decline in 125I-BTX binding site concentration in neonatal rat triceps surae muscle homogenates towards low, adult levels followed a simple exponential with a time constant of 8 days. This decline occurred while the muscle is still rapidly growing, before the postnatal increase in numbers of sodium channels. It also preceded the decline in muscle ACh receptor alpha-subunit mRNA, reported in other studies, suggesting that subunit levels are not regulated only by mRNA availability. 3. Muscle denervation in the first two weeks of life prevented this developmental decline. Denervation increased the concentration of 125I-BTX binding sites but the magnitude of this increase became progressively smaller as the muscle matured, showing that removal of innervation during adult life does not revert the muscle, in toto, to its pre-innervation state. 4. Blockade of neuromuscular activity with BoTX increased 125I-BTX binding sites to a lesser extent than muscle denervation during neonatal life. This lesser effect of BoTX blockade contrasts with the equal effects of BoTX blockade and denervation in the adult. PMID:1522519

  2. A Neonate with Susceptibility to Long QT Syndrome Type 6 who Presented with Ventricular Fibrillation and Sudden Unexpected Infant Death.

    PubMed

    Sauer, Charles W; Marc-Aurele, Krishelle L

    2016-01-01

    BACKGROUND This is a case of a neonate with susceptibility to long QT syndrome (LQTS) who presented with a sudden unexpected infant death. Experts continue to debate whether universal electrocardiogram (ECG) screening of all newborns is feasible, practical, and cost-effective. CASE REPORT A 19-day-old neonate was found unresponsive by her mother. ECG showed ventricular fibrillation and a combination of a lidocaine drip plus multiple defibrillations converted the rhythm to normal sinus. Unfortunately, MRI brain imaging showed multiple infarcts and EEG showed burst suppression pattern with frequent seizures; life supportive treatment was stopped and the infant died. Genetic testing revealed two mutations in the KCNE2 gene consistent with susceptibility to LQTS type 6. CONCLUSIONS We believe this case is the first to demonstrate both a precipitating electrocardiographic and genetic cause of death for an infant with LQTS, showing a cause-and-effect relationship between LQTS mutation, ventricular arrhythmia, and death. We wonder whether universal ECG newborn screening to prevent LQTS death could have saved this baby. PMID:27465075

  3. The effect of sildenafil on right ventricular remodeling in a rat model of monocrotaline-induced right ventricular failure

    PubMed Central

    Bae, Hyun Kyung; Lee, Hyeryon; Kim, Kwan Chang

    2016-01-01

    Purpose Pulmonary arterial hypertension (PAH) leads to right ventricular failure (RVF) as well as an increase in pulmonary vascular resistance. Our purpose was to study the effect of sildenafil on right ventricular remodeling in a rat model of monocrotaline (MCT)-induced RVF. Methods The rats were distributed randomly into 3 groups. The control (C) group, the monocrotaline (M) group (MCT 60 mg/kg) and the sildenafil (S) group (MCT 60 mg/kg+ sildenafil 30 mg/kg/day for 28 days). Masson Trichrome staining was used for heart tissues. Western blot analysis and immunohistochemical staining were performed. Results The mean right ventricular pressure (RVP) was significantly lower in the S group at weeks 1, 2, and 4. The number of intra-acinar arteries and the medial wall thickness of the pulmonary arterioles significantly lessened in the S group at week 4. The collagen content also decreased in heart tissues in the S group at week 4. Protein expression levels of B-cell lymphoma-2 (Bcl-2)-associated X, caspase-3, Bcl-2, interleukin (IL)-6, matrix metalloproteinase (MMP)-2, endothelial nitric oxide synthase (eNOS), endothelin (ET)-1 and ET receptor A (ERA) in lung tissues greatly decreased in the S group at week 4 according to immunohistochemical staining. According to Western blotting, protein expression levels of troponin I, brain natriuretic peptide, caspase-3, Bcl-2, tumor necrosis factor-α, IL-6, MMP-2, eNOS, ET-1, and ERA in heart tissues greatly diminished in the S group at week 4. Conclusion Sildenafil alleviated right ventricular hypertrophy and mean RVP. These data suggest that sildenafil improves right ventricular function. PMID:27462355

  4. Effect of maternal diabetes on gliogensis in neonatal rat hippocampus

    PubMed Central

    Sadeghi, Akram; Esfandiary, Ebrahim; Hami, Javad; Khanahmad, Hossein; Hejazi, Zahra; Razavi, Shahnaz

    2016-01-01

    Background: Diabetes in pregnancy is a common metabolic disorder associated with various adverse outcomes in the offspring including impairments in attention and memory and alterations in social behavior. Glial cells are proven to have a critical role in normal function of neurons, and alteration in their activity could contribute to disturbance in the brain function. The aim of this study was to investigate the effect of maternal diabetes on hippocampal mRNA expression and distribution pattern of glial fibrillary acidic protein (GFAP) immunoreactive glial cells in the dentate gyrus (DG) of rat neonate at postnatal day 14 (P14). Materials and Methods: Wistar female rats were randomly allocated in control, diabetic, and insulin-treated diabetic groups. Diabetes was induced by injection of streptozotocin from 4 weeks before gestation until parturition. After delivery, the male offspring was euthanized at P14. Results: Our results showed a significant higher level of hippocampal GFAP expression and an increase in the mean number of GFAP positive cells in the DG of diabetic group offspring (P < 0.05). We also found an insignificant up-regulation in the expression of GFAP and the mean number of positive cells in the insulin-treated diabetic group neonates as compared to control group (P > 0.05). Conclusion: The present study revealed that diabetes during pregnancy strongly increased the glial cells production in the developing rat hippocampus. PMID:27656611

  5. Effect of maternal diabetes on gliogensis in neonatal rat hippocampus

    PubMed Central

    Sadeghi, Akram; Esfandiary, Ebrahim; Hami, Javad; Khanahmad, Hossein; Hejazi, Zahra; Razavi, Shahnaz

    2016-01-01

    Background: Diabetes in pregnancy is a common metabolic disorder associated with various adverse outcomes in the offspring including impairments in attention and memory and alterations in social behavior. Glial cells are proven to have a critical role in normal function of neurons, and alteration in their activity could contribute to disturbance in the brain function. The aim of this study was to investigate the effect of maternal diabetes on hippocampal mRNA expression and distribution pattern of glial fibrillary acidic protein (GFAP) immunoreactive glial cells in the dentate gyrus (DG) of rat neonate at postnatal day 14 (P14). Materials and Methods: Wistar female rats were randomly allocated in control, diabetic, and insulin-treated diabetic groups. Diabetes was induced by injection of streptozotocin from 4 weeks before gestation until parturition. After delivery, the male offspring was euthanized at P14. Results: Our results showed a significant higher level of hippocampal GFAP expression and an increase in the mean number of GFAP positive cells in the DG of diabetic group offspring (P < 0.05). We also found an insignificant up-regulation in the expression of GFAP and the mean number of positive cells in the insulin-treated diabetic group neonates as compared to control group (P > 0.05). Conclusion: The present study revealed that diabetes during pregnancy strongly increased the glial cells production in the developing rat hippocampus.

  6. Topography of Striate-Extrastriate Connections in Neonatally Enucleated Rats

    PubMed Central

    Laing, Robyn J.; Lasiene, Jurate; Olavarria, Jaime F.

    2013-01-01

    It is known that retinal input is necessary for the normal development of striate cortex and its corticocortical connections, but there is little information on the role that retinal input plays in the development of retinotopically organized connections between V1 and surrounding visual areas. In nearly all lateral extrastriate areas, the anatomical and physiological representation of the nasotemporal axis of the visual field mirrors the representation of this axis in V1. To determine whether the mediolateral topography of striate-extrastriate projections is preserved in neonatally enucleated rats, we analyzed the patterns of projections resulting from tracer injections placed at different sites along the mediolateral axis of V1. We found that the correlation between the distance from injection sites to the lateral border of V1 and the distance of the labeling patterns in area 18a was strong in controls and much weaker in enucleates. Data from pairs of injections in the same animal revealed that the separation of area 18a projection fields for a given separation of injection sites was more variable in enucleated than in control rats. Our analysis of single and double tracer injections suggests that neonatal bilateral enucleation weakens, but not completely abolishes, the mediolateral topography in area 18a. PMID:24199194

  7. Islands of spatially discordant APD alternans underlie arrhythmogenesis by promoting electrotonic dyssynchrony in models of fibrotic rat ventricular myocardium.

    PubMed

    Majumder, Rupamanjari; Engels, Marc C; de Vries, Antoine A F; Panfilov, Alexander V; Pijnappels, Daniël A

    2016-01-01

    Fibrosis and altered gap junctional coupling are key features of ventricular remodelling and are associated with abnormal electrical impulse generation and propagation. Such abnormalities predispose to reentrant electrical activity in the heart. In the absence of tissue heterogeneity, high-frequency impulse generation can also induce dynamic electrical instabilities leading to reentrant arrhythmias. However, because of the complexity and stochastic nature of such arrhythmias, the combined effects of tissue heterogeneity and dynamical instabilities in these arrhythmias have not been explored in detail. Here, arrhythmogenesis was studied using in vitro and in silico monolayer models of neonatal rat ventricular tissue with 30% randomly distributed cardiac myofibroblasts and systematically lowered intercellular coupling achieved in vitro through graded knockdown of connexin43 expression. Arrhythmia incidence and complexity increased with decreasing intercellular coupling efficiency. This coincided with the onset of a specialized type of spatially discordant action potential duration alternans characterized by island-like areas of opposite alternans phase, which positively correlated with the degree of connexinx43 knockdown and arrhythmia complexity. At higher myofibroblast densities, more of these islands were formed and reentrant arrhythmias were more easily induced. This is the first study exploring the combinatorial effects of myocardial fibrosis and dynamic electrical instabilities on reentrant arrhythmia initiation and complexity. PMID:27072041

  8. Islands of spatially discordant APD alternans underlie arrhythmogenesis by promoting electrotonic dyssynchrony in models of fibrotic rat ventricular myocardium

    NASA Astrophysics Data System (ADS)

    Majumder, Rupamanjari; Engels, Marc C.; de Vries, Antoine A. F.; Panfilov, Alexander V.; Pijnappels, Daniël A.

    2016-04-01

    Fibrosis and altered gap junctional coupling are key features of ventricular remodelling and are associated with abnormal electrical impulse generation and propagation. Such abnormalities predispose to reentrant electrical activity in the heart. In the absence of tissue heterogeneity, high-frequency impulse generation can also induce dynamic electrical instabilities leading to reentrant arrhythmias. However, because of the complexity and stochastic nature of such arrhythmias, the combined effects of tissue heterogeneity and dynamical instabilities in these arrhythmias have not been explored in detail. Here, arrhythmogenesis was studied using in vitro and in silico monolayer models of neonatal rat ventricular tissue with 30% randomly distributed cardiac myofibroblasts and systematically lowered intercellular coupling achieved in vitro through graded knockdown of connexin43 expression. Arrhythmia incidence and complexity increased with decreasing intercellular coupling efficiency. This coincided with the onset of a specialized type of spatially discordant action potential duration alternans characterized by island-like areas of opposite alternans phase, which positively correlated with the degree of connexinx43 knockdown and arrhythmia complexity. At higher myofibroblast densities, more of these islands were formed and reentrant arrhythmias were more easily induced. This is the first study exploring the combinatorial effects of myocardial fibrosis and dynamic electrical instabilities on reentrant arrhythmia initiation and complexity.

  9. Islands of spatially discordant APD alternans underlie arrhythmogenesis by promoting electrotonic dyssynchrony in models of fibrotic rat ventricular myocardium

    PubMed Central

    Majumder, Rupamanjari; Engels, Marc C.; de Vries, Antoine A. F.; Panfilov, Alexander V.; Pijnappels, Daniël A.

    2016-01-01

    Fibrosis and altered gap junctional coupling are key features of ventricular remodelling and are associated with abnormal electrical impulse generation and propagation. Such abnormalities predispose to reentrant electrical activity in the heart. In the absence of tissue heterogeneity, high-frequency impulse generation can also induce dynamic electrical instabilities leading to reentrant arrhythmias. However, because of the complexity and stochastic nature of such arrhythmias, the combined effects of tissue heterogeneity and dynamical instabilities in these arrhythmias have not been explored in detail. Here, arrhythmogenesis was studied using in vitro and in silico monolayer models of neonatal rat ventricular tissue with 30% randomly distributed cardiac myofibroblasts and systematically lowered intercellular coupling achieved in vitro through graded knockdown of connexin43 expression. Arrhythmia incidence and complexity increased with decreasing intercellular coupling efficiency. This coincided with the onset of a specialized type of spatially discordant action potential duration alternans characterized by island-like areas of opposite alternans phase, which positively correlated with the degree of connexinx43 knockdown and arrhythmia complexity. At higher myofibroblast densities, more of these islands were formed and reentrant arrhythmias were more easily induced. This is the first study exploring the combinatorial effects of myocardial fibrosis and dynamic electrical instabilities on reentrant arrhythmia initiation and complexity. PMID:27072041

  10. Effects of hindlimb unloading on neuromuscular development of neonatal rats

    NASA Technical Reports Server (NTRS)

    Huckstorf, B. L.; Slocum, G. R.; Bain, J. L.; Reiser, P. M.; Sedlak, F. R.; Wong-Riley, M. T.; Riley, D. A.

    2000-01-01

    We hypothesized that hindlimb suspension unloading of 8-day-old neonatal rats would disrupt the normal development of muscle fiber types and the motor innervation of the antigravity (weightbearing) soleus muscles but not extensor digitorum longus (EDL) muscles. Five rats were suspended 4.5 h and returned 1.5 h to the dam for nursing on a 24 h cycle for 9 days. To control for isolation from the dam, the remaining five littermates were removed on the same schedule but not suspended. Another litter of 10 rats housed in the same room provided a vivarium control. Fibers were typed by myofibrillar ATPase histochemistry and immunostaining for embryonic, slow, fast IIA and fast IIB isomyosins. The percentage of multiple innervation and the complexity of singly-innervated motor terminal endings were assessed in silver/cholinesterase stained sections. Unique to the soleus, unloading accelerated production of fast IIA myosin, delayed expression of slow myosin and retarded increases in standardized muscle weight and fiber size. Loss of multiple innervation was not delayed. However, fewer than normal motor nerve endings achieved complexity. Suspended rats continued unloaded hindlimb movements. These findings suggest that motor neurons resolve multiple innervation through nerve impulse activity, whereas the postsynaptic element (muscle fiber) controls endplate size, which regulates motor terminal arborization. Unexpectedly, in the EDL of unloaded rats, transition from embryonic to fast myosin expression was retarded. Suspension-related foot drop, which stretches and chronically loads EDL, may have prevented fast fiber differentiation. These results demonstrate that neuromuscular development of both weightbearing and non-weightbearing muscles in rats is dependent upon and modulated by hindlimb loading.

  11. Buyanghuanwu Tang therapy for neonatal rats with hypoxic ischemic encephalopathy

    PubMed Central

    Liu, Xiyao; Min, Yue; Gu, Weiwang; Wang, Yujue; Tian, Yuguang

    2015-01-01

    Background: Neonatal hypoxic-ischemic encephalopathy (HIE) is a clinical syndrome manifested by neurological symptoms in the first days of life in term infants. Purpose: To investigate the therapy effect of Buyanghuanwu Tang (BYHWT), a decoction with 7 herbal ingredients, on neonatal rats with hypoxic ischemic encephalopathy (HIE) and its mechanism. Methods: 50 3-week male Sprague-Dawley rats were divided into normal control group, model group, BYHWT 1d group, BYHWT 3d group and BYHWT 7d group, 10 rats in each group. The HIE model of was established in later 4 groups. The later 3 groups were treated with BYHWT for 1, 3 and 7 days, respectively, and the normal control group and model group were treated with PBS. The Morris water maze test and dynamic 18F-FDG-PET/CT imaging were performed. The changes of hippocampal tissue observed by histopathologic examination, and the expressions of JNK1/JNK2 and TNF-α protein were observed western blotting. Results: Compared with model group, the impaired performance on distance and latency parameters was mitigated in BYHWT 1d group, BYHWT 3d group and BYHWT 7d group (P < 0.01), the FDG uptake was decreased in BYHWT 3d group and BYHWT 7d group, the apoptotic cells and inflammatory cells were significantly decreased in BYHWT 3d group and BYHWT 7d group, and the expressions of JNK1/JNK2 and TNF-α protein were significantly decreased in BYHWT 7d group (P < 0.05). Conclusion: BYHWT can delay the HIE onset and preserve the motor function, primarily by regulating inflammation, apoptosis and inhibition by mediating JNK signaling. PMID:26770451

  12. A Case of Neonatal Heart Failure Caused by Left Ventricular Diverticulum: Successful ECMO Support Application.

    PubMed

    Gocen, Ugur; Atalay, Atakan; Salih, Orhan Kemal

    2016-01-01

    Congenital left ventricular diverticulum is a rare cardiac anomaly. During the newborn period, symptomatic patients are diagnosed with heart failure findings. We present a 23-day-old male newborn with congenital left ventricular diverticulum diagnosed during fetal echocardiographic examination. After the birth, the patient had heart failure symptoms and his echocardiographic examination showed low cardiac ejection fraction. Diverticulum was operated with endoventricular circular patch plasty (DOR) technique, and after, cardiopulmonary bypass venoarterial extracorporeal membrane oxygenation (ECMO) support was performed because of low cardiac output syndrome. On postoperative day 17, he was discharged with no problem. PMID:27585200

  13. The relationship between contraction and intracellular sodium in rat and guinea-pig ventricular myocytes.

    PubMed Central

    Harrison, S M; McCall, E; Boyett, M R

    1992-01-01

    1. The contraction, measured optically, and the intracellular Na+ activity (aNai), measured with the Na(+)-sensitive fluorescent dye SBFI, have been recorded simultaneously in rat and guinea-pig ventricular myocytes. 2. In rat and guinea-pig ventricular myocytes at rest, aNai was 7.8 +/- 0.3 mM (n = 4) and 5.1 +/- 0.3 mM (n = 16), respectively. 3. When both rat and guinea-pig ventricular myocytes were stimulated at 1 Hz after a rest there was usually a gradual increase in twitch shortening (referred to as a 'staircase') over several minutes accompanied by an increase in aNai over a similar time course. Twitch shortening increased by 21 +/- 3% (n = 6) and 20 +/- 4% (n = 16) (of steady-state twitch shortening during 1 Hz stimulation) per millimolar rise in aNai in rat and guinea-pig ventricular myocytes, respectively. 4. When rat and guinea-pig ventricular myocytes were exposed to strophanthidin to block the Na(+)-K+ pump, there were increases in twitch shortening and aNai over similar time courses. Twitch shortening increased by 24 +/- 4% (n = 5) and 20 +/- 3% (n = 10) (of control twitch shortening) per millimolar rise in aNai in rat and guinea-pig ventricular myocytes respectively. 5. The inotropic effect of cardiac glycosides, such as strophanthidin, is widely regarded to be principally the result of the rise in aNai. The similarity of the relation between twitch shortening and aNai during the staircase and on application of strophanthidin suggests that the progressive increase in the strength of contraction during the staircase was also linked to the rise in aNai. 6. In guinea-pig, but not rat, ventricular myocytes there was hysteresis in the relation between twitch shortening and aNai on application and wash-off of strophanthidin. This indicates that strophanthidin has another inotropic action in guinea-pig ventricular myocytes. 7. A computer model of excitation-contraction coupling has been developed to simulate the staircase and the action of cardiac glycoside

  14. Human milk oligosaccharides are differentially metabolised in neonatal rats.

    PubMed

    Jantscher-Krenn, Evelyn; Marx, Carolin; Bode, Lars

    2013-08-01

    Human milk oligosaccharides (HMO) are complex glycans that are highly abundant in human milk, but not in infant formula. Accumulating data, mostly from in vitro and animal studies, indicate that HMO benefit the breast-fed infant in multiple ways and in different target organs. In vitro incubation studies suggest that HMO can resist the low pH in the infant's stomach and enzymatic degradation in the small intestine and reach the colon in the same composition as in the mother's milk. The oligosaccharide composition in faeces of breast-fed infants is, however, very different from that in the mother's milk, raising questions on when, where and how HMO are metabolised between ingestion and excretion. To answer some of these questions, we established a pulse-chase model in neonatal rats and analysed HMO profiles to track their composition over time in five consecutive equal-length intestinal segments as well as in serum and urine. The relative abundance of individual HMO changed significantly within the first 2 h after feeding and already in the segments of the small intestine prior to reaching the colon. Only 3'-sialyllactose, the major oligosaccharide in rat milk, and hardly any other HMO appeared in the serum and the urine of HMO-fed rats, indicating a selective absorption of rat milk-specific oligosaccharides. The present results challenge the paradigm that HMO reach the colon and other target organs in the same composition as originally secreted with the mother's milk. The present results also raise questions on whether rats and other animals represent suitable models to study the effects of HMO.

  15. Neonatal injections of methoxychlor decrease adult rat female reproductive behavior.

    PubMed

    Bertolasio, Jennifer; Fyfe, Susanne; Snyder, Ben W; Davis, Aline M

    2011-12-01

    Methoxychlor (MXC), a commonly used pesticide, has been labeled as an endocrine disruptor. To evaluate the impact of neonatal exposure to MXC on female reproduction, female Sprague-Dawley rats were given subcutaneous injections on postnatal days 1, 3, and 5. The injections contained 1.0mg MXC, 2.0mg MXC, 10 μg 17β-estradiol benzoate (positive control), or sesame oil (vehicle). The injections of MXC had no effect on anogenital distance or day of vaginal opening. Treatment with either 2.0mg MXC or estradiol significantly increased the total number of days with vaginal keratinization. Treatment with MXC had no effect on ability to exhibit a mating response as an adult female, although the high dose MXC (2.0) and the positive control (estradiol) animals demonstrated a decrease in degree of receptivity, a decrease in proceptive behavior and an increase in rejection behavior. These data suggest that higher doses of MXC given directly to pups during the neonatal period can act as an estrogen and alter aspects of the nervous system, impacting adult reproductive characteristics.

  16. Outcome of prolonged ventricular fibrillation and CPR in a rat model of chronic ischemic left ventricular dysfunction.

    PubMed

    Fang, Xiangshao; Huang, Lei; Sun, Shijie; Weil, Max Harry; Tang, Wanchun

    2013-01-01

    Patients with chronic left ventricular (LV) dysfunction are assumed to have a lower chance of successful CPR and lower likelihood of ultimate survival. However, these assumptions have rarely been documented. Therefore, we investigated the outcome of prolonged ventricular fibrillation (VF) and CPR in a rat model of chronic LV dysfunction. Sprague-Dawley rats were randomized to (1) chronic LV dysfunction: animals underwent left coronary artery ligation; and (2) sham control. Echocardiography was used to measure cardiac performance before surgery and 4 weeks after surgery. Four weeks after surgical intervention, 8 min of VF was induced and defibrillation was delivered after 8 min of CPR. LV dilation and low ejection fraction were observed 4 weeks after coronary ligation. With optimal chest compressions, coronary perfusion pressure values during CPR were well maintained and indistinguishable between groups. There were no differences in resuscitability and numbers of shock required for successful resuscitation between groups. Despite the significantly decreased cardiac index in LV dysfunction animals before induction of VF, no differences in cardiac index were observed between groups following resuscitation, which was associated with the insignificant difference in postresuscitation survival. In conclusion, the outcomes of CPR were not compromised by the preexisting chronic LV dysfunction. PMID:24455704

  17. Development of chemosensitivity in neurons from the nucleus tractus solitarii (NTS) of neonatal rats.

    PubMed

    Conrad, Susan C; Nichols, Nicole L; Ritucci, Nick A; Dean, Jay B; Putnam, Robert W

    2009-03-31

    We studied the development of chemosensitivity during the neonatal period in rat nucleus tractus solitarii (NTS) neurons. We determined the percentage of neurons activated by hypercapnia (15% CO(2)) and assessed the magnitude of the response by calculating the chemosensitivity index (CI). There were no differences in the percentage of neurons that were inhibited (9%) or activated (44.8%) by hypercapnia or in the magnitude of the activated response (CI 164+/-4.9%) in NTS neurons from neonatal rats of all ages. To assess the degree of intrinsic chemosensitivity in these neurons we used chemical synaptic block medium and the gap junction blocker carbenoxolone. Chemical synaptic block medium slightly decreased basal firing rate but did not affect the percentage of NTS neurons that responded to hypercapnia at any neonatal age. However, in neonates aged neonates, chemical synaptic block medium increased CI. Carbenoxolone did not significantly alter the number of NTS neurons activated by hypercapnia in neonatal rats of any age. In summary, the response of NTS neurons from neonatal rats appears to be intrinsic and largely unchanged throughout early development. In young neonates (

  18. GESTATIONAL MERCURY VAPOR EXPOSURE AND DIET CONTRIBUTE TO MERCURY ACCUMULATION IN NEONATAL RATS.

    EPA Science Inventory

    Exposure of pregnant Long-Evans rats to elemental mercury (Hg0) vapor resulted in a significant

    accumulation of Hg in tissues of neonates. Because elevated Hg in neonatal tissues may adversely

    affect growth and development, we were interested in how rapidly Hg was...

  19. Vitamin D supply to the rat fetus and neonate.

    PubMed Central

    Clements, M R; Fraser, D R

    1988-01-01

    The prevention of neonatal rickets by oral supplementation with vitamin D2 (ergocalciferol) has tended to obscure our ignorance of the natural mechanism by which young mammals receive an adequate supply of vitamin D. To investigate the possibility of specific intrauterine transfer and storage of vitamin D in fetal tissues, vitamin D-deficient female rats were given depot injections of 3H- or 14C-labeled vitamin D3 (cholecalciferol) before mating and the 3H-labeled animals were killed at stages during the last third of gestation. Analysis of lipid extracts from whole fetuses revealed a linear increase in the concentration of 25-hydroxyvitamin D3, 24,25-dihydroxyvitamin D3, and D3 itself between days 14 and 19 of gestation. During this period the elimination half-time of 3H-labeled molecules in maternal plasma fell from 27.1 to 4.4 d, suggesting that a specific mechanism was transferring vitamin D molecules into the fetuses. The vitamin was stored predominantly as 25-hydroxyvitamin D3 and 24,25-dihydroxyvitamin D3, with the highest concentrations in fetal muscle. Immediately after birth, pups from 3H- and 14C-labeled mothers were exchanged and later killed after 1-3 wk of suckling. Analysis of total lipid extracts for 3H and 14C content determined the relative contributions of vitamin D supplied before birth via the placenta and after birth in the maternal milk. The vitamin D content of the rat milk was relatively high, between 1.0 and 3.5 micrograms/liter. Nevertheless, the supply of vitamin D in utero, rather than from milk, was the main determinant of vitamin D status in early neonatal life. This is the first indication in a mammal of a specific transfer mechanism that allows the fetus to accumulate vitamin D from the mother during the last third of gestation. PMID:2838521

  20. Hybrid stage I palliation in a 1.1 kg, 28-week preterm neonate with posterior malalignment ventricular septal defect, left ventricular outflow tract obstruction, and coarctation of the aorta.

    PubMed

    Karani, Kunal B; Zafar, Farhan; Morales, David L S; Goldstein, Bryan H

    2014-10-01

    The hybrid stage I procedure has emerged as a less-invasive alternative to the standard surgical Norwood procedure in the palliation of high-risk hypoplastic left heart syndrome and variants. This approach may also benefit patients requiring complex neonatal repair who have significant anatomic and/or perioperative risk factors that either prevent or complicate durable and robust biventricular circulation from being safely achieved. An extremely low-birth weight (1.1 kg) 28-week gestation preterm neonate with postnatal diagnosis of posterior malalignment ventricular septal defect, severe left ventricular outflow tract obstruction, aortic annular hypoplasia, and aortic arch obstruction underwent initial palliation with a hybrid stage I procedure. In this case, hybrid stage I palliation allowed for both somatic and left heart growth followed by ultimate uncomplicated biventricular repair.

  1. Ligand activation of cannabinoid receptors attenuates hypertrophy of neonatal rat cardiomyocytes.

    PubMed

    Lu, Yan; Akinwumi, Bolanle C; Shao, Zongjun; Anderson, Hope D

    2014-11-01

    : Endocannabinoids are bioactive amides, esters, and ethers of long-chain polyunsaturated fatty acids. Evidence suggests that activation of the endocannabinoid pathway offers cardioprotection against myocardial ischemia, arrhythmias, and endothelial dysfunction of coronary arteries. As cardiac hypertrophy is a convergence point of risk factors for heart failure, we determined a role for endocannabinoids in attenuating endothelin-1-induced hypertrophy and probed the signaling pathways involved. The cannabinoid receptor ligand anandamide and its metabolically stable analog, R-methanandamide, suppressed hypertrophic indicators including cardiomyocyte enlargement and fetal gene activation (ie, the brain natriuretic peptide gene) elicited by endothelin-1 in isolated neonatal rat ventricular myocytes. The ability of R-methanandamide to suppress myocyte enlargement and fetal gene activation was mediated by CB2 and CB1 receptors, respectively. Accordingly, a CB2-selective agonist, JWH-133, prevented only myocyte enlargement but not brain natriuretic peptide gene activation. A CB1/CB2 dual agonist with limited brain penetration, CB-13, inhibited both hypertrophic indicators. CB-13 activated AMP-activated protein kinase (AMPK) and, in an AMPK-dependent manner, endothelial nitric oxide synthase (eNOS). Disruption of AMPK signaling, using compound C or short hairpinRNA knockdown, and eNOS inhibition using L-NIO abolished the antihypertrophic actions of CB-13. In conclusion, CB-13 inhibits cardiomyocyte hypertrophy through AMPK-eNOS signaling and may represent a novel therapeutic approach to cardioprotection. PMID:24979612

  2. Cardio-protecteffect of qiliqiangxin capsule on left ventricular remodeling, dysfunction and apoptosis in heart failure rats after chronic myocardial infarction

    PubMed Central

    Liang, Tuo; Zhang, Yuhui; Yin, Shijie; Gan, Tianyi; An, Tao; Zhang, Rongcheng; Wang, Yunhong; Huang, Yan; Zhou, Qiong; Zhang, Jian

    2016-01-01

    Background: Qiliqiangxin (QL) capsule is a traditional Chinese medicine which has been approved for the treatment of chronic heart failure. Evidences proved that QL capsules further reduced the NT-proBNP levels and improved left ventricular ejection fraction in CHF patients but the evidence supporting its underlying mechanism is still unclear. Methods and Results: Myocardial infarction (MI) -Heart failure (HF) Sprague-Dawley ratsmodel and neonatal rat cardiac myocytes (NRCMs) were used. Animals were assigned into 4 groups, normal group (n=6), shame-operation group (n=6), MI rats 4 weeks after left anterior descending coronary artery ligation were randomized into vehicle group (n=8), QL group (n=8). QL significantly attenuated cardiac dysfunction and ventricle remodeling as echocardiography and hemodynamic measurements showed improvement in left ventricular ejection fraction, fractional shortening, ±dp/dt and left ventricular end diastolic and systolic diameters in QL treated group compared with the vehicle group. Improvements ininterstitial fibrosisand mitochondrial structures were also exhibited by Sirius Red staining, RT-PCR and electron microscopy. QL treatment improved apoptosis and VEGF expression in rats marginal infract area. Complementary experiments analyzed the improved apoptosis and up-regulate of VEGF in ischemia-hypoxia cultivated NRCMs is in an Akt dependent manner and can be reversed by Akt inhibitor. Conclusion: QL capsule can improve cardiac dysfunction and ventricular remodeling in MI-HF ratsmodel, this cardiac protective efficacy may be concerned with attenuated apoptosis and cardiac fibrosis. Up-regulated VEGF expression and Akt phosphorylation may take part in this availability. PMID:27347313

  3. Cardioprotective effect of polydatin on ventricular remodeling after myocardial infarction in coronary artery ligation rats.

    PubMed

    Gao, Yan; Gao, Jianping; Chen, Changxun; Wang, Huilin; Guo, Juan; Wu, Rong

    2015-05-01

    The purpose of this study was to explore the effect of polydatin on ventricular remodeling after myocardial infarction in coronary artery ligation rats and to elucidate the underlying mechanisms. A rat model of ventricular remodeling after myocardial infarction was established by left coronary artery ligation. Rats with coronary artery ligation were randomly divided into five groups: control, plus 40 mg/kg captopril, plus 25 mg/kg polydatin, plus 50 mg/kg polydatin, and plus 100 mg/kg polydatin. The sham-operated group was used as a negative control. Rats were administered intragastrically with the corresponding drugs or drinking water for seven weeks. At the end of the treatment, the left ventricular weight index and heart weight index were assessed. The cross-sectional size of cardiomyocytes was measured by staining myocardium tissue with hematoxylin and eosin. Collagen content was counted by Sirius red in aqueous saturated picric acid. The concentrations of angiotensin I, angiotensin II, aldosterone, and endothelin 1 in myocardium or serum were determined by radioimmunoassay. Hydroxyproline and nitric oxide concentrations and glutathione peroxidase and catalase activities in serum were measured by ultraviolet spectrophotometry. Our results showed that seven weeks of polydatin treatment resulted in a significantly reduced left ventricular weight index, heart weight index, serum concentrations of hydroxyproline and aldosterone, an increased concentration of nitric oxide as well as enhanced activities of glutathione peroxidase and catalase. Myocardial angiotensin I, angiotensin II, and endothelin 1 levels were also reduced. The cardiomyocyte cross-sectional area and collagen deposition diminished. This study suggests that polydatin may attenuate ventricular remodeling after myocardial infarction in coronary artery ligation rats through restricting the excessive activation of the renin-angiotensin-aldosterone system and inhibiting peroxidation.

  4. Persistent Pulmonary Hypertension in a Neonate With Transposition of Great Arteries and Intact Ventricular Septum: A Case Report and Review of the Literature.

    PubMed

    Karimi, Mohsen; Kirshbom, Paul M; Kopf, Gary S; Steele, Margaret M; Sullivan, Jill M

    2015-07-01

    Transposition of the great arteries (TGA) with intact ventricular septum (IVS) has very favorable short- and long-term surgical outcome. Although rare, when associated with persistent pulmonary hypertension (PPH), it exhibits significant mortality risk and management challenges. We report the case of a neonate with TGA with IVS and PPH who underwent successful early surgical repair with emphasis on clinical management and review of the literature.

  5. Hydrogen sulfide improves left ventricular function in smoking rats via regulation of apoptosis and autophagy.

    PubMed

    Zhou, Xiang; An, Guoyin; Chen, Jianchang

    2014-06-01

    The present study was designed to investigate the protective effects of hydrogen sulfide (H2S) against cigarette smoking-induced left ventricular dysfunction in rats. Left ventricular structure and function were assessed using two-dimensional echocardiography. Cardiomyocyte apoptosis was determined by Annexin V/PI and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining. Cardiac autophagy was evaluated by detection of autophagy-related protein expression and observation of autophagosomes. Our results indicated that administration of NaHS (a donor of H2S) could protect against smoking-induced left ventricular systolic dysfunction. H2S was found to exert anti-apoptotic effects in the myocardium of smoking rats by inhibiting JNK and P38 mitogen-activated protein kinases pathways and activating PI3K/Akt signaling. Moreover, H2S could also reduce smoking-induced autophagic cell death via regulation of AMPK/mTOR signaling pathway. In conclusion, our study demonstrates that H2S can improve left ventricular systolic function in smoking rats via regulation of apoptosis and autophagy.

  6. [Rat cardiomyocyte remodeling after neonatal cryptosporidiosis. II. Elongation, excessive polyploidization and HIF-1alpha overexpression].

    PubMed

    Anatskaia, O V; Sidorenko, N V; Matveev, I V; Kropotov, A V; Vinogradov, A E

    2012-01-01

    Retrospective epidemyological studies evidence that infant diseases leave survivors with an increased susceptibility to cardiovascular diseases in later life. At the same time, the mechanisms of this link remain poorly understood. Based on medical statistics reporting that infectious gastroenteritis is the most common cause of maladies in babies, infants and children, we analysed the effects of moderate cryptosporidial gastroenteritis on the heart and ventricular cardiomyocyte remodelling in rats of the first month of life. The disease was challenged by a worldwide human protozoic pathogen Cryptosporidium parvum (Apicomplexa, Sporozoa). The main symptoms manifested in the growth retardation moderate diarrhea. Using real-time PCR, cytophotometry, confocal microscopy and image analysis, we indicated that cryptosporidiosis was associated, with the atrophy heart and the elongation, narrowing, protein content decrease and hyperpolyploidization of cardiomyocytes and the moderate overexpression of hypoxia inducible factor 1alpha (HIF-1alpha) mRNA. Cardiomyocyte shape remodeling and heart atrophy presented in all age groups. The severity of these changes, hovewer, declined gradually from younger to older groups. In contrast, hyperpolyploidization and HIF-1alpha mRNA overexpression were registered mainly among animals aged between 6 and 13 days, and were barely detected and non-significant in older age groups. In the rat the time period covering 6-13 days after birth is known to coincide with the intensive cardiomyocyte polyploidization and the switch from proliferation to hypertrophy. Thus, our data indicate that neonatal cryptosporidiosis may be potential cardiovascular diseases risk factor and that one of the critical time windows for the growing heart covers the time period when cardiomyocyte undergo polyploidization. PMID:23074852

  7. [The influence of interfered circadian rhythm on pregnancy and neonatal rats].

    PubMed

    Chen, Wen-Jun; Sheng, Wen-Jie; Guo, Yin-Hua; Tan, Yong

    2015-10-25

    The aim of this study was to observe the influence of interfered circadian rhythm on pregnancy of rats and growth of neonatal rats, and to explore the relationship between the interfered circadian rhythm and the changes of melatonin and progesterone. Continuous light was used to inhibit melatonin secretion and therefore the interfered circadian rhythm animal model was obtained. The influence of interfered circadian rhythm on delivery of pregnant rats was observed. Serum was collected from rats during different stages of pregnancy to measure the concentrations of melatonin and progesterone. In order to observe the embryo resorption rate, half of pregnant rats were randomly selected to undergo a laparotomy, and the remainder was used to observe delivery and assess the growth of neonatal rats after delivery. The results showed that the interfered circadian rhythm induced adverse effects on pregnancy outcomes, including an increase of embryo resorption rate and a decrease in the number of live births; inhibited the secretion of melatonin along with decreased serum progesterone level; prolonged the stage of labor, but not the duration of pregnancy; and disturbed the fetal intrauterine growth and the growth of neonatal rats. The results suggest that interfered circadian rhythm condition made by continuous light could make adverse effects on both pregnant rats and neonatal rats. The results of our study may provide a way to modulate pregnant women's circadian rhythm and a possibility of application of melatonin on pregnant women.

  8. Neonatal sex hormones have 'organizational' effects on the hypothalamic-pituitary-adrenal axis of male rats.

    PubMed

    McCormick, C M; Furey, B F; Child, M; Sawyer, M J; Donohue, S M

    1998-02-10

    Sex hormones have activational effects on the hypothalamic-pituitary-adrenal (HPA) axis in adulthood: For example, corticosterone release is influenced by gonadal status. These experiments investigated whether sex hormones have organizational effects on the HPA axis of male rats: Do sex hormones have relatively permanent effects on its development? In adults, both neonatal (neoGDX) and adult gonadectomy (adult GDX) resulted in elevated corticosterone (CORT) levels in response to stress compared to intact rats. Five days of testosterone propionate (TP) replacement was not as effective at attenuating CORT levels in neoGDX rats as in adult GDX rats. Neonatal GDX elevated corticosterone binding globulin (CBG) levels, whereas adult GDX was without effect. In Experiment 2 the effects of neonatal gonadectomy and neonatal treatment with either TP, estradiol benzoate (EB), or oil vehicle was examined. Despite 14 days of hormone replacement, neoGDX showed elevated CORT levels in response to stress compared to all other groups. A single neonatal dose of TP or EB in neoGDX rats eliminated the increased responsiveness. Neonatal TP and EB were without effect in sham-operated rats. Plasma CBG levels were elevated in neoGDX groups regardless of neonatal hormone treatment. Corticosteroid receptor binding levels were examined in various brain areas and the pituitary in two groups most different in their androgen experience: NeoGDX and shams that did not receive treatments as adults. NeoGDX had lower levels of glucocorticoid receptor, and higher levels of mineralocorticoid receptor binding in the pituitary. No other receptor differences were found. These experiments suggest that neonatal sex hormones influence the sensitivity of the HPA axis to sex hormones in adulthood and, thus, that they have organizational effects in addition to activational effects on HPA function.

  9. Structural characterization of rat ventricular tissue exposed to the smoke of two types of waterpipe

    PubMed Central

    Al-Awaida, Wajdy; Najjar, Hossam; Shraideh, Ziad

    2015-01-01

    Objective(s): this study focused on the effect of waterpipe smoke exposure toxicity on the structure of albino rat’s ventricular tissue and their recovery. Materials and Methods: Albino rats were divided into three groups: control, flavored, and unflavored. The control group was exposed to normal air while the flavored and unflavored groups were exposed to waterpipe smoke for a period of 90 days. Each group was followed by a period of 90 days of fresh air exposure. Following each period, the ventricular tissue was removed for biochemical and histopathological studies. Results: The ventricular tissues of waterpipe exposed rats showed some degree of separation between cardiac muscle fibers, infiltration of lymphocytes, and congestion of blood vessel. Also, thin cross sections of ventricular cells revealed pleomorphic mitochondria with partially disrupted cristae, partial disruption of the myofibrils, and deposited toxic materials. The unflavored waterpipe has more deleterious effects on heart ventricular tissues than the flavored one. Waterpipe smoke didn’t induce apoptosis in the ventricular tissue. We also found very high levels of plasma thiocyanate after exposure to smoke in the flavored and unflavored groups, while the control group showed no increase. After the recovery period, those tissues showed partial recovery. Conclusion: Waterpipe smoke induces structural changes in the heart ventricle tissues, causing a negative impact on the capacity of the cardiac muscle for pumping blood and may lead to heart attack due to accumulation of free radicals and tissue inflammation. Cessation of smoking is important in returning most of these changes to their normal structure. PMID:26730327

  10. Contribution of baroreceptors and chemoreceptors to ventricular hypertrophy produced by sino-aortic denervation in rats.

    PubMed

    Van Vliet, B N; Chafe, L L; Montani, J P

    1999-05-01

    1. To test whether sino-aortic denervation (SAD)-induced right ventricular hypertrophy (RVH) is a consequence of baroreceptor or chemoreceptor denervation, we compared the effects of aortic denervation (AD), carotid denervation (CD), SAD and a SAD procedure modified to spare the carotid chemoreceptors (mSAD), 6 weeks after denervation surgery in rats. A sham surgery group served as the control. 2. The blood pressure (BP) level was unaffected by AD, CD or SAD, but increased (9 %) following mSAD. The mean heart rate level was not affected. Short-term BP variability was elevated following AD (81 %), SAD (144 %) and mSAD (146 %), but not after CD. Baroreflex heart rate responses to phenylephrine were attenuated in all denervation groups. 3. Significant RVH occurred only following CD and SAD. These procedures also produced high mortality (CD and SAD) and significant increases in right ventricular pressures and haematocrit (CD). 4. Significant left ventricular hypertrophy occurred following CD, SAD and mSAD. Normalized left ventricular weight was significantly correlated with indices of BP variability. 5. These results suggest that SAD-induced RVH is a consequence of chemoreceptor, not baroreceptor, denervation. Our results also demonstrate that a mSAD procedure designed to spare the carotid chemoreceptors produced profound baroreflex dysfunction and significant left, but not right, ventricular hypertrophy.

  11. Behavioral deficits in adult rats treated neonatally with glutamate.

    PubMed

    Hlinák, Zdenek; Gandalovicová, Dana; Krejcí, Ivan

    2005-01-01

    The present study evaluated long-term behavioral consequences of neonatal monosodium-l-glutamate (MSG) treatment in rats. The pups received MSG (3 mg/g sc) daily from postnatal day (PD) 5-12. Data from an automatic activity monitor showed that locomotion of MSG-treated females and males aged 56 and 84 days was significantly reduced. Beginning PD 120, three behavioral tests were performed. As compared to the controls, in the elevated plus maze test, modified to evaluate the adaptive form of spatial memory, MSG-treated animals of both sex had significantly prolonged start and transfer latencies. In the social recognition test, assessing olfactory working memory, MSG-treated males displayed a reduced interest in the juvenile conspecific as the stimulus partner during both the initial exposure and re-exposure performed 30 min later. In the open field test, a significant decrease in the habituation rate was found in MSG-treated animals. Sex-dependent differences in behavioral performance were suggested in the open field and elevated plus maze tests. Behavioral changes are discussed in light of the deficits in perception and processing of visual and olfactory stimuli.

  12. Pancreatic exocrine enzymes during the neonatal period in postmature rats.

    PubMed

    Merchant, Z; Jiang, L X; Lebenthal, E; Lee, P C

    1987-01-01

    Pancreatic content of exocrine enzymes in newborn rat pups shows a sharp decline soon after birth. To investigate if this decline is a preprogrammed and, therefore, inherently controlled phenomenon, or a result of external stimulus, prolonged gestation, or postmaturity (2 extra days in utero) in pregnant dams was induced by daily subcutaneous injection of progesterone from the 20th to 22nd days of gestation. Postmature pups showed the same high levels of lipase, trypsin(ogen), and amylase as control pups at birth. They also exhibited the same decline in these enzymes as control pups by the 2nd day after birth, suggesting that it is a response to external stimulus. Pups prevented from suckling retained the high levels of lipase, amylase, and trypsin(ogen) by the 2nd day. The stimulus, therefore, appeared to be the initiation of suckling. Pups prevented from suckling but given 5% glucose water orally every 4 h starting from birth for 24 h showed a sharp decline in amylase with only slight decreases in lipase and trypsin(ogen) by the 2nd day. The components in the feed, therefore, also seem to be an important determinant for selective enzyme release from the pancreas of the neonates. Electron microscopic studies revealed a sharp decrease in the number of zymogen granules in the continuously-suckled pups as compared to age-matched non-suckled counterparts. The reduction in enzyme content thus is the result of secretion in response to suckling.

  13. Vitamin A Kinetics in Neonatal Rats vs. Adult Rats: Comparisons from Model-Based Compartmental Analysis12

    PubMed Central

    Tan, Libo; Green, Michael H; Ross, A Catharine

    2015-01-01

    A critical role for vitamin A (VA) in development is well established, but still relatively little is known about whole-body VA metabolism in early postnatal life. Recently, methods of mathematical modeling have begun to shed light on retinol kinetics in the postnatal growth period and on the effect of retinoid supplementation on retinol kinetics. Comparison of kinetic parameters from tracer studies in neonatal rats with those previously determined in models of VA metabolism in the adult suggests both similarities and differences in the relative transfer rates of plasma retinol to extrahepatic tissues, resulting in similarities and differences in kinetic parameters and inferences about physiologic processes. Similarities between neonatal and adult models include the capacity for efficient digestion and absorption of VA; characteristics of a high-response system; extensive retinol recycling among liver, plasma, and extrahepatic tissues; and comparable VA disposal rates. Differences between neonatal and adult models include that, in neonates, retinol turnover is faster and retinol recycling is much more extensive; there is a greater role for extrahepatic tissues in the uptake of chylomicron VA; and the intestine plays an important role in chylomicron VA uptake, especially in neonatal rats treated with a supplement containing VA. In summary, retinol kinetic modeling in the neonatal rat has provided a first view of whole-body VA metabolism in this age group and suggests that VA kinetics in neonatal rats differs in many ways from that in adults, perhaps reflecting an adaption to the lower VA concentration found in neonates compared with adults. PMID:25540407

  14. Anoxic disturbance of the isolated respiratory network of neonatal rats.

    PubMed

    Völker, A; Ballanyi, K; Richter, D W

    1995-01-01

    Tissue oxygen (PO2), K+ (aKe), pH (pHe) and Ca2+ ([Ca2+]e) were measured in the region of the ventral respiratory group (VRG) in the in vitro brainstem-spinal cord preparation of neonatal rats. During tissue anoxia, elicited by superfusion of N2-gassed solutions, an initial increase in the frequency of respiratory activity, lasting between 2 and 12 min, turned into a frequency depression. During anoxia periods of up to 60 min, respiratory activity persisted in solutions containing CO2/bicarbonate, whereas a complete blockade was observed after 15-25 min in N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid- (Hepes)-buffered salines. After such anoxic apnea, respiratory rhythmicity could be reactivated by superfusion of hypoxic, CO2/bicarbonate-buffered solutions. In both types of hypoxic solutions, aKe increased by maximally 1.5 mM, whereas an initial increase of pHe by up to 0.05 pH units turned, after 2-4 min, into an acidification which could exceed 0.5 pH units. In contrast, [Ca2+]e remained unaffected by anoxia. Addition of 2-5 mM cyanide (CN-) to oxygenated Hepes-buffered saline evoked an increase in PO2 in the VRG from 100 to more than 300 mmHg. The effects of CN- on respiratory activity, aKe and pHe were almost identical to those during anoxia. In oxygenated, CO2/bicarbonate-free solutions of different pH, however, an increase in pHe in the VRG led to a decrease in respiratory frequency, whereas a fall of pHe produced a frequency acceleration. A rise of aKe in the VRG by more than 2 mM as induced by superfusion of a 7 mM K+ solution led to a sustained increase of respiratory frequency. The results indicate that blockade of aerobic metabolism does not severely perturb K+ and Ca2+ homeostasis and that the biphasic response to anoxia is not directly related to the observed changes in PO2, aKe, pHe, or [Ca2+]e. In the respiratory network of neonatal mammals, CO2 might provide a stimulus for long-term maintenance of respiratory activity under oxygen depletion.

  15. Hypertrophy induced KIF5B controls mitochondrial localization and function in neonatal rat cardiomyocytes.

    PubMed

    Tigchelaar, Wardit; de Jong, Anne Margreet; Bloks, Vincent W; van Gilst, Wiek H; de Boer, Rudolf A; Silljé, Herman H W

    2016-08-01

    Cardiac hypertrophy is associated with growth and functional changes of cardiomyocytes, including mitochondrial alterations, but the latter are still poorly understood. Here we investigated mitochondrial function and dynamic localization in neonatal rat ventricular cardiomyocytes (NRVCs) stimulated with insulin like growth factor 1 (IGF1) or phenylephrine (PE), mimicking physiological and pathological hypertrophic responses, respectively. A decreased activity of the mitochondrial electron transport chain (ETC) (state 3) was observed in permeabilized NRVCs stimulated with PE, whereas this was improved in IGF1 stimulated NRVCs. In contrast, in intact NRVCs, mitochondrial oxygen consumption rate (OCR) was increased in PE stimulated NRVCs, but remained constant in IGF1 stimulated NRVCs. After stimulation with PE, mitochondria were localized to the periphery of the cell. To study the differences in more detail, we performed gene array studies. IGF1 and PE stimulated NRVCs did not reveal major differences in gene expression of mitochondrial encoding proteins, but we identified a gene encoding a motor protein implicated in mitochondrial localization, kinesin family member 5b (Kif5b), which was clearly elevated in PE stimulated NRVCs but not in IGF1 stimulated NRVCs. We confirmed that Kif5b gene and protein expression were elevated in animal models with pathological cardiac hypertrophy. Silencing of Kif5b reverted the peripheral mitochondrial localization in PE stimulated NRVCs and diminished PE induced increases in mitochondrial OCR, indicating that KIF5B dependent localization affects cellular responses to PE stimulated NRVCs. These results indicate that KIF5B contributes to mitochondrial localization and function in cardiomyocytes and may play a role in pathological hypertrophic responses in vivo. PMID:27094714

  16. The effect of hexane on the ventricular fibrillation threshold of the isolated perfused rat heart.

    PubMed

    Khedun, S M; Maharaj, B; Leary, W P; Lockett, C J

    1992-01-01

    This investigation was conducted to determine the influence of hexane on the ventricular fibrillation threshold of the isolated perfused rat heart and myocardial electrolyte levels. Ventricular fibrillation threshold was measured using the Langendorff perfusion apparatus. Heart rate was measured by a universal digital counter and the cardiac flow by collecting the outflow of the heating chamber below the heart into a graduated measuring cylinder. Magnesium and zinc were measured by atomic absorption spectrophotometry and potassium by flame photometry. Two groups of rats were studied; those in the experimental group were given 0.2 ml of hexane and the control group 0.2 ml olive oil subcutaneously for 90 days. Their hearts were removed under anaesthesia. Half of the experimental and control hearts were mounted on the Langendorff perfusion apparatus and the heart rate, coronary flow and ventricular fibrillation threshold were measured. The hearts of the other half were used to measure myocardial electrolyte levels. In the experimental group the ventricular fibrillation threshold decreased (4.72 (S.D. +/- 1.87) vs 9.48 (S.D. +/- 2.98); P less than 0.001). There was no change in the coronary flow and heart rate in between the groups. The mean myocardial potassium levels (2586 (S.D. +/- 162) vs 2968 (S.D. +/- 218) micrograms/g; P less than 0.001), magnesium levels (164 (S.D. +/- 28) vs 208 (S.D. +/- 18) micrograms/g; P less than 0.001) and zinc levels (19.6 (S.D. +/- 4) vs 33.8 (S.D. +/- 6.8) micrograms/g; P less than 0.001) were significantly lower in the hexane-treated group compared to controls. Hexane, a constituent of glue and benzine, is cardiotoxic; marked derangement in myocardial electrolytes and a reduced ventricular fibrillation threshold, indicating an increased myocardial vulnerability to arrhythmias, was noted in the experimental animals. PMID:1729763

  17. Neonatal rat heart cells cultured in simulated microgravity

    NASA Technical Reports Server (NTRS)

    Akins, Robert E.; Schroedl, Nancy A.; Gonda, Steve R.; Hartzell, Charles R.

    1994-01-01

    In vitro characteristics of cardiac cells cultured in simulated microgravity are reported. Tissue culture methods performed at unit gravity constrain cells to propagate, differentiate, and interact in a two dimensional (2D) plane. Neonatal rat cardiac cells in 2D culture organize predominantly as bundles of cardiomyocytes with the intervening areas filled by non-myocyte cell types. Such cardiac cell cultures respond predictably to the addition of exogenous compounds, and in many ways they represent an excellent in vitro model system. The gravity-induced 2D organization of the cells, however, does not accurately reflect the distribution of cells in the intact tissue. We have begun characterizations of a three-dimensional (3D) culturing system designed to mimic microgravity. The NASA designed High-Aspect-Ratio-Vessel (HARV) bioreactors provide a low shear environment which allows cells to be cultured in static suspension. HARV-3D cultures were prepared on microcarrier beads and compared to control-2D cultures using a combination of microscopic and biochemical techniques. Both systems were uniformly inoculated and medium exchanged at standard intervals. Cells in control cultures adhered to the polystyrene surface of the tissue culture dishes and exhibited typical 2D organization. Cells in cultured in HARV's adhered to microcarrier beads, the beads aggregated into defined clusters containing 8 to 15 beads per cluster, and the clusters exhibited distinct 3D layers: myocytes and fibroblasts appeared attached to the surfaces of beads and were overlaid by an outer cell type. In addition, cultures prepared in HARV's using alternative support matrices also displayed morphological formations not seen in control cultures. Generally, the cells prepared in HARV and control cultures were similar, however, the dramatic alterations in 3D organization recommend the HARV as an ideal vessel for the generation of tissue-like organizations of cardiac cells in simulated microgravity.

  18. Early life triclocarban exposure during lactation affects neonate rat survival.

    PubMed

    Kennedy, Rebekah C M; Menn, Fu-Min; Healy, Laura; Fecteau, Kellie A; Hu, Pan; Bae, Jiyoung; Gee, Nancy A; Lasley, Bill L; Zhao, Ling; Chen, Jiangang

    2015-01-01

    Triclocarban (3,4,4'-trichlorocarbanilide; TCC), an antimicrobial used in bar soaps, affects endocrine function in vitro and in vivo. This study investigates whether TCC exposure during early life affects the trajectory of fetal and/or neonatal development. Sprague Dawley rats were provided control, 0.2% weight/weight (w/w), or 0.5% w/w TCC-supplemented chow through a series of 3 experiments that limited exposure to critical growth periods: gestation, gestation and lactation, or lactation only (cross-fostering) to determine the susceptible windows of exposure for developmental consequences. Reduced offspring survival occurred when offspring were exposed to TCC at concentrations of 0.2% w/w and 0.5% w/w during lactation, in which only 13% of offspring raised by 0.2% w/w TCC dams survived beyond weaning and no offspring raised by 0.5% w/w TCC dams survived to this period. In utero exposure status had no effect on survival, as all pups nursed by control dams survived regardless of their in utero exposure status. Microscopic evaluation of dam mammary tissue revealed involution to be a secondary outcome of TCC exposure rather than a primary effect of compound administration. The average concentration of TCC in the milk was almost 4 times that of the corresponding maternal serum levels. The results demonstrate that gestational TCC exposure does not affect the ability of dams to carry offspring to term but TCC exposure during lactation has adverse consequences on the survival of offspring although the mechanism of reduced survival is currently unknown. This information highlights the importance of evaluating the safety of TCC application in personal care products and the impacts during early life exposure.

  19. Neonatal rat heart cells cultured in simulated microgravity

    NASA Technical Reports Server (NTRS)

    Akins, R. E.; Schroedl, N. A.; Gonda, S. R.; Hartzell, C. R.

    1997-01-01

    In vitro characteristics of cardiac cells cultured in simulated microgravity are reported. Tissue culture methods performed at unit gravity constrain cells to propagate, differentiate, and interact in a two-dimensional (2D) plane. Neonatal rat cardiac cells in 2D culture organize predominantly as bundles of cardiomyocytes with the intervening areas filled by nonmyocyte cell types. Such cardiac cell cultures respond predictably to the addition of exogenous compounds, and in many ways they represent an excellent in vitro model system. The gravity-induced 2D organization of the cells, however, does not accurately reflect the distribution of cells in the intact tissue. We have begun characterizations of a three-dimensional (3D) culturing system designed to mimic microgravity. The NASA-designed High-Aspect Ratio Vessel (HARV) bioreactors provide a low shear environment that allows cells to be cultured in static suspension. HARV-3D cultures were prepared on microcarrier beads and compared to control-2D cultures using a combination of microscopic and biochemical techniques. Both systems were uniformly inoculated and medium exchanged at standard intervals. Cells in control cultures adhered to the polystyrene surface of the tissue culture dishes and exhibited typical 2D organization. Cells cultured in HARVs adhered to microcarrier beads, the beads aggregated into defined clusters containing 8 to 15 beads per cluster, and the clusters exhibited distinct 3D layers: myocytes and fibroblasts appeared attached to the surfaces of beads and were overlaid by an outer cell type. In addition, cultures prepared in HARVs using alternative support matrices also displayed morphological formations not seen in control cultures. Generally, the cells prepared in HARV and control cultures were similar; however, the dramatic alterations in 3D organization recommend the HARV as an ideal vessel for the generation of tissuelike organization of cardiac cells in vitro.

  20. Early Life Triclocarban Exposure During Lactation Affects Neonate Rat Survival

    PubMed Central

    Kennedy, Rebekah C. M.; Menn, Fu-Min; Healy, Laura; Fecteau, Kellie A.; Hu, Pan; Bae, Jiyoung; Gee, Nancy A.; Lasley, Bill L.; Zhao, Ling

    2015-01-01

    Triclocarban (3,4,4′-trichlorocarbanilide; TCC), an antimicrobial used in bar soaps, affects endocrine function in vitro and in vivo. This study investigates whether TCC exposure during early life affects the trajectory of fetal and/or neonatal development. Sprague Dawley rats were provided control, 0.2% weight/weight (w/w), or 0.5% w/w TCC-supplemented chow through a series of 3 experiments that limited exposure to critical growth periods: gestation, gestation and lactation, or lactation only (cross-fostering) to determine the susceptible windows of exposure for developmental consequences. Reduced offspring survival occurred when offspring were exposed to TCC at concentrations of 0.2% w/w and 0.5% w/w during lactation, in which only 13% of offspring raised by 0.2% w/w TCC dams survived beyond weaning and no offspring raised by 0.5% w/w TCC dams survived to this period. In utero exposure status had no effect on survival, as all pups nursed by control dams survived regardless of their in utero exposure status. Microscopic evaluation of dam mammary tissue revealed involution to be a secondary outcome of TCC exposure rather than a primary effect of compound administration. The average concentration of TCC in the milk was almost 4 times that of the corresponding maternal serum levels. The results demonstrate that gestational TCC exposure does not affect the ability of dams to carry offspring to term but TCC exposure during lactation has adverse consequences on the survival of offspring although the mechanism of reduced survival is currently unknown. This information highlights the importance of evaluating the safety of TCC application in personal care products and the impacts during early life exposure. PMID:24803507

  1. Pharmacologically induced hypothermia attenuates traumatic brain injury in neonatal rats.

    PubMed

    Gu, Xiaohuan; Wei, Zheng Zachory; Espinera, Alyssa; Lee, Jin Hwan; Ji, Xiaoya; Wei, Ling; Dix, Thomas A; Yu, Shan Ping

    2015-05-01

    Neonatal brain trauma is linked to higher risks of mortality and neurological disability. The use of mild to moderate hypothermia has shown promising potential against brain injuries induced by stroke and traumatic brain injury (TBI) in various experimental models and in clinical trials. Conventional methods of physical cooling, however, are difficult to use in acute treatments and in induction of regulated hypothermia. In addition, general anesthesia is usually required to mitigate the negative effects of shivering during physical cooling. Our recent investigations demonstrate the potential therapeutic benefits of pharmacologically induced hypothermia (PIH) using the neurotensin receptor (NTR) agonist HPI201 (formerly known as ABS201) in stroke and TBI models of adult rodents. The present investigation explored the brain protective effects of HPI201 in a P14 rat pediatric model of TBI induced by controlled cortical impact. When administered via intraperitoneal (i.p.) injection, HPI201 induced dose-dependent reduction of body and brain temperature. A 6-h hypothermic treatment, providing an overall 2-3°C reduction of brain and body temperature, showed significant effect of attenuating the contusion volume versus TBI controls. Attenuation occurs whether hypothermia is initiated 15min or 2h after TBI. No shivering response was seen in HPI201-treated animals. HPI201 treatment also reduced TUNEL-positive and TUNEL/NeuN-colabeled cells in the contusion area and peri-injury regions. TBI-induced blood-brain barrier damage was attenuated by HPI201 treatment, evaluated using the Evans Blue assay. HPI201 significantly decreased MMP-9 levels and caspase-3 activation, both of which are pro-apototic, while it increased anti-apoptotic Bcl-2 gene expression in the peri-contusion region. In addition, HPI201 prevented the up-regulation of pro-inflammatory tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6. In sensorimotor activity assessments, rats in the HPI201

  2. Pharmacologically Induced Hypothermia Attenuates Traumatic Brain Injury in Neonatal Rats

    PubMed Central

    Espinera, Alyssa; Lee, Jin Hwan; Ji, Xiaoya; Wei, Ling; Dix, Thomas A.; Yu, Shan Ping

    2015-01-01

    Neonatal brain trauma is linked to higher risks of mortality and neurological disability. The use of mild to moderate hypothermia has shown promising potential against brain injuries induced by stroke and traumatic brain injury (TBI) in various experimental models and in clinical trials. Conventional methods of physical cooling, however, are difficult to use in acute treatments and in induction of regulated hypothermia. In addition, general anesthesia is usually required to mitigate the negative effects of shivering during physical cooling. Our recent investigations demonstrate the potential therapeutic benefits of pharmacologically induced hypothermia (PIH) using the neurotensin receptor (NTR) agonist HPI201 (formerly known as ABS201) in stroke and TBI models of adult rodents. The present investigation explored the brain protective effects of HPI201 in a P14 rat pediatric model of TBI induced by controlled cortical impact. When administered via intraperitoneal (i.p.) injection, HPI201 induced dose-dependent reduction of body and brain temperature. A six-hour hypothermic treatment, providing an overall 2-3°C reduction of brain and body temperature, showed significant effect of attenuating the contusion volume versus TBI controls. Attenuation occurs whether hypothermia is initiated 15 min or 2 hr after TBI. No shivering response was seen in HPI201-treated animals. HPI201 treatment also reduced TUNEL-positive and TUNEL/NeuN-colabeled cells in the contusion area and peri-injury regions. TBI-induced blood brain barrier damage was attenuated by HPI201 treatment, evaluated using the Evans Blue assay. HPI201 significantly decreased MMP-9 levels and Caspase-3 activation, both of which are pro-apototic, while it increased anti-apoptotic Bcl-2 gene expression in the peri-contusion region. In addition, HPI201 prevented the up-regulation of pro-inflammatory tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6. In sensorimotor activity assessments, rats in the

  3. Hypercholesterolemic diet applied to rat dams protects their offspring against cognitive deficits. Simulated neonatal anoxia model.

    PubMed

    Bohr, Iwo

    2004-09-30

    There is accumulating data suggesting a neuroprotective activity of cholesterol, especially in stroke and Alzheimer's disease (AD). In the present study, a protective activity of this lipid in simulated neonatal anoxia was investigated. Rats were subjected to high cholesterol by feeding their dams with a diet enriched with cholesterol. Half of these rats were subjected to anoxia. One and a half months later, the rats were tested for their ability to acquire a spatial memory, one group on the linear maze and the other on the Morris water maze. After these assessments, the level of total plasma cholesterol was measured. Rats from dams subjected to neonatal anoxia on standard diet performed worse than control rats in both types of behavioral experiments, whereas anoxic rats from dams were housed on hypercholesterolemic diet performed as control animals. It suggests that dietetic cholesterol applied by their dams protected rats against cognitive deficits elicited by neonatal anoxia. Furthermore, offspring of anoxic rats housed on standard diet had elevated levels of blood cholesterol in relation to control animals. Generally, anoxia affected the concentration of this lipid much stronger than hypercholesterolemic diet of their dams. It might mean that the anoxia-related rise of cholesterol could be involved in physiological phenomenon being an adaptive response to neurotoxic processes. This concept is discussed in relation to pathological mechanisms in AD.

  4. Effects of neonatal treatment with the TRPV1 agonist, capsaicin, on adult rat brain and behaviour.

    PubMed

    Newson, Penny N; van den Buuse, Maarten; Martin, Sally; Lynch-Frame, Ann; Chahl, Loris A

    2014-10-01

    Treatment of neonatal rats with the transient receptor potential vanilloid 1 (TRPV1) channel agonist, capsaicin, produces life-long loss of sensory neurons expressing TRPV1 channels. Previously it was shown that rats treated on day 2 of life with capsaicin had behavioural hyperactivity in a novel environment at 5-7 weeks of age and brain changes reminiscent of those found in subjects with schizophrenia. The objective of the present study was to investigate brain and behavioural responses of adult rats treated as neonates with capsaicin. It was found that the brain changes found at 5-7 weeks in rats treated as neonates with capsaicin persisted into adulthood (12 weeks) but were less in older rats (16-18 weeks). Increased prepulse inhibition (PPI) of acoustic startle was found in these rats at 8 and 12 weeks of age rather than the deficit commonly found in animal models of schizophrenia. Subjects with schizophrenia also have reduced flare responses to niacin and methylnicotinate proposed to be mediated by prostaglandin D2 (PGD2). Flare responses are accompanied by cutaneous plasma extravasation. It was found that the cutaneous plasma extravasation responses to methylnicotinate and PGD2 were reduced in capsaicin-treated rats. In conclusion, several neuroanatomical changes observed in capsaicin-treated rats, as well as the reduced cutaneous plasma extravasation responses, indicate that the role of TRPV1 channels in schizophrenia is worthy of investigation.

  5. Memantine delayed N-methyl-D-aspartate -induced convulsions in neonatal rats.

    PubMed

    Dhir, Ashish; Chopra, Kanwaljit

    2015-02-01

    Memantine (1-amino-3,5-dimethyladamantane) is a moderate-affinity uncompetitive antagonist of N-methyl-d-aspartate (NMDA) receptors. In this study, we have explored the effect of memantine against N-methyl-d-aspartate (NMDA)-induced seizures in neonatal rats. Here, we evaluated various behavioral seizure abnormalities in neonatal rats (Sprague-Dawley; postnatal day 9) after an intraperitoneal administration of NMDA. Further, we explored whether an acute administration of memantine could protect these neonates against different phases of convulsions induced by NMDA. In a separate study, we have compared the effect of levetiracetam in the same animal model. Exogenous administration of NMDA (30 mg/kg., i.p.) in neonatal rats resulted in arrest of activity, emprosthotonos curvature (trunk is bent forward by the entire muscles), myoclonic jerks, and forelimb/hindlimb clonus. The clonus phase in neonates was followed by loss of righting reflex and continuous seizures (for more than 5 min) suggesting status epilepticus, tonic extension, and death. Pretreatment of memantine hydrochloride (10-30 mg/kg., i.p.) dose-dependently delayed the onset of different phases of convulsions induced by NMDA. Memantine at the highest dose was found to be ataxic in rat neonates, while lower doses were free of any observed behavioral signs of toxicity. Levetiracetam (25 mg/kg., i.p.) when administered 30 min before the NMDA challenge blocked only the jerk phase and did not affect other phases of NMDA-induced convulsions. These data indicated that memantine and other safer uncompetitive NMDA receptor antagonists may be protective in the management of neonatal seizures.

  6. Neonatal capsaicin treatment in rats induces chronic hyperthermia resulting in infectious disease

    PubMed Central

    JEONG, KEUN-YEONG; KIM, HWAN MOOK

    2015-01-01

    Treatment of neonatal animals with capsaicin has previously been associated with long-lasting hyperthermia and severe cutaneous lesions. The present study analyzed the effects of capsaicin-induced hyperthermia on the occurrence of infectious disease and pruritic dermatitis in a rat model. Pregnant Sprague-Dawley (SD) rats were obtained 1 week prior to parturition. Pups from each litter were randomly assigned to the following experimental groups: Capsaicin-treated (cap-treated; n=10) or vehicle-treated (n=5). Capsaicin (50 mg/kg) or vehicle were systemically administered to the SD rat pups (age, 48 h), after which body temperature was measured using a biotelemetry system, and the effects of hyperthermia on the ability of the rat pups to resist bacterial infection were analyzed. Furthermore, pruritus-induced scratching behavior and dermatitis were assessed, and changes in interleukin (IL)-4- and IL-13-induced immunoglobulin E expression were measured. Treatment of neonatal rats with capsaicin resulted in chronic hyperthermia, which had negative effects on the host immune defense response. The expression levels of T-helper type 2 cell-associated cytokines were significantly increased (P<0.01) in the cap-treated rats following bacterial infection with Staphylococcus aureus or Streptococcus agalactiae. Furthermore, cap-treated rats exhibited pruritus-induced scratching behavior and dermatitis. The results of the present study suggested that treatment of neonatal rats with capsaicin induces chronic hyperthermia and decreases the effectiveness of the host defense system. Therefore, a cap-treated neonatal rat model may be considered useful when investigating the association between hyperthermia and infectious disease. PMID:26668650

  7. Estrogen fails to facilitate resuscitation from ventricular fibrillation in male rats

    PubMed Central

    Miao, Yang; Edelheit, Ari; Velmurugan, Sathya; Borovnik-Lesjak, Vesna; Radhakrishnan, Jeejabai; Gazmuri, Raúl J

    2015-01-01

    Administration of 17β-estradiol has been shown to exert myocardial protective effects in hemorrhagic shock. We hypothesized that similar protective effects could help improve resuscitation from cardiac arrest. Three series of 18, 40, and 12 rats each, underwent ventricular fibrillation for 8 minutes followed by 8 minutes of chest compression and delivery of electrical shocks. In series-1, rats were randomized 1:1 to receive a bolus dose of 17β-estradiol (1 mg/kg) or 0.9% NaCl before chest compression; in series-2, rats were randomized 1:1:1:1 to receive a continuous infusion of 0.9% NaCl or a 17β-estradiol solution designed to attain a plasma level of 100, 102, or 104 nM during chest compression; and in series-3, rats were randomized 1:1 to receive a continuous infusion of 17β-estradiol to attain a plasma level of 102 nM or 0.9% NaCl during chest compression, providing inotropic support during the post-resuscitation interval using dobutamine infusion. 17β-estradiol failed to facilitate resuscitation in each of the 3 series. In series-1 and series-2, resuscitability and short-term survival was reduced in 17β-estradiol groups attaining statistical significance in series-2 when the three 17β-estradiol groups were combined (p = 0.035). In series-3, all rats were resuscitated and survived for 180 minutes aided by dobutamine which partially reversed post-resuscitation myocardial dysfunction but without additional benefits on myocardial function in the 17β-estradiol group. The present study failed to support a beneficial effect of 17β-estradiol for resuscitation from cardiac arrest and raised the possibility of detrimental cardiac effects compromising initial resuscitability and subsequent survival in a male rat model of ventricular fibrillation and closed chest resuscitation. PMID:26045892

  8. The minimal inhibitory synaptic currents evoked in neonatal rat motoneurones.

    PubMed Central

    Takahashi, T

    1992-01-01

    1. Tight-seal whole-cell recordings were made from lumbar motoneurones visually identified in thin slices of neonatal rat spinal cord. The inhibitory postsynaptic currents (IPSCs) were evoked by extracellular stimulation of a neighbouring internuncial neurone in the presence of glutamate receptor antagonists. 2. Glycinergic IPSCs were recorded in the presence of bicuculline. The IPSCs appeared in an all-or-none manner as the graded stimulus intensity exceeded a certain threshold. Their latencies showed a unimodal distribution with a mean of 0.81 ms at 37 degrees C. Thus, the observed IPSCs are suggested to be monosynaptically evoked unitary IPSCs. The mean conductance of unitary IPSCs was 2.9 +/- 1.2 nS (+/- S.D.). 3. When the external Ca2+ concentration ([Ca2+]o) was reduced, the number of failures in response to stimulation increased, thereby reducing the mean amplitude of IPSCs. The mean amplitude of IPSCs was linearly related to the [Ca2+]o (0.35-1.4 mM) with a mean slope of 3.1 +/- 0.67 on double logarithmic co-ordinates. 4. The amplitude of individual IPSCs decreased with decrease in [Ca2+]o. However, below 0.7 mM [Ca2+]o, the mean amplitude of IPSCs (excluding failures) reached a steady minimum level. The mean conductance of these IPSCs measured in 0.5 mM [Ca2+]o was 657 +/- 281 pS. 5. The minimal IPSCs had a coefficient of variation of 0.50 +/- 0.13. No clear correlation was observed between the rise time and the amplitude of minimal IPSCs evoked in individual motoneurones, indicating that the amplitude variability is not due to the different synaptic locations. 6. Spontaneous miniature IPSCs were recorded from motoneurones in the presence of tetrodotoxin. The miniature IPSCs had a mean conductance of 739 +/- 278 pS, being comparable to the minimal evoked IPSCs. 7. Under various internal and external Cl- concentration, the reversal potential of the IPSCs (EIPSC) approximately coincided with the Cl- equilibrium potential. A 730-fold change in the potassium

  9. Aspects of the Development of Housing for the Spaceflight of Pregnant and Lactating Rats with Neonates

    NASA Technical Reports Server (NTRS)

    Hinds, William E.; Mayer, David J.; Evans, Juli; Spratt, Shahn; Lane, Philip K.; Rodriguez, Shari L.; Navidi, Meena; Armstrong, Rachel; Lemos, Bonnie; Dalton, Bonnie P. (Technical Monitor)

    1996-01-01

    Recent and upcoming spaceflights are investigating the effect of weightlessness on developing neural and organ systems. Pregnant rats and dams with neonates have to be accommodated in cages that support the special requirements of these animals. Extensive ground testing of cage concepts, the effect of launch and landing stresses on the maintenance of pregnancy and maternal behavior at different neonatal ages, and techniques for monitoring adaptability to change are discussed. A spaceflight opportunity for the NlH.R3 payload of rat families at three different postnatal ages demonstrated that the survival of very young animals was not good but that older newborns could be returned to Earth in reasonably good health. The development of cages for the Research Animal Holding Facility (RAHF) to support the flight of neonates on Neurolab was continued and incorporated modifications that were demonstrated by the NIH.R3 flight. Other modifications to the RAHF are discussed. Data from biocompatibility and experiment verification testing are presented.

  10. Marginal Zone B Cells in Neonatal Rats Express Intermediate Levels of CD90 (Thy-1)

    PubMed Central

    Dammers, Peter M.; Lodewijk, Monique E.; Zandvoort, André; Kroese, Frans G. M.

    2002-01-01

    Here we show that marginal zone (MZ)-B cells in rats can already be detected in neonatal spleen from two days after birth. At this time point, morphologically distinct MZs are not present yet and the vast majority of B cells in spleen are located in a concentric area surrounding the T cell zones (PALS). Before MZs are obviously detectable in spleen (14 days after birth), MZ-B cells seem to be enriched at the outer zones of the concentric B cell areas. Similar to adult rats, neonatal MZ-B cells are intermediate-sized cells that express high levels of surface (s)IgM and HIS57 antigen, and low levels of sIgD and CD45R (HIS24). We show here, however, that in contrast to adult MZ-B cells, MZ-B cells (and also recirculating follicular (RF)-B cells) in neonatal rats express higher levels of CD90 (Thy-1). In adult rats, expression of CD90 on the B cell lineage is confined to immature B cells. We speculate that the expression of CD90 on neonatal MZ-B cells may have implications for their responsiveness to polysaccharide (T cell-independent type 2) antigens. PMID:15144015

  11. Distribution dynamics of recombinant Lactobacillus in the gastrointestinal tract of neonatal rats.

    PubMed

    Bao, Sujin; Zhu, Libin; Zhuang, Qiang; Wang, Lucia; Xu, Pin-Xian; Itoh, Keiji; Holzman, Ian R; Lin, Jing

    2013-01-01

    One approach to deliver therapeutic agents, especially proteins, to the gastro-intestinal (GI) tract is to use commensal bacteria as a carrier. Genus Lactobacillus is an attractive candidate for use in this approach. However, a system for expressing exogenous proteins at a high level has been lacking in Lactobacillus. Moreover, it will be necessary to introduce the recombinant Lactobacillus into the GI tract, ideally by oral administration. Whether orally administered Lactobacillus can reach and reside in the GI tract has not been explored in neonates. In this study, we have examined these issues in neonatal rats. To achieve a high level of protein expression in Lactobacillus, we tested the impact of three promoters and two backbones on protein expression levels using mRFP1, a red fluorescent protein, as a reporter. We found that a combination of an L-lactate dehydrogenase (ldhL) promoter of Lactobacillus sakei with a backbone from pLEM415 yielded the highest level of reporter expression. When this construct was used to transform Lactobacillus casei, Lactobacillus delbrueckii and Lactobacillus acidophilus, high levels of mRFP1 were detected in all these species and colonies of transformed Lactobacillus appeared pink under visible light. To test whether orally administered Lactobacillus can be retained in the GI tract of neonates, we fed the recombinant Lactobacillus casei to neonatal rats. We found that about 3% of the bacteria were retained in the GI tract of the rats at 24 h after oral feeding with more recombinant Lactobacillus in the stomach and small intestine than in the cecum and colon. No mortality was observed throughout this study with Lactobacillus. In contrast, all neonatal rats died within 24 hours after fed with transformed E. coli. Taken together, our results indicate that Lactobacillus has the potential to be used as a vehicle for the delivery of therapeutic agents to neonates.

  12. Effect of diazepam on sociability of rats submitted to neonatal seizures.

    PubMed

    Leite, Ingrid Stanize; Castelhano, Adelissandra S S; Cysneiros, Roberta M

    2016-06-01

    Status epilepticus (SE), an acute condition characterized by repetitive or ongoing seizures activity, may produce long-term deleterious consequences. Previous data demonstrated that Wistar rats subjected to neonatal SE displayed autistic behavior, characterized by social play impairment, low preference by novelty, deficit in social discrimination; anxiety related behavior and stereotyped behavior with no changes in locomotor activity (doi: http://dx.doi.org/10.1007/s00702-010-0460-1, doi: http://dx.doi.org/10.3389/fnbeh.2013.00036, doi: http://dx.doi.org/10.1007/s00702-014-1291-2[1], [2], [3]). Taking into account the bi-directional relationship between the state of anxiety and social interaction (doi: http://dx.doi.org/10.1007/s10567-009-0062-3[4]), we evaluated the impact of the state of anxiety on social interaction. Male Wistar rats at postnatal day 9 were subjected to pilocarpine-induced neonatal SE (380 mg/kg, ip) and the controls received 0.9% saline (0.1 ml/10 g). The groups received saline or diazepam (1.0 mg/kg) 45 min prior each behavioral testing that started from 60 days of postnatal life. In the open field, rats subjected to neonatal seizure exhibited less central zone activity as compared to animals treated with diazepam, with no changes in the total locomotor activity. In elevated plus maze, rats subjected to neonatal seizure and treated with diazepam exhibited higher locomotor activity and spent more time on the open arms as compared to untreated animals. In approach phase of sociability paradigm, animals subjected to neonatal seizures similarly to controls, regardless the treatment, spent more time with social stimulus as compared to non social stimulus. In social novelty phase of sociability paradigm, animals subjected to neonatal seizures differently of controls, regardless the treatment, spent similar time with familiar and novel stimulus.

  13. Effect of diazepam on sociability of rats submitted to neonatal seizures

    PubMed Central

    Leite, Ingrid Stanize; Castelhano, Adelissandra S.S.; Cysneiros, Roberta M.

    2016-01-01

    Status epilepticus (SE), an acute condition characterized by repetitive or ongoing seizures activity, may produce long-term deleterious consequences. Previous data demonstrated that Wistar rats subjected to neonatal SE displayed autistic behavior, characterized by social play impairment, low preference by novelty, deficit in social discrimination; anxiety related behavior and stereotyped behavior with no changes in locomotor activity (doi: http://dx.doi.org/10.1007/s00702-010-0460-1, doi: http://dx.doi.org/10.3389/fnbeh.2013.00036, doi: http://dx.doi.org/10.1007/s00702-014-1291-2[1], [2], [3]). Taking into account the bi-directional relationship between the state of anxiety and social interaction (doi: http://dx.doi.org/10.1007/s10567-009-0062-3[4]), we evaluated the impact of the state of anxiety on social interaction. Male Wistar rats at postnatal day 9 were subjected to pilocarpine-induced neonatal SE (380 mg/kg, ip) and the controls received 0.9% saline (0.1 ml/10 g). The groups received saline or diazepam (1.0 mg/kg) 45 min prior each behavioral testing that started from 60 days of postnatal life. In the open field, rats subjected to neonatal seizure exhibited less central zone activity as compared to animals treated with diazepam, with no changes in the total locomotor activity. In elevated plus maze, rats subjected to neonatal seizure and treated with diazepam exhibited higher locomotor activity and spent more time on the open arms as compared to untreated animals. In approach phase of sociability paradigm, animals subjected to neonatal seizures similarly to controls, regardless the treatment, spent more time with social stimulus as compared to non social stimulus. In social novelty phase of sociability paradigm, animals subjected to neonatal seizures differently of controls, regardless the treatment, spent similar time with familiar and novel stimulus. PMID:27054178

  14. Comparison of sarcolemmal calcium channel current in rabbit and rat ventricular myocytes.

    PubMed Central

    Yuan, W; Ginsburg, K S; Bers, D M

    1996-01-01

    1. Fundamental properties of Ca2+ channel currents in rat and rabbit ventricular myocytes were measured using whole cell voltage clamp. 2. In rat, as compared with rabbit myocytes, Ca2+ channel current (ICa) was half-activated at about 10 mV more negative potential, decayed slower, was half-inactivated (in steady state) at about 5 mV more positive potential, and recovered faster from inactivation. 3. These features result in a larger steady-state window current in rat, and also suggest that under comparable voltage clamp conditions, including action potential (AP) clamp, more Ca2+ influx would be expected in rat myocytes. 4. Ca2+ channel current carried by Na+ and Cs+ in the absence of divalent ions (Ins) also activated at more negative potential and decayed more slowly in rat. 5. The reversal potential for Ins was 6 mV more positive in rabbit, consistent with a larger permeability ratio (PNa/PCs) in rabbit than in rat. ICa also reversed at slightly more positive potentials in rabbit (such that PCa/PCs might also be higher). 6. Ca2+ influx was calculated by integration of ICa evoked by voltage clamp pulses (either square pulses or pulses based on recorded rabbit or rat APs). For a given clamp waveform, the Ca2+ influx was up to 25% greater in rat, as predicted from the fundamental properties of ICa and Ins. 7. However, the longer duration of the AP in rabbit myocytes compensated for the difference in influx, such that the integrated Ca2+ influx via ICa in response to the species-appropriate waveform was about twice as large as that seen in rat. PMID:8799895

  15. Pharmacokinetics of bisphenol A in neonatal and adult Sprague-Dawley rats

    SciTech Connect

    Doerge, Daniel R.; Twaddle, Nathan C.; Vanlandingham, Michelle; Fisher, Jeffrey W.

    2010-09-01

    Bisphenol A (BPA) is an important industrial chemical used in the manufacture of polycarbonate plastic products and epoxy resin-based food can liners. The presence of BPA in urine of > 90% of Americans aged 6-60 suggests ubiquitous and frequent exposure. The current study used LC/MS/MS to measure serum pharmacokinetics of aglycone (active) and conjugated (inactive) BPA in adult and neonatal Sprague-Dawley rats by oral and injection routes. Deuterated BPA was used to avoid issues of background contamination. Linear pharmacokinetics were observed in adult rats treated orally in the range of 0-200 {mu}g/kg bw. Evidence for enterohepatic recirculation of conjugated, but not aglycone, BPA was observed in adult rats. Significant inverse relationships were observed between postnatal age and measures of internal exposures to aglycone BPA and its elimination. In neonatal rats treated orally, internal exposures to aglycone BPA were substantially lower than from subcutaneous injection. The results reinforce the critical role for first-pass Phase II metabolism of BPA in gut and liver after oral exposure that attenuates internal exposure to the aglycone form in rats of all ages. The internal exposures to aglycone BPA observed in adult and neonatal rats following a single oral dose of 100 {mu}g/kg bw are inconsistent with effects mediated by classical estrogen receptors based on binding affinities. However, an impact on alternative estrogen signaling pathways that have higher receptor affinity cannot be excluded in neonatal rats. These findings emphasize the importance of matching aglycone BPA internal dosimetry with receptor affinities in experimental animal studies reporting toxicity.

  16. Analysis of the hypothalamic-pituitary-ovary axis in the neonatally-androgenized female rat.

    PubMed

    Spinedi, E; Mariani, V; Bulfon, M; Colombani-Vidal, M; Scaglia, H

    1990-06-01

    The administration of testosterone propionate (TP) in the female rat at the neonatal age has been used for several yr as a model to study anovulation during adulthood. The present work was designed in order to see whether some neuroendocrine parameters vary with age in this animal model. Hypothalamic LHRH content and LH-FSH anterior pituitary (AP) content and plasma levels were evaluated in samples taken from both neonatally-androgenized and littermate control female rats at different ages (15 to 100 days old). Additionally, we have studied pulsatile LH-FSH released in plasma and in vivo AP response to LHRH in both neonatally-androgenized and control female rats during adulthood. The results indicate that the neonatal TP treatment did not induce any change in hypothalamic LHRH content over development. Neonatally androgenized rats have decreased both LH-FSH AP content and plasma levels at the infantile age (15-day old). LH-FSH AP content remained reduced in samples taken up to the 30th day of age. Plasma LH-FSH levels on the day 30 of age were similar in both groups. TP-treated rats studied on the 100th day of age had: a) an altered pulsatile rhythm of gonadotropin release in plasma due to the decreased LH-FSH trough and average mean values, and to the diminished FSH peak amplitude values, as well as an increased LH:FSH ratio; and b) an impaired in vivo LHRH-induced LH-FSH release.(ABSTRACT TRUNCATED AT 250 WORDS)

  17. Neonatal hyperglycemia induces oxidative stress in the rat brain: the role of pentose phosphate pathway enzymes and NADPH oxidase.

    PubMed

    Rosa, Andrea Pereira; Jacques, Carlos Eduardo Dias; de Souza, Laila Oliveira; Bitencourt, Fernanda; Mazzola, Priscila Nicolao; Coelho, Juliana Gonzales; Mescka, Caroline Paula; Dutra-Filho, Carlos Severo

    2015-05-01

    Recently, the consequences of diabetes on the central nervous system (CNS) have received great attention. However, the mechanisms by which hyperglycemia affects the central nervous system remain poorly understood. In addition, recent studies have shown that hyperglycemia induces oxidative damage in the adult rat brain. In this regard, no study has assessed oxidative stress as a possible mechanism that affects the brain normal function in neonatal hyperglycemic rats. Thus, the present study aimed to investigate whether neonatal hyperglycemia elicits oxidative stress in the brain of neonate rats subjected to a streptozotocin-induced neonatal hyperglycemia model (5-day-old rats). The activities of glucose-6-phosphate-dehydrogenase (G6PD), 6-phosphogluconate-dehydrogenase (6-PGD), NADPH oxidase (Nox), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSHPx), the production of superoxide anion, the thiobarbituric acid-reactive substances (TBA-RS), and the protein carbonyl content were measured. Neonatal hyperglycemic rats presented increased activities of G6PD, 6PGD, and Nox, which altogether may be responsible for the enhanced production of superoxide radical anion that was observed. The enhanced antioxidant enzyme activities (SOD, CAT, and GSHPx) that were observed in neonatal hyperglycemic rats, which may be caused by a rebound effect of oxidative stress, were not able to hinder the observed lipid peroxidation (TBA-RS) and protein damage in the brain. Consequently, these results suggest that oxidative stress could represent a mechanism that explains the harmful effects of neonatal hyperglycemia on the CNS.

  18. Current-Voltage Relationship for Late Na(+) Current in Adult Rat Ventricular Myocytes.

    PubMed

    Clark, R B; Giles, W R

    2016-01-01

    It is now well established that the slowly inactivating component of the Na(+) current (INa-L) in the mammalian heart is a significant regulator of the action potential waveform. This insight has led to detailed studies of the role of INa-L in a number of important and challenging pathophysiological settings. These include genetically based ventricular arrhythmias (LQT 1, 2, and 3), ventricular arrhythmias arising from progressive cardiomyopathies (including diabetic), and proarrhythmic abnormalities that develop during local or global ventricular ischemia. Inhibition of INa-L may also be a useful strategy for management of atrial flutter and fibrillation. Many important biophysical parameters that characterize INa-L have been identified; and INa-L as an antiarrhythmia drug target has been studied extensively. However, relatively little information is available regarding (1) the ion transfer or current-voltage relationship for INa-L or (2) the time course of its reactivation at membrane potentials similar to the resting or diastolic membrane potential in mammalian ventricle. This chapter is based on our preliminary findings concerning these two very important physiological/biophysical descriptors for INa-L. Our results were obtained using whole-cell voltage clamp methods applied to enzymatically isolated rat ventricular myocytes. A chemical agent, BDF 9148, which was once considered to be a drug candidate in the Na(+)-dependent inotropic agent category has been used to markedly enhance INa-L current. BDF acts in a potent, selective, and reversible fashion. These BDF 9148 effects are compared and contrasted with the prototypical activator of INa-L, a sea anemone toxin, ATX II. PMID:27586292

  19. Current-Voltage Relationship for Late Na(+) Current in Adult Rat Ventricular Myocytes.

    PubMed

    Clark, R B; Giles, W R

    2016-01-01

    It is now well established that the slowly inactivating component of the Na(+) current (INa-L) in the mammalian heart is a significant regulator of the action potential waveform. This insight has led to detailed studies of the role of INa-L in a number of important and challenging pathophysiological settings. These include genetically based ventricular arrhythmias (LQT 1, 2, and 3), ventricular arrhythmias arising from progressive cardiomyopathies (including diabetic), and proarrhythmic abnormalities that develop during local or global ventricular ischemia. Inhibition of INa-L may also be a useful strategy for management of atrial flutter and fibrillation. Many important biophysical parameters that characterize INa-L have been identified; and INa-L as an antiarrhythmia drug target has been studied extensively. However, relatively little information is available regarding (1) the ion transfer or current-voltage relationship for INa-L or (2) the time course of its reactivation at membrane potentials similar to the resting or diastolic membrane potential in mammalian ventricle. This chapter is based on our preliminary findings concerning these two very important physiological/biophysical descriptors for INa-L. Our results were obtained using whole-cell voltage clamp methods applied to enzymatically isolated rat ventricular myocytes. A chemical agent, BDF 9148, which was once considered to be a drug candidate in the Na(+)-dependent inotropic agent category has been used to markedly enhance INa-L current. BDF acts in a potent, selective, and reversible fashion. These BDF 9148 effects are compared and contrasted with the prototypical activator of INa-L, a sea anemone toxin, ATX II.

  20. Effects of valsartan on ventricular arrhythmia induced by programmed electrical stimulation in rats with myocardial infarction

    PubMed Central

    Jiao, Kun-Li; Li, Yi-Gang; Zhang, Peng-Pai; Chen, Ren-Hua; Yu, Yi

    2012-01-01

    Abstract The impact of angiotensin II receptor blockers (ARBs) on electrical remodelling after myocardial infarction (MI) remains unclear. The purpose of the present study was to evaluate the effect of valsartan on incidence of ventricular arrhythmia induced by programmed electrical stimulation (PES) and potential link to changes of myocardial connexins (Cx) 43 expression and distribution in MI rats. Fifty-nine rats were randomly divided into three groups: Sham (n = 20), MI (n = 20) and MI + Val (20 mg/kg/day per gavage, n = 19). After eight weeks, the incidence of PES-induced ventricular tachycardia (VT) and fibrillation (VF) was compared among groups. mRNA and protein expressions of Cx43, angiotensin II type 1 receptor (AT1R) in the LV border zone (BZ) and non-infarct zone (NIZ) were determined by real-time PCR and Western blot, respectively. Connexins 43 protein and collagen distribution were examined by immunohistochemistry in BZ and NIZ sections from MI hearts. Valsartan effectively improved the cardiac function, reduced the prolonged QTc (163.7 ± 3.7 msec. versus 177.8 ± 4.5 msec., P < 0.05) after MI and the incidence of VT or VF evoked by PES (21.1% versus 55%, P < 0.05). Angiotensin II type 1 receptor expression was significantly increased in BZ and NIZ sections after MI, which was down-regulated by valsartan. The mRNA and protein expressions of Cx43 in BZ were significantly reduced after MI and up-regulated by valsartan. Increased collagen deposition and reduced Cx43 expression in BZ after MI could be partly attenuated by Valsartan. Valsartan reduced the incidence of PES-induced ventricular arrhythmia, this effect was possibly through modulating the myocardial AT1R and Cx43 expression. PMID:22128836

  1. Toluene and benzene inhalation influences on ventricular arrhythmias in the rat.

    PubMed

    Magos, G A; Lorenzana-Jiménez, M; Vidrio, H

    1990-01-01

    We have previously found that toluene did not share the capacity of benzene for increasing the arrhythmogenic action of epinephrine in the rat, but appeared to elicit the opposite effect. The present experiments were carried out to verify this observation in rats subjected to more severe ventricular arrhythmias. In animals previously inhaling either air, toluene or benzene and anesthetized with pentobarbital, arrhythmias were produced by coronary ligation or aconitine. In both models, toluene decreased and benzene increased the number of ectopic ventricular beats in the 30 min following induction of arrhythmia. Gas chromatographic measurement of toluene levels in the heart during and after inhalation revealed essentially constant concentrations at the time of arrhythmia evaluation, equivalent to approximately one-third the peak levels observed at the end of inhalation. Although the mechanism of the effect of toluene on arrhythmia could not be ascertained, nonspecific membrane stabilization or central serotonergic stimulation were considered as possible explanations. Since both mechanisms could be operant also in the case of benzene, the opposite effects of the solvents on arrhythmia could not be readily accounted for.

  2. Immediate and Enduring Effects of Neonatal Isolation on Maternal Behavior in Rats

    PubMed Central

    Kosten, Therese A.; Kehoe, Priscilla

    2009-01-01

    Previously, we showed that neonatal isolation (1-hr isolation/day from dam, litter, and nest on PND 2-9) facilitates cocaine self-administration and increases extracellular dopamine responses in ventral striatum after stimulant administration in adulthood. Recent studies suggest that enduring alterations in neurobehavioral responses associated with early life manipulations reflect changes in maternal behavior. Thus, we sought to determine if neonatal isolation alters maternal care and if dams with neonatal isolation experience as pups showed differential maternal care towards their pups. In Experiment 1, litters were assigned to one of three conditions: neonatal isolation, handled (5-min separation of dam from litter), or non-handled (no separation). Maternal behaviors were rated on PND 2-9 for 60-min immediately following reunion of mother and litter. In Experiment 2, female rats with or without neonatal isolation experience were assigned to either the neonatal isolation or non-handled litter condition and maternal behaviors rated. Dams of isolated and handled litters spent more time licking pups and less time picking up pups to put outside the nest than dams of non-handled litters. Further, dams of isolated and handled vs non-handled litters showed less non-maternal behaviors of burrowing and grooming. Neonatal isolation-experienced dams with isolated litters failed to increase pup-licking and decrease non-maternal behaviors. Rather, these dams picked up pups to place outside the nest more than non-handled-experienced dams. Neonatal isolation alters maternal behavior that, in turn, may shape neurobehavioral responses of offspring including effects on maternal care. Such changes may reflect epigenetic effects resulting from changes in maternal behavior. PMID:19782745

  3. Neuron-astrocyte interactions, pyruvate carboxylation and the pentose phosphate pathway in the neonatal rat brain.

    PubMed

    Morken, Tora Sund; Brekke, Eva; Håberg, Asta; Widerøe, Marius; Brubakk, Ann-Mari; Sonnewald, Ursula

    2014-01-01

    Glucose and acetate metabolism and the synthesis of amino acid neurotransmitters, anaplerosis, glutamate-glutamine cycling and the pentose phosphate pathway (PPP) have been extensively investigated in the adult, but not the neonatal rat brain. To do this, 7 day postnatal (P7) rats were injected with [1-(13)C]glucose and [1,2-(13)C]acetate and sacrificed 5, 10, 15, 30 and 45 min later. Adult rats were injected and sacrificed after 15 min. To analyse pyruvate carboxylation and PPP activity during development, P7 rats received [1,2-(13)C]glucose and were sacrificed 30 min later. Brain extracts were analysed using (1)H- and (13)C-NMR spectroscopy. Numerous differences in metabolism were found between the neonatal and adult brain. The neonatal brain contained lower levels of glutamate, aspartate and N-acetylaspartate but similar levels of GABA and glutamine per mg tissue. Metabolism of [1-(13)C]glucose at the acetyl CoA stage was reduced much more than that of [1,2-(13)C]acetate. The transfer of glutamate from neurons to astrocytes was much lower while transfer of glutamine from astrocytes to glutamatergic neurons was relatively higher. However, transport of glutamine from astrocytes to GABAergic neurons was lower. Using [1,2-(13)C]glucose it could be shown that despite much lower pyruvate carboxylation, relatively more pyruvate from glycolysis was directed towards anaplerosis than pyruvate dehydrogenation in astrocytes. Moreover, the ratio of PPP/glucose-metabolism was higher. These findings indicate that only the part of the glutamate-glutamine cycle that transfers glutamine from astrocytes to neurons is operating in the neonatal brain and that compared to adults, relatively more glucose is prioritised to PPP and pyruvate carboxylation. Our results may have implications for the capacity to protect the neonatal brain against excitotoxicity and oxidative stress.

  4. Human neonatal hepatocyte transplantation induces long-term rescue of unconjugated hyperbilirubinemia in the Gunn rat.

    PubMed

    Tolosa, Laia; López, Silvia; Pareja, Eugenia; Donato, María Teresa; Myara, Anne; Nguyen, Tuan Huy; Castell, José Vicente; Gómez-Lechón, María José

    2015-06-01

    Crigler-Najjar type 1 disease is a rare inherited metabolic disease characterized by high levels of unconjugated bilirubin due to the complete absence of hepatic uridine diphosphoglucuronate-glucuronosyltransferase activity. Hepatocyte transplantation (HT) has been proposed as an alternative treatment for Crigler-Najjar syndrome, but it is still limited by the quality and the low engraftment and repopulation ability of the cells used. Because of their attachment capability and expression of adhesion molecules as well as the higher proportion of hepatic progenitor cells, neonatal hepatocytes may have an advantage over adult cells. Adult or neonatal hepatocytes were transplanted into Gunn rats, a model for Crigler-Najjar disease. Engraftment and repopulation were studied and compared by immunofluorescence (IF). Additionally, the serum bilirubin levels, the presence of bilirubin conjugates in rat serum, and the expression of uridine diphosphate glucuronosyltransferase 1 family polypeptide A1 (UGT1A1) in rat liver samples were also analyzed. Here we show that neonatal HT results in long-term correction in Gunn rats. In comparison with adult cells, neonatal cells showed better engraftment and repopulation capability 3 days and 6 months after transplantation, respectively. Bilirubinemia decreased in the transplanted animals during the whole experimental follow-up (6 months). Bilirubin conjugates were also present in the serum of the transplanted animals. Western blots and IF confirmed the presence and expression of UGT1A1 in the liver. This work is the first to demonstrate the advantage of using neonatal hepatocytes for the treatment of Crigler-Najjar in vivo. PMID:25821167

  5. Impairment of Central Chemoreception in Neonatal Rats Induced by Maternal Cigarette Smoke Exposure during Pregnancy.

    PubMed

    Lei, Fang; Yan, Xiang; Zhao, Fusheng; Zhang, Senfeng; Zhang, Qilan; Zhou, Hua; Zheng, Yu

    2015-01-01

    It has been postulated that prenatal cigarette smoke exposure (CSE) increases the risk for sudden infant death syndrome. The victims of infant death syndrome suffer from respiratory abnormalities, such as central apnea, diminished chemoreflex and alteration in respiratory pattern during sleep. However, no experimental evidence on CSE model exists to confirm whether prenatal CSE gives rise to reduction of neonatal central chemoreception in in vitro preparations in absence of peripheral sensory feedback. The aim of the present study was to test the hypothesis that maternal CSE during pregnancy depresses central chemoreception of the neonatal rats. The pregnant rats were divided into two groups, control (n = 8) and CSE (n = 8). Experiments were performed on neonatal (0-3days) rat pups. Fictive respiratory activity was monitored by recording the rhythmic discharge from the hypoglossal rootlets of the medullary slices obtained from the neonatal rats. The burst frequency (BF) and integrated amplitude (IA) of the discharge were analyzed. Their responses to acidified artificial cerebrospinal fluid (aCSF) were tested to indicate the change of the central chemosensitivity. Under condition of perfusing with standard aCSF (pH 7.4), no significant difference was detected between the two groups in either BF or IA (P>0.05). Under condition of perfusing with acidified aCSF (pH 7.0), BF was increased and IA was decreased in both groups (P<0.01). However, their change rates in the CSE group were obviously smaller than that in the control group, 66.98 ± 10.11% vs. 143.75 ± 15.41% for BF and -22.38 ± 2.51% vs. -44.90 ± 3.92% for IA (P<0.01). In conclusion, these observations, in a prenatal CSE model, provide important evidence that maternal smoking during pregnancy exerts adverse effects on central chemoreception of neonates. PMID:26333001

  6. Testosterone potentiates the hypoxic ventilatory response of adult male rats subjected to neonatal stress.

    PubMed

    Fournier, Sébastien; Gulemetova, Roumiana; Joseph, Vincent; Kinkead, Richard

    2014-05-01

    Neonatal stress disrupts development of homeostatic systems. During adulthood, male rats subjected to neonatal maternal separation (NMS) are hypertensive and show a larger hypoxic ventilatory response (HVR), with greater respiratory instability during sleep. Neonatal stress also affects sex hormone secretion; hypoxia increases circulating testosterone of NMS (but not control) male rats. Given that these effects of NMS are not observed in females, we tested the hypothesis that testosterone elevation is necessary for the stress-related increase of the HVR in adult male rats. Pups subjected to NMS were placed in an incubator for 3 h per day from postnatal day 3 to 12. Control pups remained undisturbed. Rats were reared until adulthood, and the HVR was measured by plethysmography (fractional inspired O2 = 0.12, for 20 min). We used gonadectomy to evaluate the effects of reducing testosterone on the HVR. Gonadectomy had no effect on the HVR of control animals but reduced that of NMS animals below control levels. Immunohistochemistry was used to quantify androgen receptors in brainstem areas involved in the HVR. Androgen receptor expression was generally greater in NMS rats than in control rats; the most significant increase was noted in the caudal region of the nucleus tractus solitarii. We conclude that the abnormal regulation of testosterone is important in stress-related augmentation of the HVR. The greater number of androgen receptors within the brainstem may explain why NMS rats are more sensitive to testosterone withdrawal. Based on the similarities of the cardiorespiratory phenotype of NMS rats and patients suffering from sleep-disordered breathing, these results provide new insight into its pathophysiology, especially sex-based differences in its prevalence.

  7. Methanolic Extract of Ceplukan Leaf (Physalis minima L.) Attenuates Ventricular Fibrosis through Inhibition of TNF-α in Ovariectomized Rats

    PubMed Central

    Lestari, Bayu; Permatasari, Nur; Rohman, Mohammad Saifur

    2016-01-01

    The increase of heart failure prevalence on menopausal women was correlated with the decrease of estrogen level. The aim of this study is to investigate the effects of ceplukan leaf (Physalis minima L.), which contains phytoestrogen physalin and withanolides, on ventricular TNF-α level and fibrosis in ovariectomized rats. Wistar rats were divided into six groups (control (—); OVX 5: 5-week ovariectomy (OVX); OVX 9: 9-week ovariectomy; treatments I, II, and III: 9-weeks OVX + 4-week ceplukan leaf's methanolic extract doses 500, 1500, and 2500 mg/kgBW, resp.). TNF-α levels were measured with ELISA. Fibrosis was counted as blue colored tissues percentage using Masson's Trichrome staining. This study showed that prolonged hypoestrogen increases ventricular fibrosis (p < 0.05). Ceplukan leaf treatment also resulted in a decrease of ventricular fibrosis and TNF-α level in dose dependent manner compared to without treatment group (p < 0.05). Furthermore, the TNF-α level was normalized in 2500 mg/kgBW Physalis minima L. (p < 0.05) treatment. The reduction of fibrosis positively correlated with TNF-α level (p < 0.05, r = 0.873). Methanolic extract of ceplukan leaf decreases ventricular fibrosis through the inhibition of ventricular TNF-α level in ovariectomized rats. PMID:26941790

  8. Effects of neonatal methamphetamine treatment on adult stress-induced corticosterone release in rats.

    PubMed

    Grace, Curtis E; Schaefer, Tori L; Herring, Nicole R; Williams, Michael T; Vorhees, Charles V

    2012-01-01

    In rats, neonatal (+)-methamphetamine (MA) exposure and maternal separation stress increase corticosterone during treatment and result in learning and memory impairments later in life. Early-life stress also changes later responses to acute stress. We tested the hypothesis that neonatal MA exposure would alter adult corticosterone after acute stress or MA challenge. Rats were treated with MA (10 mg/kg × 4/day), saline, or handling on postnatal (P) days 11-15 or 11-20 (days that lead to learning and memory impairments at this dose). As adults, corticosterone was measured before and after 15 min forced swim (FS) or 15 min forced confinement (FC), counterbalanced, and after an acute MA challenge (10 mg/kg) given last. FS increased corticosterone more than FC; order and stress type interacted but did not interact with treatment; treatment interacted with FS but not with FC. In the P11-15 regimen, MA-treated rats showed more rapid increases in corticosterone after FS than controls. In the P11-20 regimen, MA-treated rats showed a trend toward more rapid decrease in corticosterone after FS. No differences were found after MA challenge. The data do not support the hypothesis that neonatal MA causes changes in adult stress responsiveness to FS, FC, or an acute MA challenge.

  9. Basic fibroblast growth factor protects against excitotoxicity and chemical hypoxia in both neonatal and adult rats.

    PubMed

    Kirschner, P B; Henshaw, R; Weise, J; Trubetskoy, V; Finklestein, S; Schulz, J B; Beal, M F

    1995-07-01

    Basic fibroblast growth factor (bFGF) is a polypeptide growth factor that promotes neuronal survival. We recently found that systemic administration of bFGF protects against both excitotoxicity and hypoxia-ischemia in neonatal animals. In the present study, we examined whether systemically administered bFGF could prevent neuronal death induced by intrastriatal injection of N-methyl-D-aspartate (NMDA) or chemical hypoxia induced by intrastriatal injection of malonate in adult rats and 1-methyl-4-phenylpyridinium (MPP+) in neonatal rats. Systemic administration of bFGF (100 micrograms/kg) for three doses both before and after intrastriatal injection of either NMDA or malonate in adult rats produced a significant neuroprotective effect. In neonatal rats, bFGF produced dose-dependent significant neuroprotective effects against MPP+ neurotoxicity, with a maximal protection of approximately 50% seen with either a single dose of bFGF of 300 micrograms/kg or three doses of 100 micrograms/kg. These results show that systemic administration of bFGF is effective in preventing neuronal injury under circumstances in which the blood-brain barrier may be compromised, raising the possibility that this strategy could be effective in stroke.

  10. Neonatal exposure to LPS leads to heightened exploratory activity in adolescent rats.

    PubMed

    Rico, Javier Leonardo Rodríguez; Ferraz, Denise Brufato; Ramalho-Pinto, Francisco Juarez; Morato, Silvio

    2010-12-20

    Although several reports have demonstrated physiological and behavioral changes in adult rats due to neonatal immune challenges, little is known about their effects in adolescence. Since neonatal exposure to lipopolysaccharide (LPS) alters the neural substrates involved in cognitive disorders, we tested the hypothesis that it may also alter the response to novel environments in adolescent rats. At 3 and 5 days of age, male Wistar rats received intraperitoneal injections of either vehicle solution or E. coli LPS (0.05mg/kg) or were left undisturbed. In the mid-adolescent period, between 40 and 46 days of age, the rats were exposed to the following behavioral tests: elevated plus-maze, open-field, novel-object exploration task, hole-board and the modified Porsolt forced swim test. The results showed that, in comparison with control animals, LPS-treated rats exhibited (1) less anxiety-related behaviors and enhanced patterns of locomotion and rearing in the plus-maze and the open-field tests, (2) high levels of exploration of both objects in the novel-object task and of corner and central holes in hole-board test, and (3) more time spent diving, an active behavior in the forced swim test. The present findings suggest that neonatal LPS exposure has long-lasting effects on the behavior profile adolescent rats exhibit in response to novelty. This behavioral pattern, characterized by heightened exploratory activity in novel environments, also suggests that early immune stimulation may contribute to the development of impulsive behavior in adolescent rats.

  11. Neonatal glucocorticoid treatment increased depression-like behaviour in adult rats.

    PubMed

    Ko, Meng-Chang; Hung, Yu-Hui; Ho, Pei-Yin; Yang, Yi-Ling; Lu, Kwok-Tung

    2014-12-01

    Synthetic glucocorticoid dexamethasone (DEX) is frequently used as a therapeutic agent to lessen the morbidity of chronic lung disease in premature infants. Previous studies suggested that neonatal DEX treatment altered brain development and cognitive function. It has been recognized that the amygdala is involved in emotional processes and also a critical site of neuronal plasticity for fear conditioning. Little is known about the possible long-term adverse effect of neonatal DEX treatment on amygdala function. The present study was aimed to evaluate the possible effect of neonatal DEX treatment on the synaptic function of amygdala in adult rats. Newborn Wistar rats were subjected to subcutaneous tapering-dose injections of DEX (0.5, 0.3 and 0.1 mg/kg) from post-natal day one to three, PN1-PN3. Animals were then subjected to a forced swimming test (FST) and electrophysiological recording aged eight weeks. The results of the FST showed neonatal DEX treatment increased depression-like behaviour in adulthood. After acute stress evoking, the percentage of time spent free floating is significantly increased in the DEX treated group compared with the control animals. Furthermore, neonatal DEX treatment elevated long-term potentiation (LTP) response and the phosphorylation level of MAPK in the lateral nucleus of amygdala (LA). Intracerebroventricular infusion of the MAPK inhibitor, PD98059, showed significant rescue effects including reduced depression-like behaviour and restoration of LTP to within normal range. In conclusion, our results suggested that MAPK signalling cascade in the LA plays an important role in the adverse effect of neonatal DEX treatment on amygdala function, which may result in adverse consequences in adult age, such as the enhancement of susceptibility for a depressive disorder in later life. PMID:24945924

  12. Alterations in cytochrome P-450 levels in adult rats following neonatal exposure to xenobiotics

    SciTech Connect

    Zangar, R.C. Pacific Northwest Laboratories, Richland, WA ); Springer, D.L. ); Buhler, D.R. )

    1993-01-01

    Neonatal exposure to certain xenobiotics has been shown to alter hepatic metabolism in adult rats in a manner that indicates long-term changes in enzyme regulation. Previously, the authors have observed changes in adult testosterone metabolism and in cytochrome P-450 (P-450) mRNA levels in animals neonatally exposed to phenobarbital (PB) or diethylstilbestrol (DES). In order to test for other enzyme alterations, they used Western blot procedures for specific P-450s to analyze hepatic microsomes from adult rats (24 wk old) that had been exposed neonatally to DES, PB, 7,12-dimethylbenz[a]anthracene (DMBA), or pregnenolone 16[alpha]-carbonitrile (PCN). The most striking effects were observed in the DES-treated males: P-4502C6 and an immunologically similar protein were increased 60 and 90%, respectively, relative to control values, but P-4503A2 was decreased by 44%. No changes were observed in the DES-treated males in levels of P-4502E1, P-4502B, or the male-specific P-4502C13. Adult males neonatally treated with PB had 150% increase in levels of anti-P4502B-reactive protein without significant changes in the other enzymes. The DES- and DMBA-treated females had increased levels of the female-specific P-4502C12 of 38 and 48%, respectively, but no other observed alterations. The results confirm that neonatal exposure to DES or PB can cause alterations in adult hepatic cytochrome P-450 levels but show that these chemicals act on different enzymes. Neonatal DMBA resulted in changes in adult females similar to those produced by the synthetic estrogen DES, but did so at about two-thirds lower dose. 37 refs., 5 figs.

  13. Neonatal Parathion Exposure Disrupts Serotonin and Dopamine Synaptic Function in Rat Brain Regions

    PubMed Central

    Slotkin, Theodore A.; Wrench, Nicola; Ryde, Ian T.; Lassiter, T. Leon; Levin, Edward D.; Seidler, Frederic J.

    2009-01-01

    The consequences of exposure to developmental neurotoxicants are influenced by environmental factors. In the present study, we examined the role of dietary fat intake. We administered parathion to neonatal rats and then evaluated whether a high-fat diet begun in adulthood could modulate the persistent effects on 5HT and DA systems. Neonatal rats received parathion on postnatal days 1-4 at 0.1 or 0.2 mg/kg/day, straddling the cholinesterase inhibition threshold. In adulthood, half the animals in each exposure group were given a high-fat diet for 8 weeks. We assessed 5HT and DA concentrations and turnover in brain regions containing their respective cell bodies and projections. In addition, we monitored 5HT1A and 5HT2 receptor binding and the concentration of 5HT presynaptic transporters. Neonatal parathion exposure evoked widespread increases in neurotransmitter turnover, indicative of presynaptic hyperactivity, further augmented by 5HT receptor upregulation. In control rats, consumption of a high-fat diet recapitulated many of the changes seen with neonatal parathion exposure; the effects represented convergent mechanisms, since the high-fat diet often obtunded further increases caused by parathion. Neonatal parathion exposure causes lasting hyperactivity of 5HT and DA systems accompanied by 5HT receptor upregulation, consistent with “miswiring” of neuronal projections. A high-fat diet obtunds the effect of parathion, in part by eliciting similar changes itself. Thus, dietary factors may produce similar synaptic changes as do developmental neurotoxicants, potentially contributing to the increasing incidence in neurodevelopmental disorders. PMID:19616088

  14. Impact of neonatal anoxia on adult rat hippocampal volume, neurogenesis and behavior.

    PubMed

    Takada, Silvia Honda; Motta-Teixeira, Lívia Clemente; Machado-Nils, Aline Vilar; Lee, Vitor Yonamine; Sampaio, Carlos Alberto; Polli, Roberson Saraiva; Malheiros, Jackeline Moraes; Takase, Luiz Fernando; Kihara, Alexandre Hiroaki; Covolan, Luciene; Xavier, Gilberto Fernando; Nogueira, Maria Inês

    2016-01-01

    Neonates that suffer oxygen deprivation during birth can have long lasting cognitive deficits, such as memory and learning impairments. Hippocampus, one of the main structures that participate in memory and learning processes, is a plastic and dynamic structure that conserves during life span the property of generating new cells which can become neurons, the so-called neurogenesis. The present study investigated whether a model of rat neonatal anoxia, that causes only respiratory distress, is able to alter the hippocampal volume, the neurogenesis rate and has functional implications in adult life. MRI analysis revealed significant hippocampal volume decrease in adult rats who had experienced neonatal anoxia compared to control animals for rostral, caudal and total hippocampus. In addition, these animals also had 55.7% decrease of double-labelled cells to BrdU and NeuN, reflecting a decrease in neurogenesis rate. Finally, behavioral analysis indicated that neonatal anoxia resulted in disruption of spatial working memory, similar to human condition, accompanied by an anxiogenic effect. The observed behavioral alterations caused by oxygen deprivation at birth might represent an outcome of the decreased hippocampal neurogenesis and volume, evidenced by immunohistochemistry and MRI analysis. Therefore, based on current findings we propose this model as suitable to explore new therapeutic approaches.

  15. Effects of neonatal handling on the basal forebrain cholinergic system of adult male and female rats.

    PubMed

    Pondiki, S; Stamatakis, A; Fragkouli, A; Philippidis, H; Stylianopoulou, F

    2006-10-13

    Neonatal handling is an early experience which results in improved function of the hypothalamic-pituitary-adrenal axis, increased adaptability and coping as a response to stress, as well as better cognitive abilities. In the present study, we investigated the effect of neonatal handling on the basal forebrain cholinergic system, since this system is known to play an important role in cognitive processes. We report that neonatal handling results in increased number of choline-acetyl transferase immunopositive cells in the septum/diagonal band, in both sexes, while no such effect was observed in the other cholinergic nuclei, such as the magnocellular preoptic nucleus and the nucleus basalis of Meynert. In addition, neonatal handling resulted in increased M1 and M2 muscarinic receptor binding sites in the cingulate and piriform cortex of both male and female rats. A handling-induced increase in M1 muscarinic receptor binding sites was also observed in the CA3 and CA4 (fields 3 and 4 of Ammon's horn) areas of the hippocampus. Furthermore, a handling-induced increase in acetylcholinesterase staining was found only in the hippocampus of females. Our results thus show that neonatal handling acts in a sexually dimorphic manner on one of the cholinergic parameters, and has a beneficial effect on BFCS function, which could be related to the more efficient and adaptive stress response and the superior cognitive abilities of handled animals.

  16. Caffeine in the neonatal period induces long-lasting changes in sleep and breathing in adult rats.

    PubMed

    Montandon, Gaspard; Horner, Richard L; Kinkead, Richard; Bairam, Aida

    2009-11-15

    Caffeine is commonly used clinically to treat apnoeas and unstable breathing associated with premature birth. Caffeine antagonizes adenosine receptors and acts as an efficient respiratory stimulant in neonates. Owing to its persistent effects on adenosine receptor expression in the brain, neonatal caffeine administration also has significant effects on maturation of the respiratory control system. However, since adenosine receptors are critically involved in sleep regulation, and sleep also modulates breathing, we tested the hypothesis that neonatal caffeine treatment disrupts regulation of sleep and breathing in the adult rat. Neonatal caffeine treatment (15 mg kg(-1) day(-1)) was administered from postnatal days 3-12. At adulthood (8-10 weeks old), sleep and breathing were measured with a telemetry system and whole-body plethysmography respectively. In adult rats treated with caffeine during the neonatal period, sleep time was reduced, sleep onset latency was increased, and non-rapid eye movement (non-REM) sleep was fragmented compared to controls. Ventilation at rest was higher in caffeine-treated adult rats compared to controls across sleep/wake states. Hypercapnic ventilatory responses were significantly reduced in caffeine-treated rats compared to control rats across sleep/wake states. Additional experiments in adult anaesthetized rats showed that at similar levels of arterial blood gases, phrenic nerve activity was enhanced in caffeine-treated rats. This study demonstrates that administration of caffeine in the neonatal period alters respiratory control system activity in awake and sleeping rats, as well as in the anaesthetized rats, and also has persistent disrupting effects on sleep that are apparent in adult rats.

  17. The Effects of Puerarin on Rat Ventricular Myocytes and the Potential Mechanism

    PubMed Central

    Xu, Hao; Zhao, Manxi; Liang, Shenghui; Huang, Quanshu; Xiao, Yunchuan; Ye, Liang; Wang, Qinyi; He, Longmei; Ma, Lanxiang; Zhang, Hua; Zhang, Li; Jiang, Hui; Ke, Xiao; Gu, Yuchun

    2016-01-01

    Puerarin, a known isoflavone, is commonly found as a Chinese herb medicine. It is widely used in China to treat cardiac diseases such as angina, cardiac infarction and arrhythmia. However, its cardioprotective mechanism remains unclear. In this study, puerarin significantly prolonged ventricular action potential duration (APD) with a dosage dependent manner in the micromolar range on isolated rat ventricular myocytes. However, submicromolar puerarin had no effect on resting membrane potential (RMP), action potential amplitude (APA) and maximal velocity of depolarization (Vmax) of action potential. Only above the concentration of 10 mM, puerarin exhibited more aggressive effect on action potential, and shifted RMP to the positive direction. Millimolar concentrations of puerarin significantly inhibited inward rectified K+ channels in a dosage dependent manner, and exhibited bigger effects upon Kir2.1 vs Kir2.3 in transfected HEK293 cells. As low as micromolar range concentrations of puerarin significantly inhibited Kv7.1 and IKs. These inhibitory effects may due to the direct inhibition of puerarin upon channels not via the PKA-dependent pathway. These results provided direct preclinical evidence that puerarin prolonged APD via its inhibitory effect upon Kv7.1 and IKs, contributing to a better understanding the mechanism of puerarin cardioprotection in the treatment of cardiovascular diseases. PMID:27762288

  18. Neural regulation of [3H]saxitoxin binding site numbers in rat neonatal muscle.

    PubMed Central

    Bambrick, L L; Gordon, T

    1988-01-01

    1. Neural regulation of the density of sodium (Na+) channels in rat muscle was studied by measuring specific binding of tritiated saxitoxin ([3H]STX) to muscles from rat hindlimbs during normal development and in rats in which neuromuscular function was interrupted by sciatic nerve section or neuromuscular blockade with botulinum toxin (BoTX). 2. The normal developmental increase in [3H]STX binding site numbers followed a simple exponential with a time constant of 12 days. The most rapid incorporation of channels coincided with the onset of accelerated muscle growth and increased neuromuscular activity at 2 weeks of age. 3. Elimination of neuromuscular activity retarded muscle growth and inhibited the normal incorporation of Na+ channels into neonatal muscle. Muscles denervation was more effective than BoTX paralysis: denervation at 2 weeks of age prevented the normal 3-fold increase in the binding site density between 2 and 3 weeks of age while age-matched BoTX-treated muscles incorporated an average of 66% of the normal Na+ channel incorporation. 4. Denervation and BoTX treatment were equally effective in reducing the numbers of [3H]STX binding sites in adult muscle. A reduction of 30% in binding sites brought the numbers to levels which corresponded with levels normally seen in muscles at 3 weeks of neonatal development. 5. It was concluded that the neural influence on incorporation of Na+ channels into membranes of neonatal muscle is, at least in part, mediated by neuromuscular activity. PMID:2855740

  19. Spinal tumors induced by neonatal administration of N-ethyl-N-nitrosourea in Wistar rats.

    PubMed

    Naito, M; Naito, Y; Ito, A

    1981-02-01

    The carcinogenic effect of N-ethyl-N-nitrosourea (ENU) administered by single neonatal injection (40 mg/kg) was examined in wistar rats. By 2 months after ENU administration, 30% of the examined animals had spinal cord tumors. After months all rats had neurogenic tumors, and the incidence of spinal tumor was as high as 86%. Spinal cord tumors were observed at all levels of the white matter of the spinal cord without any predilection site, though spinal root tumors were located exclusively on lumbosacral plexuses. Most of the spinal cord tumors were oligodedrogliomas or glioependymomas, whereas all the spinal root tumors were anaplastic schwannomas.

  20. The complex regulation of tanshinone IIA in rats with hypertension-induced left ventricular hypertrophy.

    PubMed

    Pang, Hui; Han, Bing; Yu, Tao; Peng, Zhen

    2014-01-01

    Tanshinone IIA has definite protective effects on various cardiovascular diseases. However, in hypertension-induced left ventricular hypertrophy (H-LVH), the signaling pathways of tanshinone IIA in inhibition of remodeling and cardiac dysfunction remain unclear. Two-kidney, one-clip induced hypertensive rats (n = 32) were randomized to receive tanshinone IIA (5, 10, 15 mg/kg per day) or 5% glucose injection (GS). Sham-operated rats (n = 8) received 5%GS as control. Cardiac function and dimensions were assessed by using an echocardiography system. Histological determination of the fibrosis and apoptosis was performed using hematoxylin eosin, Masson's trichrome and TUNEL staining. Matrix metalloproteinase 2 (MMP2) and tissue inhibitor of matrix metalloproteinases type 2 (TIMP2) protein expressions in rat myocardial tissues were detected by immunohistochemistry. Rat cardiomyocytes were isolated by a Langendorff perfusion method. After 48 h culture, the supernatant and cardiomyocytes were collected to determine the potential related proteins impact on cardiac fibrosis and apoptosis. Compared with the sham rats, the heart tissues of H-LVH (5%GS) group suffered severely from the oxidative damage, apoptosis of cardiomyocytes and extracellular matrix (ECM) deposition. In the H-LVH group, tanshinone IIA treated decreased malondialdehyde (MDA) content and increased superoxide dismutase (SOD) activity. Tanshinone IIA inhibited cardiomyocytes apoptosis as confirmed by the reduction of TUNEL positive cardiomyocytes and the down-regulation of Caspase-3 activity and Bax/Bcl-2 ratio. Meanwhile, plasma apelin level increased with down-regulation of APJ receptor. Tanshinone IIA suppressed cardiac fibrosis through regulating the paracrine factors released by cardiomyocytes and the TGF-β/Smads signaling pathway activity. In conclusion, our in vivo study showed that tanshinone IIA could improve heart function by enhancing myocardial contractility, inhibiting ECM deposition

  1. Pharmacological inhibition of IK1 by PA-6 in isolated rat hearts affects ventricular repolarization and refractoriness.

    PubMed

    Skarsfeldt, Mark A; Carstensen, Helena; Skibsbye, Lasse; Tang, Chuyi; Buhl, Rikke; Bentzen, Bo H; Jespersen, Thomas

    2016-04-01

    The inwardly rectifying potassium current (IK 1) conducted through Kir2.X channels contribute to repolarization of the cardiac action potential and to stabilization of the resting membrane potential in cardiomyocytes. Our aim was to investigate the effect of the recently discovered IK 1 inhibitor PA-6 on action potential repolarization and refractoriness in isolated rat hearts. Transiently transfected HEK-293 cells expressing IK 1 were voltage-clamped with ramp protocols. Langendorff-perfused heart experiments were performed on male Sprague-Dawley rats, effective refractory period, Wenckebach cycle length, and ventricular effective refractory period were determined following 200 nmol/L PA-6 perfusion. 200 nmol/L PA-6 resulted in a significant time-latency in drug effect on the IK 1 current expressed in HEK-293 cells, giving rise to a maximal effect at 20 min. In the Langendorff-perfused heart experiments, PA-6 prolonged the ventricular action potential duration at 90% repolarization (from 41.8 ± 6.5 msec to 72.6 ± 21.1 msec, 74% compared to baseline, P < 0.01, n = 6). In parallel, PA-6 significantly prolonged the ventricular effective refractory period compared to baseline (from 34.8 ± 4.6 msec to 58.1 ± 14.7 msec, 67%, P < 0.01, n = 6). PA-6 increased the short-term beat-to-beat variability and ventricular fibrillation was observed in two of six hearts. Neither atrial ERP nor duration of atrial fibrillation was altered following PA-6 application. The results show that pharmacological inhibition of cardiac IK 1 affects ventricular action potential repolarization and refractoriness and increases the risk of ventricular arrhythmia in isolated rat hearts. PMID:27117805

  2. Pharmacological inhibition of IK1 by PA-6 in isolated rat hearts affects ventricular repolarization and refractoriness.

    PubMed

    Skarsfeldt, Mark A; Carstensen, Helena; Skibsbye, Lasse; Tang, Chuyi; Buhl, Rikke; Bentzen, Bo H; Jespersen, Thomas

    2016-04-01

    The inwardly rectifying potassium current (IK 1) conducted through Kir2.X channels contribute to repolarization of the cardiac action potential and to stabilization of the resting membrane potential in cardiomyocytes. Our aim was to investigate the effect of the recently discovered IK 1 inhibitor PA-6 on action potential repolarization and refractoriness in isolated rat hearts. Transiently transfected HEK-293 cells expressing IK 1 were voltage-clamped with ramp protocols. Langendorff-perfused heart experiments were performed on male Sprague-Dawley rats, effective refractory period, Wenckebach cycle length, and ventricular effective refractory period were determined following 200 nmol/L PA-6 perfusion. 200 nmol/L PA-6 resulted in a significant time-latency in drug effect on the IK 1 current expressed in HEK-293 cells, giving rise to a maximal effect at 20 min. In the Langendorff-perfused heart experiments, PA-6 prolonged the ventricular action potential duration at 90% repolarization (from 41.8 ± 6.5 msec to 72.6 ± 21.1 msec, 74% compared to baseline, P < 0.01, n = 6). In parallel, PA-6 significantly prolonged the ventricular effective refractory period compared to baseline (from 34.8 ± 4.6 msec to 58.1 ± 14.7 msec, 67%, P < 0.01, n = 6). PA-6 increased the short-term beat-to-beat variability and ventricular fibrillation was observed in two of six hearts. Neither atrial ERP nor duration of atrial fibrillation was altered following PA-6 application. The results show that pharmacological inhibition of cardiac IK 1 affects ventricular action potential repolarization and refractoriness and increases the risk of ventricular arrhythmia in isolated rat hearts.

  3. Noradrenaline depletion blocks behavioral sparing and alters cortical morphogenesis after neonatal frontal cortex damage in rats.

    PubMed

    Kolb, B; Sutherland, R J

    1992-06-01

    The possibility that cortical noradrenaline (NA) is necessary for sparing of function that occurs after neonatal frontal cortex damage was examined. Spatial localization by rats with frontal cortex damage on postnatal day 7 (P7) was better than that by rats with similar damage sustained as adults. The sparing was abolished in rats depleted of cortical NA by means of neonatal 6-hydroxydopamine (6HDA) administration. The blockade of sparing in the P7 frontal operates was associated with a smaller brain, thinner cortex, and reduced cortical dendritic branching relative to saline-treated P7 frontal operates. NA depletion alone in unoperated rats did not affect spatial learning but did reduce brain size and dendritic branching. Rats with frontal lesions on P4 did not show sparing of spatial localization, and 6HDA administration had no additional behavioral effect. Overall, these data are consistent with the notion that NA has some general function in maintaining some forms of plasticity in posterior cortex. PMID:1607943

  4. γ/δ Cells in Fetal, Neonatal, and Adult Rat Lymphoid Organs

    PubMed Central

    Kühnlein, P.; Vicente, A.; Varas, A.; Hünig, T.

    1995-01-01

    In the present study, we have analyzed the appearance and maturation of γ/δ T cells, recognized with a new mAb V65, in the central and peripheral lymphoid organs of fetal, neonatal, and adult Wistar rats. Cytofluorometrical analysis demonstrated the first V65+ γ/δ T cells in the thymus of 16-17-day embryonic rats, although by immunohistology, they were identified only in 19-day rat embryos in both the cortico-medullary border and thymic medulla. Phenotypically, γ/δ thymocytes from fetal and neonatal thymus expressed CD3, CD2, and CD5, but only 60-80% were CD8+ and approximately 40-50% expressed the α chain (p55) of the IL-2R. In the periphery, the immunohistological study identified for the first time ,γ/δ T cells in the splenic white pulp and the gut of 21-day fetal rats, where they occurred within the epithelium as well as in the lamina propria. After birth, γ/δ lymphocytes appeared in the skin, where they were present as dendritic epidermal T cells in increasing numbers during postnatal life. Whereas these γ/δ T cells formed the predominant T-cell population in the rat skin, γ/δ T cells in peripheral lymphoid organs, BALT, or the gut only represented a minor T-cell population. These results are discussed in comparison to γ/δ T cells of other vertebrate species. PMID:8770557

  5. [SUSTENTOCYTE NUMBERS IN THE NEONATAL PERIOD IN THE OFFSPRING OF FEMALE RATS WITH EXPERIMENTAL LIVER DAMAGE].

    PubMed

    Briukhin, G V; Sizonenko, M L

    2016-01-01

    On serial histological sections of the testes, stained with hematoxylin-eosin, using a morphometric device, the total numbers of spermatogenic cells and sustentocytes (Sertoli cells) were measured in the convoluted seminiferous tubules of neonatal rat pups. Experimental groups consisted of rats born from females with experimental liver damage of various origins--autoimmune (n = 33), toxic (n = 32), alcoholic (n = 12), and medicinal (n = 27). The control group included pups born from normal female rats (n = 14). In experimental rats both increase and decrease of the total number of sustentocytes was detected. In the animals of most of the experimental groups, sustentocyte cell index reflecting the ratio of the number of spermatogenic cells and sustentocytes, was decreased. PMID:27487667

  6. Deferoxamine prevents cerebral glutathione and vitamin E depletions in asphyxiated neonatal rats: role of body temperature.

    PubMed

    Kletkiewicz, Hanna; Nowakowska, Anna; Siejka, Agnieszka; Mila-Kierzenkowska, Celestyna; Woźniak, Alina; Caputa, Michał; Rogalska, Justyna

    2016-01-01

    Hypoxic-ischaemic brain injury involves increased oxidative stress. In asphyxiated newborns iron deposited in the brain catalyses formation of reactive oxygen species. Glutathione (GSH) and vitamin E are key factors protecting cells against such agents. Our previous investigation has demonstrated that newborn rats, showing physiological low body temperature as well as their hyperthermic counterparts injected with deferoxamine (DF) are protected against iron-mediated, delayed neurotoxicity of perinatal asphyxia. Therefore, we decided to study the effects of body temperature and DF on the antioxidant status of the brain in rats exposed neonatally to critical anoxia. Two-day-old newborn rats were exposed to anoxia in 100% nitrogen atmosphere for 10 min. Rectal temperature was kept at 33 °C (physiological to rat neonates), or elevated to the level typical of healthy adult rats (37 °C), or of febrile adult rats (39 °C). Half of the rats exposed to anoxia under extremely hyperthermic conditions (39 °C) were injected with DF. Cerebral concentrations of malondialdehyde (MDA, lipid peroxidation marker) and the levels of GSH and vitamin E were determined post-mortem, (1) immediately after anoxia, (2) 3 days, (3) 7 days, and (4) 2 weeks after anoxia. There were no post-anoxic changes in MDA, GSH and vitamin E concentrations in newborn rats kept at body temperature of 33 °C. In contrast, perinatal anoxia at elevated body temperatures intensified oxidative stress and depleted the antioxidant pool in a temperature-dependent manner. Both the depletion of antioxidants and lipid peroxidation were prevented by post-anoxic DF injection. The data support the idea that hyperthermia may extend perinatal anoxia-induced brain lesions.

  7. Deferoxamine prevents cerebral glutathione and vitamin E depletions in asphyxiated neonatal rats: role of body temperature.

    PubMed

    Kletkiewicz, Hanna; Nowakowska, Anna; Siejka, Agnieszka; Mila-Kierzenkowska, Celestyna; Woźniak, Alina; Caputa, Michał; Rogalska, Justyna

    2016-01-01

    Hypoxic-ischaemic brain injury involves increased oxidative stress. In asphyxiated newborns iron deposited in the brain catalyses formation of reactive oxygen species. Glutathione (GSH) and vitamin E are key factors protecting cells against such agents. Our previous investigation has demonstrated that newborn rats, showing physiological low body temperature as well as their hyperthermic counterparts injected with deferoxamine (DF) are protected against iron-mediated, delayed neurotoxicity of perinatal asphyxia. Therefore, we decided to study the effects of body temperature and DF on the antioxidant status of the brain in rats exposed neonatally to critical anoxia. Two-day-old newborn rats were exposed to anoxia in 100% nitrogen atmosphere for 10 min. Rectal temperature was kept at 33 °C (physiological to rat neonates), or elevated to the level typical of healthy adult rats (37 °C), or of febrile adult rats (39 °C). Half of the rats exposed to anoxia under extremely hyperthermic conditions (39 °C) were injected with DF. Cerebral concentrations of malondialdehyde (MDA, lipid peroxidation marker) and the levels of GSH and vitamin E were determined post-mortem, (1) immediately after anoxia, (2) 3 days, (3) 7 days, and (4) 2 weeks after anoxia. There were no post-anoxic changes in MDA, GSH and vitamin E concentrations in newborn rats kept at body temperature of 33 °C. In contrast, perinatal anoxia at elevated body temperatures intensified oxidative stress and depleted the antioxidant pool in a temperature-dependent manner. Both the depletion of antioxidants and lipid peroxidation were prevented by post-anoxic DF injection. The data support the idea that hyperthermia may extend perinatal anoxia-induced brain lesions. PMID:26794834

  8. Effects of Sleep Deprivation on Action Potential and Transient Outward Potassium Current in Ventricular Myocytes in Rats

    PubMed Central

    Fang, Zhou; Ren, Yi-Peng; Lu, Cai-Yi; Li, Yang; Xu, Qiang; Peng, Li; Fan, Yong-Yan

    2015-01-01

    Background Sleep deprivation contributes to the development and recurrence of ventricular arrhythmias. However, the electrophysiological changes in ventricular myocytes in sleep deprivation are still unknown. Material/Methods Sleep deprivation was induced by modified multiple platform technique. Fifty rats were assigned to control and sleep deprivation 1, 3, 5, and 7 days groups, and single ventricular myocytes were enzymatically dissociated from rat hearts. Action potential duration (APD) and transient outward current (Ito) were recorded using whole-cell patch clamp technique. Results Compared with the control group, the phases of APD of ventricular myocytes in 3, 5, and 7 days groups were prolonged and APD at 20% and 50% level of repolarization (APD20 and APD50) was significantly elongated (The APD20 values of control, 1, 3, 5, and 7 days groups: 5.66±0.16 ms, 5.77±0.20 ms, 8.28±0.30 ms, 11.56±0.32 ms, 13.24±0.56 ms. The APD50 values: 50.66±2.16 ms, 52.77±3.20 ms, 65.28±5.30 ms, 83.56±7.32 ms, 89.24±5.56 ms. P<0.01, n=18). The current densities of Ito significantly decreased. The current density-voltage (I–V) curve of Ito was vitally suppressed downward. The steady-state inactivation curve and steady-state activation curve of Ito were shifted to left and right, respectively, in sleep deprivation rats. The inactivation recovery time of Ito was markedly retarded and the time of closed-state inactivation was markedly accelerated in 3, 5, and 7 days groups. Conclusions APD of ventricular myocytes in sleep deprivation rats was significantly prolonged, which could be attributed to decreased activation and accelerated inactivation of Ito. PMID:25694200

  9. PRENATAL WINDOW OF SUSCEPTIBILITY TO PERFLUOROOCTANE SULFONATE-INDUCED NEONATAL MORTALITY IN THE SPRAGUE-DAWLEY RAT

    EPA Science Inventory

    Abstract
    The critical period for increased neonatal mortality induced by PFOS exposure was evaluated in the rat . Timed-pregnant Sprague-Dawley rats were treated by oral gavage with 25 mg/kg/d PFOS/K+ on four consecutive days during gestation (gestation days (GD) 2-5, 6-9, 1...

  10. NEONATAL LOW- AND HIGH-DOSE EXPOSURE TO ESTRADIOL BENZOATE IN THE MALE RAT: I. EFFECTS ON THE PROSTATE GLAND

    EPA Science Inventory

    Neonatal Low- And High-Dose Exposure To Estradiol Benzoate In The Male Rat: 1. Effects On The Prostate Gland. Oliver Putz, Christian B. Schwartz, Steve Kim, Gerald A. LeBlanc Ralph L. Cooper, Gail S. Prins

    ABSTRACT
    Brief exposure of rats to high doses of natural estro...

  11. Latent inhibition in rats neonatally treated chronically with MK-801: differential effects on conditioned taste aversion and conditioned emotional response.

    PubMed

    Niikura, Ryo; Nozawa, Takashi; Yamada, Kazuo; Kato, Katsunori; Ichitani, Yukio

    2015-04-15

    Chronic neonatal blockade of N-methyl-d-aspartate (NMDA) receptors produces various abnormal behaviors in adulthood animals. This study investigated the effects of neonatal treatment chronically with MK-801 in rats on the preexposure-induced retardation of CS-US association, i.e. latent inhibition (LI), of two aversive classical conditioning tasks in adulthood. In conditioned taste aversion (CTA) using sucrose taste and LiCl, neonatal chronic MK-801 (0.4 mg/kg twice/day) treatment attenuated the inhibitory effect of sucrose preexposure on the aversive conditioning, although the treatment did not affect CTA conditioning itself. On the other hand, in conditioned emotional response (CER) using tone and electrical foot shock, rats neonatally treated with MK-801 showed the same degree of inhibitory effect of tone preexposure on the aversive conditioning compared with neonatally vehicle-treated rats, and also showed the same level of CER conditioning itself. Thus, the effect of chronic neonatal blockade of NMDA receptors on the LI of classical conditioning in adulthood was differentiated by the task employed. Results suggest that LI of CTA paradigm compared with that of CER is more sensitive to abnormal development after chronic neonatal blockade of NMDA receptors as an index of cognitive/attentional deficits caused by the treatment.

  12. Activity and Social Behavior in a Complex Environment in Rats Neonatally Exposed to Alcohol

    PubMed Central

    Boschen, Karen E.; Hamilton, Gillian F.; Delorme, James E.; Klintsova, Anna Y.

    2014-01-01

    Environmental complexity (EC) is a powerful, stimulating paradigm that engages animals through a variety of sensory and motor pathways. Exposure to EC (30 days) following 12 days of wheel running preserves hippocampal neuroplasticity in male rats neonatally exposed to alcohol during the third-trimester equivalent (binge-like exposure on postnatal days [PD] 4–9). The current experiment investigates the importance of various components of EC (physical activity, exploration, social interaction, novelty) and examines whether neonatal alcohol exposure affects how male rats interact with their environment and other male rats. Male pups were assigned to 1 of 3 neonatal conditions from PD 4–9: suckle control (SC), sham-intubated (SI), or alcohol-exposed (AE, 5.25 g/kg/day). From PD 30–42 animals were housed with 24-h access to a voluntary running wheel. The animals were then placed in EC from PD 42–72 (9 animals/cage, counterbalanced by neonatal condition). During EC, the animals were filmed for five 30-min sessions (PD 42, 48, 56, 64, 68). For the first experiment, the videos were coded for distance traveled in the cage, overall locomotor activity, time spent near other animals, and interaction with toys. For the second experiment, the videos were analyzed for wrestling, mounting, boxing, grooming, sniffing, and crawling over/under. AE animals were found to be less active and exploratory and engaged in fewer mounting behaviors compared to control animals. Results suggest that after exposure to wheel running, AE animals still have deficits in activity and social behaviors while housed in EC compared to control animals with the same experience. PMID:25150044

  13. Blood-brain barrier permeability is increased after acute adult stroke but not neonatal stroke in the rat.

    PubMed

    Fernández-López, David; Faustino, Joel; Daneman, Richard; Zhou, Lu; Lee, Sarah Y; Derugin, Nikita; Wendland, Michael F; Vexler, Zinaida S

    2012-07-11

    The immaturity of the CNS at birth greatly affects injury after stroke but the contribution of the blood-brain barrier (BBB) to the differential response to stroke in adults and neonates is poorly understood. We asked whether the structure and function of the BBB is disrupted differently in neonatal and adult rats by transient middle cerebral artery occlusion. In adult rats, albumin leakage into injured regions was markedly increased during 2-24 h reperfusion but leakage remained low in the neonates. Functional assays employing intravascular tracers in the neonates showed that BBB permeability to both large (70 kDa dextran) and small (3 kDa dextran), gadolinium (III)-diethyltriaminepentaacetic acid tracers remained largely undisturbed 24 h after reperfusion. The profoundly different functional integrity of the BBB was associated with the largely nonoverlapping patterns of regulated genes in endothelial cells purified from injured and uninjured adult and neonatal brain at 24 h (endothelial transcriptome, 31,042 total probe sets). Within significantly regulated 1266 probe sets in injured adults and 361 probe sets in neonates, changes in the gene expression of the basal lamina components, adhesion molecules, the tight junction protein occludin, and matrix metalloproteinase-9 were among the key differences. The protein expression of collagen-IV, laminin, claudin-5, occludin, and zonula occludens protein 1 was also better preserved in neonatal rats. Neutrophil infiltration remained low in acutely injured neonates but neutralization of cytokine-induced neutrophil chemoattractant-1 in the systemic circulation enhanced neutrophil infiltration, BBB permeability, and injury. The markedly more integrant BBB in neonatal brain than in adult brain after acute stroke may have major implications for the treatment of neonatal stroke. PMID:22787045

  14. The effect of exposure to hypergravity on pregnant rat dams, pregnancy outcome and early neonatal development

    NASA Astrophysics Data System (ADS)

    Ladd, B.; Nguon, K.; Sajdel-Sulkowska, E. M.

    2006-01-01

    We previously reported that hypergravity exposure affects food intake and mass gain during pregnancy. In the present study, we explored the hypothesis that changes in maternal body mass in hypergravity-exposed pregnant rat dams affect pregnancy outcome and early offspring development. Furthermore, we hypothesized that the changes observed at 1.5G will be magnified at higher gravity and by exposure during critical developmental periods. To test this hypothesis, we compared maternal body mass gain, food consumption, birth outcome and early offspring development between Sprague Dawley rat dams exposed to graded (1.5 1.75G) chronic hypergravity (HG) or rotation (rotational control, RC) on a 24-ft centrifuge for 22.5 h starting on gestational day (G) 10 with dams housed under identical conditions but not exposed to hypergravity (SC). We also compared maternal body mass, food consumption, birth outcome and early offspring development between rat dams exposed to 1.65G during different stages of pregnancy and nursing. Exposure to hypergravity resulted in transient loss in body mass and prolonged decrease in food consumption in HG dams, but the changes observed at 1.5G were not magnified at 1.65G or 1.75G. On the other hand RC dams gained more mass and consumed more food than SC dams. Exposure to hypergravity also affected pregnancy outcome as evidenced by decreased litter size, lowered neonatal mass at birth, and higher neonatal mortality; pregnancy outcome was not affected in RC dams. Neonatal changes evidenced by impaired righting response observed at 1.5G was magnified at higher gravity and was dependent on the period of hypergravity exposure. On the other hand, righting response was improved in RC neonates. Hypergravity exposure during early postpartum affected the food consumption of nursing mothers and affected early survival of their offspring. The changes observed in dams and neonates appear to be due to hypergravity exposure since animals exposed to the rotation

  15. The Physiologic Effects of Isoflurane, Sevoflurane, and Hypothermia Used for Anesthesia in Neonatal Rats (Rattus norvegicus)

    PubMed Central

    Huss, Monika K; Chum, Helen H; Chang, Angela G; Jampachairsi, Katechan; Pacharinsak, Cholawat

    2016-01-01

    Information regarding effective anesthetic regimens for neonatal rat pups is limited. Here we investigated whether isoflurane or sevoflurane anesthesia maintains physiologic parameters more consistently than does hypothermia anesthesia in neonatal rat pups. Rat pups (age, 4 d) were randomly assigned to receive isoflurane, sevoflurane, or hypothermia. Physiologic parameters monitored at 1, 5, 10, and 15 min included heart rate (HR), respiratory rate (RR), and oxygen saturation (%SpO2). Other parameters evaluated were loss and return of righting reflex, paw withdrawal reflex, and maternal acceptance. Corticosterone and glucose were sampled at 20 min and 24 h after anesthesia induction. Once a surgical plane of anesthesia was achieved, a skin incision was made on the right lateral thigh. After the procedure, all pups were accepted and cared for by their dam. Isoflurane- and sevoflurane-treated pups maintained higher HR, RR, %SpO2, and glucose levels than did hypothermia-treated pups. For both the isoflurane and sevoflurane groups, HR and RR were significantly lower at 10 and 15 min after anesthesia than at 1 min. Compared with hypothermia, isoflurane and sevoflurane anesthesia provided shorter times to loss of and return of the righting reflex. Although corticosterone did not differ among the groups, glucose levels were higher at 20 min after anesthesia induction than at 24 h in all anesthetic groups. We conclude that both isoflurane and sevoflurane anesthesia maintain physiologic parameters (HR, RR, %SpO2) more consistently than does hypothermia anesthesia in 4-d-old rat pups. PMID:26817984

  16. Environmental Enrichment Decreases Asphyxia-Induced Neurobehavioral Developmental Delay in Neonatal Rats

    PubMed Central

    Kiss, Peter; Vadasz, Gyongyver; Kiss-Illes, Blanka; Horvath, Gabor; Tamas, Andrea; Reglodi, Dora; Koppan, Miklos

    2013-01-01

    Perinatal asphyxia during delivery produces long-term disability and represents a major problem in neonatal and pediatric care. Numerous neuroprotective approaches have been described to decrease the effects of perinatal asphyxia. Enriched environment is a popular strategy to counteract nervous system injuries. The aim of the present study was to investigate whether enriched environment is able to decrease the asphyxia-induced neurobehavioral developmental delay in neonatal rats. Asphyxia was induced in ready-to-deliver mothers by removing the pups by caesarian section after 15 min of asphyxia. Somatic and neurobehavioral development was tested daily and motor coordination weekly. Our results show that rats undergoing perinatal asphyxia had a marked developmental delay and worse performance in motor coordination tests. However, pups kept in enriched environment showed a decrease in the developmental delay observed in control asphyctic pups. Rats growing up in enriched environment did not show decrease in weight gain after the first week and the delay in reflex appearance was not as marked as in control rats. In addition, the development of motor coordination was not as strikingly delayed as in the control group. Short-term neurofunctional outcome are known to correlate with long-term deficits. Our results thus show that enriched environment could be a powerful strategy to decrease the deleterious developmental effects of perinatal asphyxia. PMID:24232451

  17. Antihyperlipidemic potential of Cedrus deodara extracts in monosodium glutamate induced obesity in neonatal rats

    PubMed Central

    Patil, Sudhir; Prakash, T.; Kotresha, D.; Rao, N. Rama; Pandy, Naitik

    2011-01-01

    Objective: To study the antihyperlipidemic effect of Cedrus deodara (C. deodara) against monosodium glutamate (MSG) induced obesity in neonatal rats. Materials and Methods: The studies were carried out on newborn neonatal rats and were injected intraperitoneally with 2 mg/g of MSG on the 2nd and 4th postnatal days and 4 mg/g on 6th, 8th and 10th postnatal days. Ethanolic extract (EE) and acetone extract (AE) of C. deodara was administered in a dose of 100 and 200 mg/kg, p.o./day at the age of 65 days. On day 60 of treatment, body weight, locomotor activity, body temperature, and various biochemical parameters like serum glucose, total cholesterol, triglyceride, and organs weights were recorded. Results: There was a significant reduction in body weight, organs and increased body temperature, locomotor activity after treatment with extracts. C. deodara decreased serum glucose, total cholesterol and triglyceride, low density lipoprotein (LDL) and very low density lipoprotein (VLDL) levels and increased high density lipoprotein (HDL) significantly has compared to MSG-control rats. Conclusion: C. deodara extracts exhibited antihyperlipidemic effect and it possesses anti-obesity properties in MSG induced obese rats. PMID:22144766

  18. Retinol kinetics in unsupplemented and vitamin A-retinoic acid supplemented neonatal rats: a preliminary model

    PubMed Central

    Tan, Libo; Wray, Amanda E.; Green, Michael H.; Ross, A. Catharine

    2014-01-01

    Vitamin A (VA) metabolism in neonates is virtually uncharacterized. Our objective was to develop a compartmental model of VA metabolism in unsupplemented and VA-supplemented neonatal rats. On postnatal day 4, pups (n = 3/time) received 11,12-[3H]retinol orally, in either oil (control) or VA combined with retinoic acid (VARA) [VA (∼6 mg/kg body weight) + 10% retinoic acid]. Plasma and tissues were collected at 14 time points up to 14 days after dose administration. VARA supplementation rapidly, but transiently, increased total retinol mass in plasma, liver, and lung. It decreased the peak fraction of the dose in plasma. A multi-compartmental model developed to fit plasma [3H]retinol data predicted more extensive recycling of retinol between plasma and tissues in neonates compared with that reported in adults (144 vs. 12–13 times). In VARA pups, the recycling number for retinol between plasma and tissues (100 times) and the time that retinol spent in plasma were both lower compared with controls; VARA also stimulated the uptake of plasma VA into extravascular tissues. A VARA perturbation model indicated that the effect of VARA in stimulating VA uptake into tissues in neonates is both dramatic and transient. PMID:24711633

  19. Simvastatin ameliorates ventricular remodeling via the TGF-β1 signaling pathway in rats following myocardial infarction

    PubMed Central

    XIAO, XIANGBIN; CHANG, GUANGLEI; LIU, JIAN; SUN, GUANGYUN; LIU, LI; QIN, SHU; ZHANG, DONGYING

    2016-01-01

    Statins are widely used in patients with cardiovascular diseases. A considerable number of previous studies revealed that the intracellular signaling of transforming growth factor (TGF)-β1 mediated the development of cardiomyocyte hypertrophy and interstitial fibrosis. However, whether statins can ameliorate ventricular remodeling in post-myocardial infarction via the TGF-β1 signaling pathway remains to be rigorously tested. The left anterior descending artery was ligated to induce a rat model of myocardial infarction. The rat model of myocardial infarction was treated with simvastatin through gastric gavage (10, 20 or 40 mg kg−1·d−1). All rats were sacrificed on day 28 after the myocardial infarction operation. The results revealed that simvastatin significantly improved the hemodynamic indexes, left ventricular mass index, the myocardial tissue structure, the cardiomyocyte cross-sectional area and the collagen volume fraction, and also showed that the levels of TGF-β1, TGF-activated kinase (TAK)1 and drosophila mothers against decapentaplegic (Smad)3 were significantly reduced following treatment with simvastatin, while the levels of Smad7 in the simvastatin treatment groups were markedly increased. The results of the present study suggested that statins ameliorated ventricular remodeling in post-myocardial infarction rats via the TGF-β1 signaling pathway, which provided a novel explanation for the pleiotropic effects of statins that benefit the cardiovascular system. PMID:27121011

  20. Time course of myosin heavy chain transitions in neonatal rats: importance of innervation and thyroid state

    NASA Technical Reports Server (NTRS)

    Adams, G. R.; McCue, S. A.; Zeng, M.; Baldwin, K. M.

    1999-01-01

    During the postnatal period, rat limb muscles adapt to weight bearing via the replacement of embryonic (Emb) and neonatal (Neo) myosin heavy chains (MHCs) by the adult isoforms. Our aim was to characterize this transition in terms of the six MHC isoforms expressed in skeletal muscle and to determine the importance of innervation and thyroid hormone status on the attainment of the adult MHC phenotype. Neonatal rats were made hypothyroid via propylthiouracil (PTU) injection. In normal and PTU subgroups, leg muscles were unilaterally denervated at 15 days of age. The MHC profiles of plantaris (PLN) and soleus (Sol) muscles were determined at 7, 14, 23, and 30 days postpartum. At day 7, the Sol MHC profile was 55% type I, 30% Emb, and 10% Neo; in the PLN, the pattern was 60% Neo and 25% Emb. By day 30 the Sol and PLN had essentially attained an adult MHC profile in the controls. PTU augmented slow MHC expression in the Sol, whereas in the PLN it markedly repressed IIb MHC by retaining neonatal MHC expression. Denervation blunted the upregulation of IIb in the PLN and of Type I in the Sol and shifted the pattern to greater expression of IIa and IIx MHCs in both muscles. In contrast to previous observations, these findings collectively suggest that both an intact thyroid and innervation state are obligatory for the attainment of the adult MHC phenotype, particularly in fast-twitch muscles.

  1. Striatal GABA receptor alterations in hypoxic neonatal rats: role of glucose, oxygen and epinephrine treatment.

    PubMed

    Anju, T R; Binoy, J; Anitha, M; Paulose, C S

    2012-03-01

    Hypoxia in neonates disrupts the oxygen flow to the brain, essentially starving the brain and preventing it from performing vital biochemical processes important for central nervous system development. Hypoxia results in a permanent brain damage by gene and receptor level alterations mediated through neurotransmitters. The present study evaluated GABA, GABAA, GABAB receptor functions and gene expression changes in glutamate decarboxylase in the corpus striatum of hypoxic neonatal rats and the treatment groups with glucose, oxygen and epinephrine. Since GABA is the principal neurotransmitter involved in hypoxic ventilatory decline, the alterations in its level under hypoxic stress points to an important aspect of respiratory control. Following hypoxic stress, a significant decrease in total GABA, GABAA and GABAB receptors function and GAD expression was observed in the striatum, which accounts for the ventilator decline. Hypoxic rats treated with glucose alone and with oxygen showed a reversal of the receptor alterations and changes in GAD to near control. Being a source of immediate energy, glucose can reduce the ATP-depletion-induced changes in GABA and oxygenation helps in overcoming reduction in oxygen supply. Treatment with oxygen alone and epinephrine was not effective in reversing the altered receptor functions. Thus, our study point to the functional role of GABA receptors in mediating ventilatory response to hypoxia and the neuroprotective role of glucose treatment. This has immense significance in the proper management of neonatal hypoxia for a better intellect in the later stages of life.

  2. Neonatal anoxia in rats: hippocampal cellular and subcellular changes related to cell death and spatial memory.

    PubMed

    Takada, S H; dos Santos Haemmerle, C A; Motta-Teixeira, L C; Machado-Nils, A V; Lee, V Y; Takase, L F; Cruz-Rizzolo, R J; Kihara, A H; Xavier, G F; Watanabe, I-S; Nogueira, M I

    2015-01-22

    Neonatal anoxia in rodents has been used to understand brain changes and cognitive dysfunction following asphyxia. This study investigated the time-course of cellular and subcellular changes and hippocampal cell death in a non-invasive model of anoxia in neonatal rats, using Terminal deoxynucleotidyl transferase-mediated dUTP Nick End Labeling (TUNEL) to reveal DNA fragmentation, Fluoro-Jade® B (FJB) to show degenerating neurons, cleaved caspase-3 immunohistochemistry (IHC) to detect cells undergoing apoptosis, and transmission electron microscopy (TEM) to reveal fine ultrastructural changes related to cell death. Anoxia was induced by exposing postnatal day 1 (P1) pups to a flow of 100% gaseous nitrogen for 25 min in a chamber maintained at 37 °C. Control rats were similarly exposed to this chamber but with air flow instead of nitrogen. Brain changes following anoxia were evaluated at postnatal days 2, 14, 21 and 60 (P2, P14, P21 and P60). In addition, spatial reference memory following anoxia and control treatments was evaluated in the Morris water maze, starting at P60. Compared to their respective controls, P2 anoxic rats exhibited (1) higher TUNEL labeling in cornus ammonis (CA) 1 and the dentate gyrus (DG), (2) higher FJB-positive cells in the CA2-3, and (3) somato-dendritic swelling, mitochondrial injury and chromatin condensation in irregular bodies, as well as other subcellular features indicating apoptosis, necrosis, autophagy and excitotoxicity in the CA1, CA2-3 and DG, as revealed by TEM. At P14, P21 and P60, both groups showed small numbers of TUNEL-positive and FJB-positive cells. Stereological analysis at P2, P14, P21 and P60 revealed a lack of significant differences in cleaved caspase-3 IHC between anoxic and control subjects. These results suggest that the type of hippocampal cell death following neonatal anoxia is likely independent of caspase-3 activation. Neonatal anoxia induced deficits in acquisition and performance of spatial reference

  3. Neonatal anoxia in rats: hippocampal cellular and subcellular changes related to cell death and spatial memory.

    PubMed

    Takada, S H; dos Santos Haemmerle, C A; Motta-Teixeira, L C; Machado-Nils, A V; Lee, V Y; Takase, L F; Cruz-Rizzolo, R J; Kihara, A H; Xavier, G F; Watanabe, I-S; Nogueira, M I

    2015-01-22

    Neonatal anoxia in rodents has been used to understand brain changes and cognitive dysfunction following asphyxia. This study investigated the time-course of cellular and subcellular changes and hippocampal cell death in a non-invasive model of anoxia in neonatal rats, using Terminal deoxynucleotidyl transferase-mediated dUTP Nick End Labeling (TUNEL) to reveal DNA fragmentation, Fluoro-Jade® B (FJB) to show degenerating neurons, cleaved caspase-3 immunohistochemistry (IHC) to detect cells undergoing apoptosis, and transmission electron microscopy (TEM) to reveal fine ultrastructural changes related to cell death. Anoxia was induced by exposing postnatal day 1 (P1) pups to a flow of 100% gaseous nitrogen for 25 min in a chamber maintained at 37 °C. Control rats were similarly exposed to this chamber but with air flow instead of nitrogen. Brain changes following anoxia were evaluated at postnatal days 2, 14, 21 and 60 (P2, P14, P21 and P60). In addition, spatial reference memory following anoxia and control treatments was evaluated in the Morris water maze, starting at P60. Compared to their respective controls, P2 anoxic rats exhibited (1) higher TUNEL labeling in cornus ammonis (CA) 1 and the dentate gyrus (DG), (2) higher FJB-positive cells in the CA2-3, and (3) somato-dendritic swelling, mitochondrial injury and chromatin condensation in irregular bodies, as well as other subcellular features indicating apoptosis, necrosis, autophagy and excitotoxicity in the CA1, CA2-3 and DG, as revealed by TEM. At P14, P21 and P60, both groups showed small numbers of TUNEL-positive and FJB-positive cells. Stereological analysis at P2, P14, P21 and P60 revealed a lack of significant differences in cleaved caspase-3 IHC between anoxic and control subjects. These results suggest that the type of hippocampal cell death following neonatal anoxia is likely independent of caspase-3 activation. Neonatal anoxia induced deficits in acquisition and performance of spatial reference

  4. Tyrosine kinase inhibitor BIBF1000 does not hamper right ventricular pressure adaptation in rats.

    PubMed

    de Raaf, Michiel Alexander; Herrmann, Franziska Elena; Schalij, Ingrid; de Man, Frances S; Vonk-Noordegraaf, Anton; Guignabert, Christophe; Wollin, Lutz; Bogaard, Harm Jan

    2016-09-01

    BIBF1000 is a small molecule tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), and platelet-derived growth factor receptor (PDGFR) and is a powerful inhibitor of fibrogenesis. BIBF1000 is very similar to BIBF1120 (nintedanib), a drug recently approved for the treatment of idiopathic pulmonary fibrosis (IPF). A safety concern pertaining to VEGFR, FGFR, and PDGFR inhibition is the possible interference with right ventricular (RV) responses to an increased afterload, which could adversely affect clinical outcome in patients with IPF who developed pulmonary hypertension. We tested the effect of BIBF1000 on the adaptation of the RV in rats subjected to mechanical pressure overload. BIBF1000 was administered for 35 days in pulmonary artery-banded (PAB) rats. RV adaptation was assessed by echocardiography, pressure volume loop analysis, histology, and determination of atrial natriuretic peptide (ANP) expression. BIBF1000 treatment resulted in growth attenuation but had no effects on RV function after PAB, given absence of changes in cardiac index, end-systolic elastance, connective tissue disposition, and capillary density. We conclude that, in this experimental model of increased afterload, combined VEGFR, FGFR, and PDGFR inhibition does not hamper RV adaptation to pressure overload. PMID:27342880

  5. Development of insulation in neonatal cotton rats (Sigmodon hispidus)

    SciTech Connect

    McClure, P.A.; Porter, W.P.

    1983-01-01

    Data on environmental temperatures, skin temperature, animal size, the depth of fur, density of hairs in fur, hair length, and diameter of hair shafts were used to calculate fur thermal conductivity and heat loss, using a porous medium model modified for that of Kowalski and Mitchell. The total thermal conductivity of fur changed little with respect to the age of the animal, but calculated heat loss per unit area decreased because of a decrease in the thermal gradient across the fur caused by an increase in fur depth. A sensitivity analysis of the model showed that skin, air, and radiant environmental temperatures were most important in determining heat loss in all sizes of animals. Fur depth is the only important property of fur determining heat loss in nestling rats, but in adults, all the properties of fur exert significant effects on heat loss. The diameter of animals is a significant variable in all sizes of rats.

  6. Celecoxib attenuates systemic lipopolysaccharide-induced brain inflammation and white matter injury in the neonatal rats.

    PubMed

    Fan, L-W; Kaizaki, A; Tien, L-T; Pang, Y; Tanaka, S; Numazawa, S; Bhatt, A J; Cai, Z

    2013-06-14

    Lipopolysaccharide (LPS)-induced white matter injury in the neonatal rat brain is associated with inflammatory processes. Cyclooxygenase-2 (COX-2) can be induced by inflammatory stimuli, such as cytokines and pro-inflammatory molecules, suggesting that COX-2 may be considered as the target for anti-inflammation. The objective of the present study was to examine whether celecoxib, a selective COX-2 inhibitor, can reduce systemic LPS-induced brain inflammation and brain damage. Intraperitoneal (i.p.) injection of LPS (2mg/kg) was performed in postnatal day 5 (P5) of Sprague-Dawley rat pups and celecoxib (20mg/kg) or vehicle was administered i.p. 5 min after LPS injection. The body weight and wire-hanging maneuver test was performed 24h after the LPS exposure, and brain injury was examined after these tests. Systemic LPS exposure resulted in an impairment of behavioral performance and acute brain injury, as indicated by apoptotic death of oligodendrocytes (OLs) and loss of OL immunoreactivity in the neonatal rat brain. Treatments with celecoxib significantly reduced systemic LPS-induced neurobehavioral disturbance and brain damage. Celecoxib administration significantly attenuated systemic LPS-induced increments in the number of activated microglia and astrocytes, concentrations of IL-1β and TNFα, and protein levels of phosphorylated-p38 MAPK in the neonatal rat brain. The protection of celecoxib was also associated with a reduction of systemic LPS-induced COX-2+ cells which were double labeled with GFAP+ (astrocyte) cells. The overall results suggest that celecoxib was capable of attenuating the brain injury and neurobehavioral disturbance induced by systemic LPS exposure, and the protective effects are associated with its anti-inflammatory properties.

  7. Roles of thyroid hormones in follicular development in the ovary of neonatal and immature rats.

    PubMed

    Fedail, Jaafar Sulieman; Zheng, Kaizhi; Wei, Quanwei; Kong, Lingfa; Shi, Fangxiong

    2014-08-01

    Thyroid hormones (TH) play a critical role in ovarian follicular development, maturation and the maintenance of various endocrine functions. However, whether TH can affect ovarian follicular development in neonatal and immature rats remains unclear. Therefore, the aim of the present study was to elucidate the effect of TH on ovarian follicular development in neonatal and immature rats. Thirty female post-lactation mothers of Sprague-Dawley rat pups were randomly divided into three groups: control, hyperthyroid (hyper), and hypothyroid (hypo). On postnatal days (PND) 10 and 21, body weights, serum hormones, ovarian histologic changes, and immunohistochemistry of thyroid hormone receptor alpha 1 (TRα1) and nitric oxide synthase types (NOS), and NOS activities, were determined. The data showed that body weights significantly decreased in both hyper and hypo groups compared with the control group (P < 0.05). In addition, the hyper group had increased serum concentrations of T3, T4, and E2; whereas the hypo group manifested reduced serum concentrations of T3, T4, and E2 on PND 10 and 21. The hyper and hypo groups showed significantly reduced total number of primordial, primary and secondary follicles on PND 10 and 21 compared with the control group (P < 0.05). Similarly, antral follicle numbers in the hyper and hypo groups were significantly decreased on PND 21 compared with the control group (P < 0.05). Immunostaining indicated that TRα1 and NOS were expressed in ovarian surface epithelium and oocytes of growing and antral follicles, with strong staining of the granulosa and theca cells of follicles. NOS activities were significantly augmented in the hyper, but diminished in the hypo groups on PND 10 and 21. In summary, our findings suggest that TH play important roles in ovarian functions and in the regulation of NOS activity. Our results also indicate that a relationship exists between the TH and NO signaling pathways during the process of ovarian follicular

  8. Asiatic acid inhibits left ventricular remodeling and improves cardiac function in a rat model of myocardial infarction

    PubMed Central

    HUO, LIANYING; SHI, WENBING; CHONG, LING; WANG, JINLONG; ZHANG, KAI; LI, YUFENG

    2016-01-01

    Left ventricular remodeling results in cardiac dysfunction and accounts for the majority of the morbidity and mortality following myocardial infarction (MI). The aim of the present study was to investigate the effect of asiatic acid (AA) on cardiac function and left ventricular remodeling in a rat model of MI and explore the underlying mechanisms. Rats were subjected to coronary artery ligation to model MI and orally treated with AA. After 4 weeks, cardiac function was assessed by echocardiography. Cardiomyocyte cross-sectional area was recorded, and the expression levels of a number of inflammatory cytokines were detected using ELISA. The degree of interstitial fibrosis was determined by evaluating the mRNA expression levels of collagen II and III. Western blot analysis was performed to detect the expression levels of total and phosphorylated p38 MAPK and ERK1/2, to investigate whether they are involved in the mechanism underlying the effect of AA on the heart. Rats subjected to MI displayed significantly impaired cardiac function compared with those subjected to a sham procedure, while this change was reversed by treatment with AA. Furthermore, AA markedly inhibited cardiac hypertrophy, reduced the mRNA expression levels of inflammatory cytokines and decreased interstitial fibrosis in the infarct border zone of MI model rats compared with those in vehicle-treated MI model rats. Furthermore, the phosphorylation of p38 MAPK and ERK1/2 was blocked by AA in the MI rats but not in the sham rats. In summary, AA treatment preserved cardiac function and inhibited left ventricular remodeling, potentially by blocking the phosphorylation of p38 MAPK and ERK1/2 in the infarct border zone of the ischemic myocardium, indicating that AA may be a novel candidate for development as a therapy for MI. PMID:26889217

  9. Early environmental enrichment affects neurobehavioral development and prevents brain damage in rats submitted to neonatal hypoxia-ischemia.

    PubMed

    Schuch, Clarissa Pedrini; Diaz, Ramiro; Deckmann, Iohanna; Rojas, Joseane Jiménez; Deniz, Bruna Ferrary; Pereira, Lenir Orlandi

    2016-03-23

    Our previous results demonstrated improved cognition in adolescent rats housed in environmental enrichment (EE) that underwent neonatal hypoxia-ischemia (HI). The aim of this study was to investigate the effects of early EE on neurobehavioral development and brain damage in rats submitted to neonatal HI. Wistar rats were submitted to the HI procedure on the 7th postnatal day (PND) and housed in an enriched environment (8th-20th PND). The maturation of physical characteristics and the neurological reflexes were evaluated and the volume of striatum, corpus callosum and neocortex was measured. Data analysis demonstrated a clear effect of EE on neurobehavioral development; also, daily performance was improved in enriched rats on righting, negative geotaxis and cliff aversion reflex. HI caused a transient motor deficit on gait latency. Brain atrophy was found in HI animals and this damage was partially prevented by the EE. In conclusion, early EE stimulated neurobehavioral development in neonate rats and also protects the neocortex and the corpus callosum from atrophy following HI. These findings reinforce the potential of EE as a strategy for rehabilitation following neonatal HI and provide scientific support to the use of this therapeutic strategy in the treatment of neonatal brain injuries in humans. PMID:26872850

  10. Early environmental enrichment affects neurobehavioral development and prevents brain damage in rats submitted to neonatal hypoxia-ischemia.

    PubMed

    Schuch, Clarissa Pedrini; Diaz, Ramiro; Deckmann, Iohanna; Rojas, Joseane Jiménez; Deniz, Bruna Ferrary; Pereira, Lenir Orlandi

    2016-03-23

    Our previous results demonstrated improved cognition in adolescent rats housed in environmental enrichment (EE) that underwent neonatal hypoxia-ischemia (HI). The aim of this study was to investigate the effects of early EE on neurobehavioral development and brain damage in rats submitted to neonatal HI. Wistar rats were submitted to the HI procedure on the 7th postnatal day (PND) and housed in an enriched environment (8th-20th PND). The maturation of physical characteristics and the neurological reflexes were evaluated and the volume of striatum, corpus callosum and neocortex was measured. Data analysis demonstrated a clear effect of EE on neurobehavioral development; also, daily performance was improved in enriched rats on righting, negative geotaxis and cliff aversion reflex. HI caused a transient motor deficit on gait latency. Brain atrophy was found in HI animals and this damage was partially prevented by the EE. In conclusion, early EE stimulated neurobehavioral development in neonate rats and also protects the neocortex and the corpus callosum from atrophy following HI. These findings reinforce the potential of EE as a strategy for rehabilitation following neonatal HI and provide scientific support to the use of this therapeutic strategy in the treatment of neonatal brain injuries in humans.

  11. Dependence of normal development of skeletal muscle in neonatal rats on load bearing

    NASA Technical Reports Server (NTRS)

    Ohira, Y.; Tanaka, T.; Yoshinaga, T.; Kawano, F.; Nomura, T.; Nonaka, I.; Allen, D. L.; Roy, R. R.; Edgerton, V. R.

    2000-01-01

    Antigravity function plays an important role in determining the morphological and physiological properties of the neuromuscular system. Inhibition of the normal development of the neuromuscular system is induced by hindlimb unloading during the neonatal period in rats. However, the role of gravitational loading on the development of skeletal muscle in rats is not well understood. It could be hypothesized that during the early postnatal period, i.e. when minimal weight-supporting activity occurs, the activity imposed by gravity would be of little consequence in directing the normal development of the skeletal musculature. We have addressed this issue by limiting the amount of postnatal weight-support activity of the hindlimbs of rats during the lactation period. We have focused on the development of three characteristics of the muscle fibers, i.e. size, myonuclear number and myosin heavy chain expression.

  12. Methylxanthine reversal of opioid-induced respiratory depression in the neonatal rat: mechanism and location of action.

    PubMed

    Mosca, E V; Ciechanski, P; Roy, A; Scheibli, E C; Ballanyi, K; Wilson, R J A

    2014-08-15

    Methylxanthines like caffeine and theophylline have long been used to treat apnea of prematurity. Despite their success in stimulating neonatal breathing, their mechanism of action remains poorly understood. Methylxanthines can act as both non-specific adenosine receptor antagonists and inhibitors of cAMP-dependent phosphodiesterases, sarcoplasmic/endoplasmic reticulum calcium ATPases or receptor-coupled anion channels, depending on the dose used. Though there is evidence for methylxanthine action at the level of the carotid body, the consensus is that methylxanthines stimulate the respiratory centers of the brainstem. Here we used the in situ neonatal rat working heart-brainstem preparation and the ex vivo neonatal rat carotid body preparation to test the hypothesis that methylxanthines act at the level of the carotid body. We conclude that although the neonatal carotid body has active adenosine receptors, the effects of methylxanthine therapy are likely mediated centrally, predominantly via inhibition of cAMP-dependent phosphodiesterase-4. PMID:24914466

  13. Intrauterine endotoxin-induced impairs pulmonary vascular function and right ventricular performance in infant rats and improvement with early vitamin D therapy.

    PubMed

    Mandell, Erica; Powers, Kyle N; Harral, Julie W; Seedorf, Gregory J; Hunter, Kendall S; Abman, Steven H; Dodson, R Blair

    2015-12-15

    High pulmonary vascular resistance (PVR), proximal pulmonary artery (PA) impedance, and right ventricular (RV) afterload due to remodeling contribute to the pathogenesis and severity of pulmonary hypertension (PH). Intra-amniotic exposure to endotoxin (ETX) causes sustained PH and high mortality in rat pups at birth, which are associated with impaired vascular growth and RV hypertrophy in survivors. Treatment of ETX-exposed pups with antenatal vitamin D (vit D) improves survival and lung growth, but the effects of ETX exposure on RV-PA coupling in the neonatal lung are unknown. We hypothesized that intrauterine ETX impairs RV-PA coupling through sustained abnormalities of PA stiffening and RV performance that are attenuated with vit D therapy. Fetal rats were exposed to intra-amniotic injections of ETX, ETX+vit D, or saline at 20 days gestation (term = 22 days). At postnatal day 14, pups had pressure-volume measurements of the RV and isolated proximal PA, respectively. Lung homogenates were assayed for extracellular matrix (ECM) composition by Western blot. We found that ETX lungs contain decreased α-elastin, lysyl oxidase, collagen I, and collagen III proteins (P < 0.05) compared control and ETX+vit D lungs. ETX-exposed animals have increased RV mechanical stroke work (P < 0.05 vs. control and ETX+vit D) and elastic potential energy (P < 0.05 vs. control and ETX+vit D). Mechanical stiffness and ECM remodeling are increased in the PA (P < 0.05 vs. control and ETX+vit D). We conclude that intrauterine exposure of fetal rats to ETX during late gestation causes persistent impairment of RV-PA coupling throughout infancy that can be prevented with early vit D treatment.

  14. Intrauterine endotoxin-induced impairs pulmonary vascular function and right ventricular performance in infant rats and improvement with early vitamin D therapy.

    PubMed

    Mandell, Erica; Powers, Kyle N; Harral, Julie W; Seedorf, Gregory J; Hunter, Kendall S; Abman, Steven H; Dodson, R Blair

    2015-12-15

    High pulmonary vascular resistance (PVR), proximal pulmonary artery (PA) impedance, and right ventricular (RV) afterload due to remodeling contribute to the pathogenesis and severity of pulmonary hypertension (PH). Intra-amniotic exposure to endotoxin (ETX) causes sustained PH and high mortality in rat pups at birth, which are associated with impaired vascular growth and RV hypertrophy in survivors. Treatment of ETX-exposed pups with antenatal vitamin D (vit D) improves survival and lung growth, but the effects of ETX exposure on RV-PA coupling in the neonatal lung are unknown. We hypothesized that intrauterine ETX impairs RV-PA coupling through sustained abnormalities of PA stiffening and RV performance that are attenuated with vit D therapy. Fetal rats were exposed to intra-amniotic injections of ETX, ETX+vit D, or saline at 20 days gestation (term = 22 days). At postnatal day 14, pups had pressure-volume measurements of the RV and isolated proximal PA, respectively. Lung homogenates were assayed for extracellular matrix (ECM) composition by Western blot. We found that ETX lungs contain decreased α-elastin, lysyl oxidase, collagen I, and collagen III proteins (P < 0.05) compared control and ETX+vit D lungs. ETX-exposed animals have increased RV mechanical stroke work (P < 0.05 vs. control and ETX+vit D) and elastic potential energy (P < 0.05 vs. control and ETX+vit D). Mechanical stiffness and ECM remodeling are increased in the PA (P < 0.05 vs. control and ETX+vit D). We conclude that intrauterine exposure of fetal rats to ETX during late gestation causes persistent impairment of RV-PA coupling throughout infancy that can be prevented with early vit D treatment. PMID:26475735

  15. Predicting sensorimotor and memory deficits after neonatal ischemic stroke with reperfusion in the rat.

    PubMed

    Bouet, Valentine; Freret, Thomas; Ankri, Steve; Bezault, Madeleine; Renolleau, Sylvain; Boulouard, Michel; Jacotot, Etienne; Chauvier, David; Schumann-Bard, Pascale

    2010-09-01

    Among experimental models of perinatal ischemic stroke, Renolleau's model mimics selected types of stroke at birth, including ischemia and reperfusion. However, its behavioural consequences on development have been poorly described. Here, ischemia-reperfusion was performed in 7-day-old Wistar rats. Between the ages of 9 and 40 days, sensorimotor and memory functions were assessed. The infarcted area was analysed by immunohistochemistry at 40 days of age. The remaining lesion was in the parietal cortex, in the form of a cone-shaped area. This area contained glial cells but neither neurons nor macrophages. Transient focal neonatal ischemia led to sensorimotor alterations in early adulthood, such as postural asymmetry, motor coordination and somatosensory deficits, and hyperactivity, as well as cognitive impairments, such as spatial reference memory deficits. Based on these results, we propose here a selection of behavioural tests that should constitute meaningful tools for assessing sensory and cognitive functions after experimental neonatal ischemic stroke.

  16. [Evaluation of a long-term sensomotor deficit after neonatal rat brain ischemia/hypoxia].

    PubMed

    Silachev, D N; Shubina, M I; Iankauskas, S S; Mkrtchian, V P; Manskikh, V N; Guliaev, M V; Zorov, D B

    2013-01-01

    The application of magnetic resonance imaging method showed that ischemia/hypoxia of the brain of neonatal rats made by the protocol suggested by Levine-Rice induces one-sided lesions in the areas of cerebral cortex, striatum and hippocampus. Unilateral ischemic injury leads to a long-term sensorimotor and behavioral distortions within 90-115 days after the operation which has been tested in animals by the battery of tests including Cylinder, Beam-walking, Staircase and Limb-placing test. Chosen battery of tests in combination with magnetic resonance imaging allows to reliably estimate the long-term sensorimotor recovery in adult animals suffered an injury in neonatal age. PMID:24450172

  17. Neonatally induced mild diabetes: influence on development, behavior and reproductive function of female Wistar rats

    PubMed Central

    2013-01-01

    Background Neonatal STZ treatment induces a state of mild hyperglycemia in adult rats that disrupts metabolism and maternal/fetal interactions. The aim of this study was investigate the effect of neonatal STZ treatment on the physical development, behavior, and reproductive function of female Wistar rats from infancy to adulthood. Methods At birth, litters were assigned either to a Control (subcutaneous (s.c.) citrate buffer, n = 10) or STZ group, (streptozotocin (STZ) - 100 mg/kg-sc, n = 6). Blood glucose levels were measured on postnatal days (PND) 35, 84 and 120. In Experiment 1 body weight, length and the appearance of developmental milestones such as eye and vaginal opening were monitored. To assess the relative contribution of the initial and long term effects of STZ treatment this group was subdivided based on blood glucose levels recorded on PND 120: STZ hyperglycemic (between 120 and 300 mg/dl) and STZ normoglycemic (under 120 mg/dl). Behavioral activity was assessed in an open field on PND 21 and 75. In Experiment 2 estrous cyclicity, sexual behavior and circulating gonadotropin, ovarian steroid, and insulin levels were compared between control and STZ-hyperglycemic rats. In all measures the litter was the experimental unit. Parametric data were analyzed using one-way or, where appropriate, two-way ANOVA and significant effects were investigated using Tukey’s post hoc test. Fisher’s exact test was employed when data did not satisfy the assumption of normality e.g. presence of urine and fecal boli on the open field between groups. Statistical significance was set at p < 0.05 for all data. Results As expected neonatal STZ treatment caused hyperglycemia and hypoinsulinemia in adulthood. STZ-treated pups also showed a temporary reduction in growth rate that probably reflected the early loss of circulating insulin. Hyperglycemic rats also exhibited a reduction in locomotor and exploratory behavior in the open field. Mild hyperglycemia did

  18. Differential metal content and gene expression in rat left ventricular hypertrophy due to hypertension and hyperactivity.

    PubMed

    Subramanian, Meenakumari; Hunt, Adam L; Petrucci, Giuseppe A; Chen, Zengyi; Hendley, Edith D; Palmer, Bradley M

    2014-07-01

    The spontaneously hypertensive rat (SHR) has been studied extensively as a model of left ventricular hypertrophy (LVH) and associated cardiac dysfunction due to hypertension (HT). The SHR also possesses a hyperactive trait (HA). Crossbreeding SHR with Wistar-Kyoto (WKY) control rats, which are nonHT and nonHA, followed by selected inbreeding produced two additional homozygous strains: WKHT and WKHA, in which the traits of HT and HA, respectively, are expressed separately. WKHT, WKHA and SHR all display LVH, but only the SHR exhibits cardiac dysfunction. We hypothesized that cardiac dysfunction in the SHR is uniquely characterized by calcium overload. We measured total cardiac Ca, Cu, Fe, K, Mg and Zn in the four strains. We found elevated Ca and depressed Cu, Mg and Zn with HT, but not unique to SHR. We surmise that HT promotes aberrant regulation of cardiac Ca(2+), Cu(2+), Mg(2+) and Zn(2+), which does not necessarily result in cardiac dysfunction. Interestingly, Cu was elevated in HA strains compared to nonHA counterparts. We then analyzed gene expression as mRNA of Cu-containing proteins, most notably mitochondrial-Cox, Dbh, Lox, Loxl1, Loxl2, Sod1 and Tyr. The gene expression profiles of Lox, Loxl1, Loxl2 and Sod1 were found especially high in the WKHA, which if reflective of protein content could account for the high Cu content in the WKHA. The mRNA of other genes, notably Mb, Fxyd1, Maoa and Maob were also examined. We found that Maoa gene expression and monoamine oxidase-A (MAO-A) protein content were low in the SHR compared to the other strains. The finding that MAO-A protein is low in the SHR and normal in the WKHT and WKHA strains is most consistent with the idea that MAO-A protects against the development of cardiac dysfunction in LVH but not against LVH in these rats.

  19. Neonatal handling causes impulsive behavior and decreased pharmacological response to methylphenidate in male adult wistar rats.

    PubMed

    Lazzaretti, Camilla; Kincheski, Grasielle Clotildes; Pandolfo, Pablo; Krolow, Rachel; Toniazzo, Ana Paula; Arcego, Danusa Mar; Couto-Pereira, Natividade de Sá; Zeidán-Chuliá, Fares; Galvalisi, Martin; Costa, Gustavo; Scorza, Cecilia; Souza, Tadeu Mello E; Dalmaz, Carla

    2016-03-01

    Neonatal handling has an impact on adult behavior of experimental animals and is associated with rapid and increased palatable food ingestion, impaired behavioral flexibility, and fearless behavior to novel environments. These symptoms are characteristic features of impulsive trait, being controlled by the medial prefrontal cortex (mPFC). Impulsive behavior is a key component of many psychiatric disorders such as attention deficit hyperactivity disorder (ADHD), manic behavior, and schizophrenia. Others have reported a methylphenidate (MPH)-induced enhancement of mPFC functioning and improvements in behavioral core symptoms of ADHD patients. The aims of the present study were: (i) to find in vivo evidence for an association between neonatal handling and the development of impulsive behavior in adult Wistar rats and (ii) to test whether neonatal handling could have an impact on monoamine levels in the mPFC and the pharmacological response to MPH in vivo. Therefore, experimental animals (litters) were classified as: "non-handled" and "handled" (10[Formula: see text]min/day, postnatal days 1-10). After puberty, they were exposed to either a larger and delayed or smaller and immediate reward (tolerance to delay of reward task). Acute MPH (3[Formula: see text]mg/Kg. i.p.) was used to suppress and/or regulate impulsive behavior. Our results show that only neonatally handled male adult Wistar rats exhibit impulsive behavior with no significant differences in monoamine levels in the medial prefrontal cortex, together with a decreased response to MPH. On this basis, we postulate that early life interventions may have long-term effects on inhibitory control mechanisms and affect the later response to pharmacological agents during adulthood.

  20. Effect of maternal ethanol consumption on foetal and neonatal rat hepatic protein synthesis.

    PubMed Central

    Rawat, A K

    1976-01-01

    Effects of maternal ethanol consumption were investigated on the rates of protein synthehsis by livers of foetal and neonatal rats both in vivo and in vitro, and on the activities of enzymes involved in protein synthesis and degradation. The rates of general protein synthesis by ribosomes in vitro studied by measuring the incorporation of [14C]leucine into ribosomal protein showed that maternal ethanol consumption resulted in an inhibition of the rates of protein synthesis by both foetal and neonatal livers from the ethanol-fed group. The rates of incorporation of intravenously injected [14C]leucine into hepatic proteins were also significantly lower in the foetal, neonatal and adult livers from the ethanol-fed group. Incubation of adult-rat liver slices with ethanol resulted in an inhibition of the incorporation of [14C]leucine into hepatic proteins; however, this effect was not observed in the foetal liver slices. This effect of externally added ethanol was at least partially prevented by the addition of pyrazole to the adult liver slices. Pyrazole addition to foetal liver slices was without significant effect on the rates of protein synthesis. Cross-mixing experiments showed that the capacity of both hepatic ribosomes and pH5 enzyme fractions to synthesize proteins was decreased in the foetal liver from the ethanol-fed group. Maternal ethanol consumption resulted in a decrease in hepatic total RNA content, RNA/DNA ratio and ribosomal protein content in the foetal liver. Foetal hepatic DNA content was not significantly affected. Ethanol consumption resulted in a significant decrease in proteolytic activity and the activity of tryptophan oxygenase in the foetal, neonatal and adult livers. It is possible that the mechanisms of inhibition of protein synthesis observed here in the foetal liver after maternal ethanol consumption may be responsible for at least some of the changes observed in 'foetal alcohol syndrome'. PMID:1016246

  1. Neonatal inflammation and primary afferent terminal plasticity in the rat dorsal horn.

    PubMed

    Walker, Suellen M; Meredith-Middleton, Jacqueta; Cooke-Yarborough, Claire; Fitzgerald, Maria

    2003-09-01

    Abnormal or excessive activity related to pain and injury in early life may alter normal synaptic development and lead to changes in somatosensory processing. The aim of the current study was to define the critical factors that determine long-term plasticity in spinal cord afferent terminals following neonatal inflammation. Hindpaw inflammation was produced in neonatal rat pups with 5 or 25 microl 2% carrageenan, and 5 or 25 microl complete Freund's adjuvant (CFA). All groups displayed a clear inflammatory response that recovered in 2 weeks in all but the 25 microl CFA group, who had persistent chronic inflammation confirmed by histological examination of the paw at 8 weeks. The 25 microl CFA group was also the only group that displayed a significant expansion of the sciatic and saphenous nerve terminal field in lamina II of the dorsal horn at 8 weeks, using wheat-germ agglutinin-horse radish peroxidase transganglionic labelling. This effect was not accompanied by changes in dorsal root ganglion (DRG) cell number, expression of activating transcription factor 3 (ATF3), or alterations in calcitonin gene related peptide (CGRP) or isolectin B4 binding; and was not mimicked by partial nerve damage. No long-term change in mechanical or thermal behavioural sensory thresholds was seen in any group. Lower dose CFA caused an acute, reversible expansion of terminal fields in lamina II in neonatal animals, while CFA did not produce this effect in adults. The duration and effect of neonatal inflammation is therefore dependent on the type and volume of inflammatory agent used. The expansion of afferent terminals in lamina II following neonatal CFA inflammation is maintained into adulthood if the inflammation is also maintained, as seen following 25 microl CFA. This effect is not seen in adult animals, emphasising the plasticity of the nervous system early in development.

  2. Long Term Hippocampal and Cortical Changes Induced by Maternal Deprivation and Neonatal Leptin Treatment in Male and Female Rats.

    PubMed

    Mela, Virginia; Díaz, Francisca; Borcel, Erika; Argente, Jesús; Chowen, Julie A; Viveros, Maria-Paz

    2015-01-01

    Maternal deprivation (MD) during neonatal life has diverse long-term behavioral effects and alters the development of the hippocampus and frontal cortex, with several of these effects being sexually dimorphic. MD animals show a marked reduction in their circulating leptin levels, not only during the MD period, but also several days later (PND 13). A neonatal leptin surge occurs in rodents (beginning around PND 5 and peaking between PND 9 and 10) that has an important neurotrophic role. We hypothesized that the deficient neonatal leptin signaling of MD rats could be involved in the altered development of their hippocampus and frontal cortex. Accordingly, a neonatal leptin treatment in MD rats would at least in part counteract their neurobehavioural alterations. MD was carried out in Wistar rats for 24 h on PND 9. Male and female MD and control rats were treated from PND 9 to 13 with rat leptin (3 mg/kg/day sc) or vehicle. In adulthood, the animals were submitted to the open field, novel object memory test and the elevated plus maze test of anxiety. Neuronal and glial population markers, components of the glutamatergic and cannabinoid systems and diverse synaptic plasticity markers were evaluated by PCR and/or western blotting. Main results include: 1) In some of the parameters analyzed, neonatal leptin treatment reversed the effects of MD (eg., mRNA expression of hippocampal IGF1 and protein expression of GFAP and vimentin) partially confirming our hypothesis; 2) The neonatal leptin treatment, per se, exerted a number of behavioral (increased anxiety) and neural effects (eg., expression of the following proteins: NG2, NeuN, PSD95, NCAM, synaptophysin). Most of these effects were sex dependent. An adequate neonatal leptin level (avoiding excess and deficiency) appears to be necessary for its correct neuro-programing effect. PMID:26382238

  3. Long Term Hippocampal and Cortical Changes Induced by Maternal Deprivation and Neonatal Leptin Treatment in Male and Female Rats.

    PubMed

    Mela, Virginia; Díaz, Francisca; Borcel, Erika; Argente, Jesús; Chowen, Julie A; Viveros, Maria-Paz

    2015-01-01

    Maternal deprivation (MD) during neonatal life has diverse long-term behavioral effects and alters the development of the hippocampus and frontal cortex, with several of these effects being sexually dimorphic. MD animals show a marked reduction in their circulating leptin levels, not only during the MD period, but also several days later (PND 13). A neonatal leptin surge occurs in rodents (beginning around PND 5 and peaking between PND 9 and 10) that has an important neurotrophic role. We hypothesized that the deficient neonatal leptin signaling of MD rats could be involved in the altered development of their hippocampus and frontal cortex. Accordingly, a neonatal leptin treatment in MD rats would at least in part counteract their neurobehavioural alterations. MD was carried out in Wistar rats for 24 h on PND 9. Male and female MD and control rats were treated from PND 9 to 13 with rat leptin (3 mg/kg/day sc) or vehicle. In adulthood, the animals were submitted to the open field, novel object memory test and the elevated plus maze test of anxiety. Neuronal and glial population markers, components of the glutamatergic and cannabinoid systems and diverse synaptic plasticity markers were evaluated by PCR and/or western blotting. Main results include: 1) In some of the parameters analyzed, neonatal leptin treatment reversed the effects of MD (eg., mRNA expression of hippocampal IGF1 and protein expression of GFAP and vimentin) partially confirming our hypothesis; 2) The neonatal leptin treatment, per se, exerted a number of behavioral (increased anxiety) and neural effects (eg., expression of the following proteins: NG2, NeuN, PSD95, NCAM, synaptophysin). Most of these effects were sex dependent. An adequate neonatal leptin level (avoiding excess and deficiency) appears to be necessary for its correct neuro-programing effect.

  4. Long Term Hippocampal and Cortical Changes Induced by Maternal Deprivation and Neonatal Leptin Treatment in Male and Female Rats

    PubMed Central

    Mela, Virginia; Díaz, Francisca; Borcel, Erika; Argente, Jesús; Chowen, Julie A.; Viveros, Maria-Paz

    2015-01-01

    Maternal deprivation (MD) during neonatal life has diverse long-term behavioral effects and alters the development of the hippocampus and frontal cortex, with several of these effects being sexually dimorphic. MD animals show a marked reduction in their circulating leptin levels, not only during the MD period, but also several days later (PND 13). A neonatal leptin surge occurs in rodents (beginning around PND 5 and peaking between PND 9 and 10) that has an important neurotrophic role. We hypothesized that the deficient neonatal leptin signaling of MD rats could be involved in the altered development of their hippocampus and frontal cortex. Accordingly, a neonatal leptin treatment in MD rats would at least in part counteract their neurobehavioural alterations. MD was carried out in Wistar rats for 24 h on PND 9. Male and female MD and control rats were treated from PND 9 to 13 with rat leptin (3 mg/kg/day sc) or vehicle. In adulthood, the animals were submitted to the open field, novel object memory test and the elevated plus maze test of anxiety. Neuronal and glial population markers, components of the glutamatergic and cannabinoid systems and diverse synaptic plasticity markers were evaluated by PCR and/or western blotting. Main results include: 1) In some of the parameters analyzed, neonatal leptin treatment reversed the effects of MD (eg., mRNA expression of hippocampal IGF1 and protein expression of GFAP and vimentin) partially confirming our hypothesis; 2) The neonatal leptin treatment, per se, exerted a number of behavioral (increased anxiety) and neural effects (eg., expression of the following proteins: NG2, NeuN, PSD95, NCAM, synaptophysin). Most of these effects were sex dependent. An adequate neonatal leptin level (avoiding excess and deficiency) appears to be necessary for its correct neuro-programing effect. PMID:26382238

  5. Prevention of airway hyperresponsiveness induced by left ventricular dysfunction in rats

    PubMed Central

    2012-01-01

    Background The effectiveness of strategies for treatment of the altered static lung volume and against the development of bronchial hyperreactivity (BHR) following a left ventricular dysfunction (LVD) induced by myocardial ischaemia was investigated in a rat model of sustained postcapillary pulmonary hypertension. Methods Airway resistance (Raw) was identified from the respiratory system input impedance (Zrs) in four groups of rats. End-expiratory lung volume (EELV) was determined plethysmographically, and Zrs was measured under baseline conditions and following iv infusions of 2, 6 or 18 μg/kg/min methacholine. Sham surgery was performed in the rats in Group C, while the left interventricular coronary artery was ligated and Zrs and its changes following identical methacholine challenges were reassessed in the same rats 8 weeks later, during which no treatment was applied (Group I), or the animals were treated daily with a combination of an angiotensin enzyme converter inhibitor and a diuretic (enalapril and furosemide, Group IE), or a calcium channel blocker (diltiazem, Group ID). The equivalent dose of methacholine causing a 100% increase in Raw (ED50) was determined in each group. Diastolic pulmonary arterial pressure (PapD) was assessed by introducing a catheter into the pulmonary artery. Results The sustained presence of a LVD increased PapD in all groups of rats, with variable but significant elevations in Groups I (p = 0.004), ID (p = 0.013) and IE (p = 0.006). A LVD for 8 weeks induced no changes in baseline Raw but elevated the EELV independently of the treatments. In Group I, BHR consistently developed following the LVD, with a significant decrease in ED50 from 10.0 ± 2.5 to 6.9 ± 2.5 μg/kg/min (p = 0.006). The BHR was completely abolished in both Groups ID and IE, with no changes in ED50 (9.5 ± 3.6 vs. 10.7 ± 4.7, p = 0.33 and 10.6 ± 2.1 vs. 9.8 ± 3.5 μg/kg/min p = 0.56, respectively). Conclusions

  6. Long-term potentiation in the neonatal rat barrel cortex in vivo.

    PubMed

    An, Shuming; Yang, Jenq-Wei; Sun, Haiyan; Kilb, Werner; Luhmann, Heiko J

    2012-07-11

    Long-term potentiation (LTP) is important for the activity-dependent formation of early cortical circuits. In the neonatal rodent barrel cortex, LTP has been studied only in vitro. We combined voltage-sensitive dye imaging with extracellular multielectrode recordings to study whisker stimulation-induced LTP in the whisker-to-barrel cortex pathway of the neonatal rat barrel cortex in vivo. Single whisker stimulation at 2 Hz for 10 min induced an age-dependent expression of LTP in postnatal day (P) 0 to P14 rats, with the strongest expression of LTP at P3-P5. The magnitude of LTP was largest in the activated barrel-related column, smaller in the surrounding septal region, and no LTP could be observed in the neighboring barrel. Current source density analyses revealed an LTP-associated increase of synaptic current sinks in layer IV/lower layer II/III at P3-P5 and in the cortical plate/upper layer V at P0-P1. Our study demonstrates for the first time an age-dependent and spatially confined LTP in the barrel cortex of the newborn rat in vivo.

  7. Digestive enzyme expression and epithelial structure of small intestine in neonatal rats after 16 days spaceflight

    NASA Astrophysics Data System (ADS)

    Miyake, M.; Yamasaki, M.; Hazama, A.; Ijiri, K.; Shimizu, T.

    It is important to assure whether digestive system can develop normally in neonates during spaceflight. Because the small intestine changes its function and structure drastically around weaning known as redifferentiation. Lactase expression declines and sucrase increases in small intestine for digestion of solid food before weaning. In this paper, we compared this enzyme transition and structural development of small intestine in neonatal rats after spaceflight. To find digestive genes differentially expressed in fight rats, DNA membrane macroarray was also used. Eight-day old rats were loaded to Space Shuttle Columbia, and housed in the animal facility for 16 days in space (STS-90, Neurolab mission). Two control groups (AGC; asynchronous ground control and VIV; vivarium) against flight group (FLT) were prepared. There was no difference in structure (crypt depth) and cell differentiation of epithelium between FLT and AGC by immunohistochemical analysis. We found that the amount of sucrase mRNA compared to lactase was decreased in FLT by RT-PCR. It reflected the enzyme transition was inhibited. Increase of 5 genes (APO A-I, APO A-IV, ACE, aFABP and aminopeptidase M) and decrease of carboxypeptidase-D were detected in FLT using macroarray. We think nutrition differences (less nourishment and late weaning) during spaceflight may cause inhibition of enzyme transition at least partly. The weightlessness might contribute to the inhibition through behavioral change.

  8. Studies on cerebral protection of digoxin against hypoxic-ischemic brain damage in neonatal rats.

    PubMed

    Peng, Kaiwei; Tan, Danfeng; He, Miao; Guo, Dandan; Huang, Juan; Wang, Xia; Liu, Chentao; Zheng, Xiangrong

    2016-08-17

    Hypoxic-ischemic brain damage (HIBD) is a major cause of neonatal acute deaths and chronic nervous system damage. Our present study was designed to investigate the possible neuroprotective effect of digoxin-induced pharmacological preconditioning after hypoxia-ischemia and underlying mechanisms. Neonatal rats were assigned randomly to control, HIBD, or HIBD+digoxin groups. Pharmacological preconditioning was induced by administration of digoxin 72 h before inducing HIBD by carotid occlusion+hypoxia. Behavioral assays, and neuropathological and apoptotic assessments were performed to examine the effects; the expression of Na/K ATPase was also assessed. Rats in the HIBD group showed deficiencies on the T-maze, radial water maze, and postural reflex tests, whereas the HIBD+digoxin group showed significant improvements on all behavioral tests. The rats treated with digoxin showed recovery of pathological conditions, increased number of neural cells and proliferative cells, and decreased number of apoptotic cells. Meanwhile, an increased expression level of Na/K ATPase was observed after digoxin preconditioning treatment. The preconditioning treatment of digoxin contributed toward an improved functional recovery and exerted a marked neuroprotective effect including promotion of cell proliferation and reduction of apoptosis after HIBD, and the neuroprotective action was likely associated with increased expression of Na/K ATPase. PMID:27362436

  9. Dexamethasone suppresses the locomotor response of neonatal rats to novel environment.

    PubMed

    Menshanov, Petr N; Bannova, Anita V; Dygalo, Nikolay N

    2014-09-01

    Locomotion of animals in the novel environment is determined by two main factors-the intrinsic motor activity and the specific locomotor response to novelty. Glucocorticoids alter neurobehavioral development of mammals and its locomotor manifestations. However, it remains unclear whether the intrinsic and/or the novelty-induced activity are affected by glucocorticoids during early life. Here, the principal component analysis was used to determine the main factors that underlie alterations in locomotion of rat pups treated with dexamethasone. It was shown that neonatal rats exhibited an enhanced locomotion in the novel environment beginning from postnatal day (PD) 5. We found for the first time that this reaction was significantly suppressed by dexamethasone. The effect was specific to the novelty-induced component of behavior, while the intrinsic locomotor activity was not affected by glucocorticoid treatment. The suppression of the behavioral response to novelty was maximal at PD7 and vanquished at PD10-11. In parallel with the hormonal effect on the behavior, dexamethasone upregulated the main cell death executor-active caspase-3 in the prefrontal cortex of 7-day old rats. Thus, dexamethasone-induced alterations in the novelty-related behavior may be the earliest visible signs of the brain damage that could lead to forthcoming depressive state or schizophrenia, emerging as a result of neonatal stress or glucocorticoid treatment.

  10. Immunoreactive somatostatin and. beta. -endorphin content in the brain of mature rats after neonatal exposure to propylthiouracil

    SciTech Connect

    Kato, N.; Sundmark, V.C.; Van Middlesworth, L.; Havlicek, V.; Friesen, H.G.

    1982-06-01

    The contents of immunoreactive somatostatin (IR-SRIF) and ..beta..-endorphin (IR-..beta..-EP) in 12 brain regions were examined in rats exposed neonatally to propylthiouracil (PTU) through the mother's milk. Since the dose of PTU used in the study is lower than the usual dose employed to induce hypothyroidism, a milder form of neonatal hypothyroidism resulted. This conclusion is supported by the only mild subnormal growth of rats to adulthood and serum T/sub 4/ and T/sub 3/ concentrations in the normal range. Adult rats treated with PTU neonatally had significantly higher IR-SRIF contents in several brain regions compared to controls, whereas IR-..beta..-EP levels were not significantly different (significant increase only in the thalamus) in most regions. The results indicate that even mild hypothyroidism during early postnatal development causes permanent impairment of brain function, which manifests itself in part by an altered brain content of IR-SRIF.

  11. Immunoreactive somatostatin and. beta. -endorphin content in the brain of mature rats after neonatal exposure to propylthiouacil. [Propylthiouracil

    SciTech Connect

    Kato, N.; Sundmark, V.C.; Van Middlesworth, L.; Havlicek, V.; Friesen, H.G.

    1982-01-01

    The contents of immunoreactive somatostatin (IR-SRIF) and ..beta..-endorphin (IR-..beta..-EP) in 12 brain regions were examined in rats exposed neonatally to propylthiouracil (PTU) through the mother's milk. Since the dose of PTU used in this study is lower than the usual dose employed to induce hypothyroidism, a milder form of neonatal hypothyroidism resulted. This conclusion is supported by the only mild subnormal growth of rats to adulthood and serum T/sub 4/ and T/sub 3/ concentrations in the normal range. Adult rats treated with PTU neonatally had significantly higher IR-SRIF contents in several brain regions compared to controls, whereas IR-..beta..-EP levels were not significantly different in most regions. The results indicate that even mild hypothyroidism during early postnatal development causes permanent impairment of brain function, which manifests itself in part by an altered brain content of IR-SRIF.

  12. Characterization of a beta-adrenergically inhibited K+ current in rat cardiac ventricular cells.

    PubMed Central

    Scamps, F

    1996-01-01

    1. The electrophysiological properties and beta-adrenergic regulation of a non-inactivating K+ current were studied using the whole-cell patch-clamp technique (22 +/- 2 degrees C) in adult rat ventricular cells. 2. In the presence of 4-aminopyridine, an inhibitor of the rapidly inactivating current, the depolarization-activated current consisted only of a slowly decaying outward current (IK). The presence of a non-inactivating current (ISS) was revealed when analysing inactivation curves. 3. IK and ISS were both sensitive to 50 mM tetraethylammonium and 10 mM 4-aminopyridine inhibition. IK was totally blocked by 100 microM clofilium, while ISS was not inhibited but rather enhanced by this class III anti-arrhythmic agent. 4. Unlike IK, ISS was only slightly decreased by depolarizing prepulses and it did not show time-dependent inactivation when measured during 500 ms depolarizations. 5. ISS was decreased by the beta-adrenergic agonist isoprenaline (1 microM). Forskolin (10 microM) mimicked the effects of isoprenaline. The non-specific beta-adrenergic antagonist, propranolol (3 microM), and a specific beta 1-adrenergic antagonist, CGP 20712A (0.3 microM), both prevented the effects of isoprenaline. Cell perfusion with 100 microM PKI6-22, a peptide inhibitor of the cyclic AMP-dependent protein kinase, reduced or abolished the effects of isoprenaline. 6. The dose-response curve for the inhibition of ISS by isoprenaline was positioned to the left of that for the calcium current. The threshold dose and the dose giving 50% of the maximal effect were, respectively, 0.1 and 0.21 nM for ISS and 1 and 4.3 nM for ICa. 7. In view of the high sensitivity of ISS to isoprenaline, its possible physiological effect was evaluated on action potential duration during beta-adrenergic stimulation. At 1 nM, a concentration that did not increase ICa, isoprenaline induced a significant prolongation of action potential duration as a consequence of ISS inhibition. With 1 microM isoprenaline

  13. Phosphatidylcholine kinetics in neonatal rat lungs and the effects of rhuKGF and betamethasone.

    PubMed

    Bernhard, Wolfgang; Gesche, Jens; Raith, Marco; Poets, Christian F

    2016-05-15

    Surfactant, synthesized by type II pneumocytes (PN-II), mainly comprises phosphatidylcholine (PC) and is essential to prevent neonatal respiratory distress. Furthermore, PC is essential to lung tissue growth and maintenance as a membrane component. Recent findings suggest that the lung contributes to systemic lipid homeostasis via PC export through ABC-A1 transporter expression. Hence it is important to consider pharmacological interventions in neonatal lung PC metabolism with respect to such export. Five-day-old rats were treated with carrier (control), intraperitoneal betamethasone, subcutaneous recombinant human keratinocyte growth factor (rhuKGF), or their combination for 48 h. Animals were intraperitoneally injected with 50 mg/kg [D9-methyl]choline chloride 1.5, 3.0, and 6.0 h before death at day 7, and lung lavage fluid (LLF) and tissue were harvested. Endogenous PC, D9-labeled PC species, and their water-soluble precursors (D9-)choline and (D9-)phosphocholine were determined by tandem mass spectrometry. Treatment increased secreted and tissue PC pools but did not change equilibrium composition of PC species in LLF. However, all treatments increased specific surfactant components in tissue. In control rats, peak D9-PC in lavaged lung was reached after 3 h and was decreased at 6 h. Only 13% of this net loss in lavaged lung was found in LLF. Such decrease was not present in lungs treated with betamethasone and/or with rhuKGF. D9-PC loss at 3-6 h and PC synthesis calculated from D9 enrichment of phosphocholine indicated that daily synthesis rate is higher than total pool size. We conclude that lung tissue contributes to systemic PC homeostasis in neonatal rats, which is altered by glucocorticoid and rhuKGF treatment. PMID:26944086

  14. Aluminum overload increases oxidative stress in four functional brain areas of neonatal rats

    PubMed Central

    2012-01-01

    Background Higher aluminum (Al) content in infant formula and its effects on neonatal brain development are a cause for concern. This study aimed to evaluate the distribution and concentration of Al in neonatal rat brain following Al treatment, and oxidative stress in brain tissues induced by Al overload. Methods Postnatal day 3 (PND 3) rat pups (n =46) received intraperitoneal injection of aluminum chloride (AlCl3), at dosages of 0, 7, and 35 mg/kg body wt (control, low Al (LA), and high Al (HA), respectively), over 14 d. Results Aluminum concentrations were significantly higher in the hippocampus (751.0 ± 225.8 ng/g v.s. 294.9 ± 180.8 ng/g; p < 0.05), diencephalon (79.6 ± 20.7 ng/g v.s. 20.4 ± 9.6 ng/g; p < 0.05), and cerebellum (144.8 ± 36.2 ng/g v.s. 83.1 ± 15.2 ng/g; p < 0.05) in the HA group compared to the control. The hippocampus, diencephalon, cerebellum, and brain stem of HA animals displayed significantly higher levels of lipid peroxidative products (TBARS) than the same regions in the controls. However, the average superoxide dismutase (SOD) activities in the cerebral cortex, hippocampus, cerebellum, and brain stem were lower in the HA group compared to the control. The HA animals demonstrated increased catalase activity in the diencephalon, and increased glutathione peroxidase (GPx) activity in the cerebral cortex, hippocampus, cerebellum, and brain stem, compared to controls. Conclusion Aluminum overload increases oxidative stress (H2O2) in the hippocampus, diencephalon, cerebellum, and brain stem in neonatal rats. PMID:22613782

  15. Direct and indirect vitamin A supplementation strategies result in different plasma and tissue retinol kinetics in neonatal rats

    PubMed Central

    Tan, Libo; Babbs, Amanda E.; Green, Michael H.; Ross, A. Catharine

    2016-01-01

    Many questions remain regarding vitamin A (VA) supplementation of infants. Herein we compared direct oral VA supplementation of the neonate and indirect treatment through maternal dietary VA (M-VA) treatment on VA status and kinetics in neonatal rats. Treatments included direct VA combined with retinoic acid (RA) [D-VARA; VA (6 mg/kg) + 10% RA, given orally to neonates on postnatal day (P)2 and P3] and indirect VA supplementation through increased M-VA, compared with each other and oil-treated neonates. [3H]retinol was administered orally to all neonates on P4. Plasma and tissue [3H]retinol kinetics were determined from 1 h to 14 days post-dosing. D-VARA versus placebo dramatically increased liver and lung retinol, but only in the first 8–10 days. In M-VA neonates, liver and lung VA increased progressively throughout the study. Compartmental modeling of plasma [3H]retinol showed that both D-VARA and indirect M-VA reduced retinol recycling between plasma and tissues. Compartmental models of individual tissues predicted that D-VARA stimulated the uptake of VA in chylomicrons to extrahepatic tissues, especially intestine, while the uptake was not observed in M-VA neonates. In conclusion, indirect maternal supplementation had a greater sustained effect than D-VARA on neonatal VA status, while also differentially affecting plasma and tissue retinol kinetics. PMID:27264735

  16. Development of motor coordination and cerebellar structure in male and female rat neonates exposed to hypergravity

    NASA Astrophysics Data System (ADS)

    Nguon, K.; Ladd, B.; Baxter, M. G.; Sajdel-Sulkowska, E. M.

    2006-01-01

    We previously reported that the developing rat cerebellum is affected by exposure to hypergravity. In the present study, we explored the hypothesis that the changes in cerebellar structure in hypergravity-exposed rat neonates may affect their motor coordination. Furthermore, we hypothesized that the changes observed at 1.5G will be magnified at higher gravitational loading. To test this hypothesis, we compared motor behavior, cerebellar structure, and protein expression in rat neonates exposed to 1.5 1.75G on a 24-ft centrifuge daily for 22.5 h starting on gestational day (G) 10, through birth on G22/G23 and through postnatal day (P) 21. Exposure to hypergravity impacted the neurodevelopmental process as indicated by: (1) impaired righting response on P3, more than doubling the righting time at 1.75G, and (2) delayed onset of the startle response by one day, from P9 in controls to P10 in hypergravity-exposed pups. Hypergravity exposure resulted in impaired motor functions as evidenced by performance on a rotarod on P21; the duration of the stay on the rotarod recorded for 1.75G pups of both sexes was one tenth that of the stationary control (SC) pups. These changes in motor behavior were associated with cerebellar changes: (1) cerebellar mass on P6 was decreased by 7.5% in 1.5G-exposed male pups, 27.5% in 1.75G-exposed male pups, 17.5% in 1.5G-exposed female pups, and 22.5% in 1.75G female pups and (2) changes in the expression of glial and neuronal proteins. The results of this study suggest that perinatal exposure to hypergravity affects cerebellar development as evidenced by decreased cerebellar mass and altered cerebellar protein expression; cerebellar changes observed in hypergravity-exposed rat neonates are associated with impaired motor behavior. Furthermore, the response to hypergravity appears to be different in male and female neonates. If one accepts that the hypergravity paradigm is a useful animal model with which to predict those biological processes

  17. Developmental vitamin D deficiency alters dopamine turnover in neonatal rat forebrain.

    PubMed

    Kesby, James P; Cui, Xiaoying; Ko, Pauline; McGrath, John J; Burne, Thomas H J; Eyles, Darryl W

    2009-09-18

    There is growing evidence that low vitamin D impacts adversely on brain development. The current study investigated the impact of developmental vitamin D (DVD) deficiency on dopamine and serotonin metabolism in the neonatal rat brain. DVD-deficiency resulted in an altered dopaminergic metabolic profile in the forebrain, with a decrease in the conversion of dihydroxyphenylacetic acid (DOPAC) to homovanillic acid (HVA). Correspondingly, expression of the enzyme required for this conversion, catechol-O-methyl transferase (COMT), was decreased. These results suggest that DVD-deficiency influences dopamine turnover during development. PMID:19500655

  18. Effects of Rosiglitazone with Insulin Combination Therapy on Oxidative Stress and Lipid Profile in Left Ventricular Muscles of Diabetic Rats

    PubMed Central

    Kavak, Servet; Ayaz, Lokman; Emre, Mustafa

    2012-01-01

    Purpose. In this study, we tested the hypothesis that rosiglitazone (RSG) with insulin is able to quench oxidative stress initiated by high glucose through prevention of NAD(P)H oxidase activation. Methods and Materials. Male albino Wistar rats were randomly divided into an untreated control group (C), a diabetic group (D) that was treated with a single intraperitoneal injection of streptozotocin (45 mgkg−1), and rosiglitazone group that was treated with RSG twice daily by gavage and insulin once daily by subcutaneous injection (group B). HbA1c and blood glucose levels in the circulation and malondialdehyde and 3-nitrotyrosine levels in left ventricular muscle were measured. Result. Treatment of D rats with group B resulted in a time-dependent decrease in blood glucose. We found that the lipid profile and HbA1c levels in group B reached the control group D rat values at the end of the treatment period. There was an increase in 3-nitrotyrosine levels in group D compared to group C. Malondialdehyde and 3-nitrotyrosine levels were found to be decreased in group B compared to group D (P < 0.05). Conclusion. Our data suggests that the treatment of diabetic rats with group B for 8 weeks may decrease the oxidative/nitrosative stress in left ventricular tissue of rats. Thus, in diabetes-related vascular diseases, group B treatment may be cardioprotective. PMID:22829806

  19. Development of hematological and immunological characteristics in neonatal rats.

    PubMed

    Sewald, Katherina; Mueller, Meike; Buschmann, Jochen; Hansen, Tanja; Lewin, Geertje

    2015-08-15

    As major immunological and hematological parameters evolve during the early period of life, laboratory data must be interpreted in relation to developmental changes. Wistar (WU) rats were sacrificed on PND2, 4, 7, 10, 14, 17 and 21. Peripheral blood, bone marrow, thymus samples and spleen cells were collected and a bronchoalveolar lavage (BAL) performed. Parameters of blood counts changed considerably between time points. IgM and IgG levels steadily increased. Spontaneous spleen cell proliferation was low before PND21, although mitogens had stimulatory effects above baseline. In the spleen, T-lymphocyte counts tripled by PND17 (mainly attributed to CD8(+) cytotoxic T-cells and CD4(+) T-helper cells). In peripheral blood an increase in B-lymphocytes to about 60% of the cell number was observed. In BAL fluid, macrophages represented 95-98% of the cells. In thymus architecture, lymphoblast migration was seen and epithelial structures appeared. The data presented will help to distinguish between maturational changes and treatment-related effects.

  20. Neuroprotective potential of Bacopa monnieri and Bacoside A against dopamine receptor dysfunction in the cerebral cortex of neonatal hypoglycaemic rats.

    PubMed

    Thomas, Roshni Baby; Joy, Shilpa; Ajayan, M S; Paulose, C S

    2013-11-01

    Neonatal hypoglycaemia initiates a series of events leading to neuronal death, even if glucose and glycogen stores return to normal. Disturbances in the cortical dopaminergic function affect memory and cognition. We recommend Bacopa monnieri extract or Bacoside A to treat neonatal hypoglycaemia. We investigated the alterations in dopaminergic functions by studying the Dopamine D1 and D2 receptor subtypes. Receptor-binding studies revealed a significant decrease (p < 0.001) in dopamine D1 receptor number in the hypoglycaemic condition, suggesting cognitive dysfunction. cAMP content was significantly (p < 0.001) downregulated in hypoglycaemic neonatal rats indicating the reduction in cell signalling of the dopamine D1 receptors. It is attributed to the deficits in spatial learning and memory. Hypoglycaemic neonatal rats treated with Bacopa extract alone and Bacoside A ameliorated the dopaminergic and cAMP imbalance as effectively as the glucose therapy. The upregulated Bax expression in the present study indicates the high cell death in hypoglycaemic neonatal rats. Enzyme assay of SOD confirmed cortical cell death due to free radical accumulation. The gene expression of SOD in the cortex was significantly downregulated (p < 0.001). Bacopa treatment showed a significant reversal in the altered gene expression parameters (p < 0.001) of Bax and SOD. Our results suggest that in the rat experimental model of neonatal hypoglycaemia, Bacopa extract improved alterations in D1, D2 receptor expression, cAMP signalling and cell death resulting from oxidative stress. This is an important area of study given the significant motor and cognitive impairment that may arise from neonatal hypoglycaemia if proper treatment is not implemented.

  1. Bacterial Pore-Forming Cytolysins Induce Neuronal Damage in a Rat Model of Neonatal Meningitis

    PubMed Central

    Reiß, Anja; Braun, Johann S.; Jäger, Katja; Freyer, Dorette; Laube, Gregor; Bührer, Christoph; Felderhoff-Müser, Ursula; Stadelmann, Christine; Nizet, Victor

    2011-01-01

    Background. Group B Streptococcus (GBS) and Streptococcus pneumoniae (SP) are leading causes of bacterial meningitis in neonates and children. Each pathogen produces a pore-forming cytolytic toxin, β-hemolysin/cytolysin (β-h/c) by GBS and pneumolysin by SP. The aim of this study was to understand the role of these pore-forming cytotoxins, in particular of the GBS β-h/c, as potential neurotoxins in experimental neonatal meningitis. Methods. Meningitis was induced in 7- and 11-day-old rats by intracisternal injection of wild type (WT) GBS or SP and compared with isogenic β-h/c- or pneumolysin-deficient mutants, or a double mutant of SP deficient in pneumolysin and hydrogen peroxide production. Results. GBS β-h/c and SP pneumolysin contributed to neuronal damage, worsened clinical outcome and weight loss, but had no influence on the early kinetics of leukocyte influx and bacterial growth in the cerebrospinal fluid. In vitro, β-h/c-induced neuronal apoptosis occurred independently of caspase-activation and was not preventable by the broad spectrum caspase-inhibitor z-VAD-fmk. Conclusions. These data suggest that both cytolytic toxins, the GBS β-h/c and SP pneumolysin, contribute to neuronal damage in meningitis and extend the concept of a key role for bacterial pore-forming cytolysins in the pathogenesis and sequelae of neonatal meningitis. PMID:21186256

  2. Ultrastructural localization of calsequestrin in adult rat atrial and ventricular muscle cells

    PubMed Central

    1985-01-01

    The distribution of calsequestrin in rat atrial and ventricular myocardial cells was determined by indirect immunocolloidal gold labeling of ultrathin frozen sections. The results presented show that calsequestrin is confined to the sarcoplasmic reticulum where it is localized in the lumen of the peripheral and the interior junctional sarcoplasmic reticulum as well as in the lumen of the corbular sarcoplasmic reticulum, but absent from the lumen of the network sarcoplasmic reticulum. Comparison of these results with our previous studies on the distribution of the Ca2+ + Mg2+-dependent ATPase of the cardiac sarcoplasmic reticulum show directly that the Ca2+ + Mg2+- dependent ATPase and calsequestrin are confined to distinct regions within the continuous sarcoplasmic reticulum membrane. Assuming that calsequestrin provides the major site of Ca2+ sequestration in the lumen of the sarcoplasmic reticulum, the results presented support the idea that both junctional (interior and peripheral) and specialized nonjunctional (corbular) regions of the sarcoplasmic reticulum are involved in Ca2+ storage and possibly release. Furthermore, the structural differences between the junctional and the corbular sarcoplasmic reticulum support the possibility that Ca2+ storage and/or release from the lumen of the junctional and the corbular sarcoplasmic reticulum are regulated by different physiological signals. PMID:4008530

  3. Biphasic effects of hyposmotic challenge on excitation-contraction coupling in rat ventricular myocytes.

    PubMed

    Brette, F; Calaghan, S C; Lappin, S; White, E; Colyer, J; Le Guennec, J Y

    2000-10-01

    The effects of short (1 min) and long (7-10 min) exposure to hyposmotic solution on excitation-contraction coupling in rat ventricular myocytes were studied. After short exposure, the action potential duration at 90% repolarization (APD(90)), the intracellular Ca(2+) concentration ([Ca(2+)](i)) transient amplitude, and contraction increased, whereas the L-type Ca(2+) current (I(Ca, L)) amplitude decreased. Fractional sarcoplasmic reticulum (SR) Ca(2+) release increased but SR Ca(2+) load did not. After a long exposure, I(Ca,L), APD(90), [Ca(2+)](i) transient amplitude, and contraction decreased. The abbreviation of APD(90) was partially reversed by 50 microM DIDS, which is consistent with the participation of Cl(-) current activated by swelling. After 10-min exposure to hyposmotic solution in cells labeled with di-8-aminonaphthylethenylpyridinium, t-tubule patterning remained intact, suggesting the loss of de-t-tubulation was not responsible for the fall in I(Ca,L). After long exposure, Ca(2+) load of the SR was not increased, and swelling had no effect on the site-specific phosphorylation of phospholamban, but fractional SR Ca(2+) release was depressed. The initial positive inotropic response to hyposmotic challenge may be accounted for by enhanced coupling between Ca(2+) entry and release. The negative inotropic effect of prolonged exposure can be accounted for by shortening of the action potential duration and a fall in the I(Ca,L) amplitude. PMID:11009486

  4. A comparative assessment of fluo Ca2+ indicators in rat ventricular myocytes

    PubMed Central

    Hagen, Brian M.; Boyman, Liron; Kao, Joseph P.Y.; Lederer, W. Jonathan

    2012-01-01

    Summary The fluo family of indicators is frequently used in studying Ca2+ physiology; however, choosing which fluo indicator to use is not obvious. Indicator properties are typically determined in well-defined aqueous solutions. Inside cells, however, the properties can change markedly. We have characterized each of three fluo variants (fluo-2MA, fluo-3 and fluo-4) in two forms—the acetoxymethyl (AM) ester and the K+ salt. We loaded indicators into rat ventricular myocytes and used confocal microscopy to monitor depolarization-induced fluorescence changes and fractional shortening. Myocytes loaded with the indicator AM esters showed significantly different Ca2+ transients and fractional shortening kinetics. Loading the K+ salts via whole-cell patch-pipette eliminated differences between fluo-3 and fluo-4, but not fluo-2. Cells loaded with different indicator AM esters showed different staining patterns—suggesting differential loading into organelles. Ca2+ dissociation constants (Kd,Ca), measured in protein-rich buffers mimicking the cytosol were significantly higher than values determined in simple buffers. This increase in Kd,Ca (decrease in Ca2+ affinity) was greatest for fluo-3 and fluo-4, and least for fluo-2. We conclude that the structurally-similar fluo variants differ with respect to cellular loading, subcellular compartmentalization, and intracellular Ca2+ affinity. Therefore, judicious choice of fluo indicator and loading procedure is advisable when designing experiments. PMID:22721780

  5. Effects of cannabidiol on contractions and calcium signaling in rat ventricular myocytes.

    PubMed

    Ali, Ramez M; Al Kury, Lina T; Yang, Keun-Hang Susan; Qureshi, Anwar; Rajesh, Mohanraj; Galadari, Sehamuddin; Shuba, Yaroslav M; Howarth, Frank Christopher; Oz, Murat

    2015-04-01

    Cannabidiol (CBD), a major nonpsychotropic cannabinoid found in Cannabis plant, has been shown to influence cardiovascular functions under various physiological and pathological conditions. In the present study, the effects of CBD on contractility and electrophysiological properties of rat ventricular myocytes were investigated. Video edge detection was used to measure myocyte shortening. Intracellular Ca(2+) was measured in cells loaded with the Ca(2+) sensitive fluorescent indicator fura-2 AM. Whole-cell patch clamp was used to measure action potential and Ca(2+) currents. Radioligand binding was employed to study pharmacological characteristics of CBD binding. CBD (1μM) caused a significant decrease in the amplitudes of electrically evoked myocyte shortening and Ca(2+) transients. However, the amplitudes of caffeine-evoked Ca(2+) transients and the rate of recovery of electrically evoked Ca(2+) transients following caffeine application were not altered. CBD (1μM) significantly decreased the duration of APs. Further studies on L-type Ca(2+) channels indicated that CBD inhibits these channels with IC50 of 0.1μM in a voltage-independent manner. Radioligand studies indicated that the specific binding of [(3)H]Isradipine, was not altered significantly by CBD. The results suggest that CBD depresses myocyte contractility by suppressing L-type Ca(2+) channels at a site different than dihydropyridine binding site and inhibits excitation-contraction coupling in cardiomyocytes.

  6. Effects of cannabidiol on contractions and calcium signaling in rat ventricular myocytes.

    PubMed

    Ali, Ramez M; Al Kury, Lina T; Yang, Keun-Hang Susan; Qureshi, Anwar; Rajesh, Mohanraj; Galadari, Sehamuddin; Shuba, Yaroslav M; Howarth, Frank Christopher; Oz, Murat

    2015-04-01

    Cannabidiol (CBD), a major nonpsychotropic cannabinoid found in Cannabis plant, has been shown to influence cardiovascular functions under various physiological and pathological conditions. In the present study, the effects of CBD on contractility and electrophysiological properties of rat ventricular myocytes were investigated. Video edge detection was used to measure myocyte shortening. Intracellular Ca(2+) was measured in cells loaded with the Ca(2+) sensitive fluorescent indicator fura-2 AM. Whole-cell patch clamp was used to measure action potential and Ca(2+) currents. Radioligand binding was employed to study pharmacological characteristics of CBD binding. CBD (1μM) caused a significant decrease in the amplitudes of electrically evoked myocyte shortening and Ca(2+) transients. However, the amplitudes of caffeine-evoked Ca(2+) transients and the rate of recovery of electrically evoked Ca(2+) transients following caffeine application were not altered. CBD (1μM) significantly decreased the duration of APs. Further studies on L-type Ca(2+) channels indicated that CBD inhibits these channels with IC50 of 0.1μM in a voltage-independent manner. Radioligand studies indicated that the specific binding of [(3)H]Isradipine, was not altered significantly by CBD. The results suggest that CBD depresses myocyte contractility by suppressing L-type Ca(2+) channels at a site different than dihydropyridine binding site and inhibits excitation-contraction coupling in cardiomyocytes. PMID:25711828

  7. Chronic lead administration in neonatal rats: electron microscopy of the retina

    SciTech Connect

    Santos-Anderson, R.M.; Tso, M.O.M.; Valdes, J.J.; Annau, Z.

    1984-03-01

    The morphologic effects on the retina resulting from chronic lead exposure were assessed in neonatal rats. Newborn rats nursed from dams were given a low (0.115%) or a high (4.5%) concentration of lead in their diet. At day 21 the pups were weaned to the mother's diet. The retinas of the pups were studied by electron microscopy at various ages up to day 60. High and low lead concentrations produced necrosis of photoreceptor cells and cells of the inner nuclear layer. The high lead concentration, in addition, was associated with swelling of endothelial cells of the retinal vessels and narrowing of the lumen. Increased permeability of the retinal vessels and pigment epithelium to horseradish peroxidase were also observed under the high-dose condition. The authors conclude that lead can produce direct neuronal damage and, at high doses, produces retinal vascular lesions and alteration of the blood-retinal barrier. 10 figures.

  8. Chronic lead administration in neonatal rats: electron microscopy of the retina

    SciTech Connect

    Santos-Anderson, R.M.; Tso, M.O.M.; Valdes, J.J.; Annau, Z.

    1984-03-01

    The morphologic effects on the retina resulting from chronic lead exposure were assessed in neonatal rats. Newborn rats nursed from dams were given a low (0.115%) or a high (4.5%) concentration of lead in their diet. At day 21 the pups were weaned to the mother's diet. The retinas of the pups were studied by electron microscopy at various ages up to day 60. High and low lead concentrations produced necrosis of photoreceptor cells and cells of the inner nuclear layer. The high lead concentration, in addition, was associated with swelling of endothelial cells of the retinal vessels and narrowing of the lumen. Increased permeability of the retinal vessels and pigment epithelium to horseradish peroxidase was also observed under the high-dose condition. The authors conclude that lead can produce direct neuronal damage and, at high doses, produces retinal vascular lesions and alteration of the blood-retinal barrier.

  9. Effects of an early treatment with lisinopril and isosorbide-5-mononitrate on hemodynamics and late ventricular remodelling in rats with 9-week myocardial infarction.

    PubMed

    Riva, E; Kurosaki, M; Porzio, S; Latini, R; Lagrasta, C; Olivetti, G

    1995-06-01

    This study was undertaken to assess whether the converting enzyme inhibitor lisinopril, and the long-acting nitrate, isosorbide-5-mononitrate, affect left ventricle dysfunction and anatomical remodelling in rats with myocardial infarction. Lisinopril, isosorbide-5-mononitrate or vehicle were given to rats (n = 10-14 per group) immediately after coronary artery occlusion (by an intravenous bolus) and then for nine weeks (in drinking water). At the end of the study, left ventricular pressures were measured, the heart arrested in diastole, and infarct size, left ventricular chamber volume and wall thicknesses measured. Lisinopril significantly lowered systemic blood pressure and left ventricular systolic pressure in rats with small (< 15% scarred tissue of the left ventricle) and large (> 15%) infarcts; the weight of the left ventricle (including the septum) was reduced by 24% and 28% in animals with small and large infarcts, respectively. Lisinopril lowered left ventricular end-diastolic pressure (by 33% and 39%) and chamber volume (by 4% and 34%) in rats with small and large infarcts, respectively, compared with controls (NS). The combined anatomical and hemodynamic changes led to a reduction of the circumferential wall stress by 20% and 44% in lisinopril-treated rats with small and large infarcts, respectively (NS). No significant changes were seen in the nitrate-treated hearts compared with controls. Lisinopril, given early after myocardial infarction and continued for nine weeks, significantly affected cardiac hemodynamics and ventricular weights in rats with infarcts of different sizes.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Effect of neonatal handling on adult rat spatial learning and memory following acute stress.

    PubMed

    Stamatakis, A; Pondiki, S; Kitraki, E; Diamantopoulou, A; Panagiotaropoulos, T; Raftogianni, A; Stylianopoulou, F

    2008-03-01

    Brief neonatal handling permanently alters hypothalamic-pituitary-adrenal axis function resulting in increased ability to cope with stress. Since stress is known to affect cognitive abilities, in the present study we investigated the effect of brief (15 min) handling on learning and memory in the Morris water maze, following exposure to an acute restraint stress either before training or recall. Exposure of non-handled rats to the acute stress prior to training resulted in quicker learning of the task, than in the absence of the stressor. When acute stress preceded acquisition, male handled rats showed an overall better learning performance, and both sexes of handled animals were less impaired in the subsequent memory trial, compared to the respective non-handled. In addition, the number of neurons immunoreactive for GR was higher in all areas of Ammon's horn of the handled rats during the recall. In contrast, the number of neurons immunoreactive for MR was higher in the CA1 and CA2 areas of the non-handled males. When the acute restraint stress was applied prior to the memory test, neonatal handling was not effective in preventing mnemonic impairment, as all animal groups showed a similar deficit in recall. In this case, no difference between handled and non-handled rats was observed in the number of GR positive neurons in the CA2 and CA3 hippocampal areas during the memory test. These results indicate that early experience interacts with sex and acute stress exposure in adulthood to affect performance in the water maze. Hippocampal corticosterone receptors may play a role in determining the final outcome.

  11. Pancreatic and Pancreatic-Like Microbial Proteases Accelerate Gut Maturation in Neonatal Rats

    PubMed Central

    Prykhodko, Olena; Pierzynowski, Stefan G.; Nikpey, Elham; Arevalo Sureda, Ester; Fedkiv, Olexandr; Weström, Björn R.

    2015-01-01

    Objectives Postnatal gut maturation in neonatal mammals, either at natural weaning or after precocious inducement, is coinciding with enhanced enzymes production by exocrine pancreas. Since the involvement of enzymes in gut functional maturation was overlooked, the present study aimed to investigate the role of enzymes in gut functional maturation using neonatal rats. Methods Suckling rats (Rattus norvegicus) were instagastrically gavaged with porcine pancreatic enzymes (Creon), microbial-derived amylase, protease, lipase and mixture thereof, while controls received α-lactalbumin or water once per day during 14–16 d of age. At 17 d of age the animals were euthanized and visceral organs were dissected, weighed and analyzed for structural and functional properties. For some of the rats, gavage with the macromolecular markers such as bovine serum albumin and bovine IgG was performed 3 hours prior to blood collection to assess the intestinal permeability. Results Gavage with the pancreatic or pancreatic-like enzymes resulted in stimulated gut growth, increased gastric acid secretion and switched intestinal disaccharidases, with decreased lactase and increased maltase and sucrase activities. The fetal-type vacuolated enterocytes were replaced by the adult-type in the distal intestine, and macromolecular transfer to the blood was declined. Enzyme exposure also promoted pancreas growth with increased amylase and trypsin production. These effects were confined to the proteases in a dose-dependent manner. Conclusion Feeding exogenous enzymes, containing proteases, induced precocious gut maturation in suckling rats. This suggests that luminal exposure to proteases by oral loading or, possibly, via enhanced pancreatic secretion involves in the gut maturation of young mammals. PMID:25658606

  12. Octreotide, a Somatostatin Analogue, Fails to Inhibit Hypoxia-induced Retinal Neovascularization in the Neonatal Rat

    PubMed Central

    Averbukh, Edward; Halpert, Michael; Yanko, Ravit; Yanko, Lutza; Peèr, Jacob; Levinger, Samuel; Flyvbjerg, Allan

    2000-01-01

    Objective: Octreotide, a somatostatin analogue, has been shown to prevent angiogenesis in diverse in vitro models. We evaluated its effect on retinal neovascularization in vivo, using a neonatal rat retinopathy model. Methods: We used, on alternating days, hypoxia (10% O2) and hyperoxia (50% O2) during the first 14 days of neonatal rats, to induce retinal neovascularization. Half of the rats were injected subcutaneously with octreotide 0.7 μg/g BW twice daily. At day 18 the eyes were evaluated for the presence of epiretinal and vitreal hemorrhage, neovascularization and epiretinal proliferation. Octreotide pharmacokinetics and its effect on serum growth hormone (GH) and insulin-like growth factor I (IGF-I) were examined in 28 rats. Results: Serum octreotide levels were 667 μg/1 two hours after injection, 26.4 μg/1 after nine hours and 3.2 μg/1 after 14 hours. GH levels were decreased by 40% (p = 0.002) two hours after injection but thereafter returned to baseline. IGF-I levels were unchanged two hours after injection and were elevated by 26% 14 hours after injection (p = 0.02). Epiretinal membranes were highly associated with epiretinal hemorrhages (p < 0.001), while retinal neovascularization was notably associated with vitreal hemorrhages (p < 0.001). Conclusions: Twice-daily injections of octreotide failed to produce sustained decrease in serum GH, but produced rebound elevation of serum IGF-I. Accordingly, no statistically significant effect of injections on retinal pathology was noted. This finding, however, does not contradict our assumption that GH suppression may decrease the severity of retinopathy. PMID:11469389

  13. Perinatal Iron and Copper Deficiencies Alter Neonatal Rat Circulating and Brain Thyroid Hormone Concentrations

    PubMed Central

    Bastian, Thomas W.; Prohaska, Joseph R.; Georgieff, Michael K.; Anderson, Grant W.

    2010-01-01

    Copper (Cu), iron (Fe), and iodine/thyroid hormone (TH) deficiencies lead to similar defects in late brain development, suggesting that these micronutrient deficiencies share a common mechanism contributing to the observed derangements. Previous studies in rodents (postweanling and adult) and humans (adolescent and adult) indicate that Cu and Fe deficiencies affect the hypothalamic-pituitary-thyroid axis, leading to altered TH status. Importantly, however, relationships between Fe and Cu deficiencies and thyroidal status have not been assessed in the most vulnerable population, the developing fetus/neonate. We hypothesized that Cu and Fe deficiencies reduce circulating and brain TH levels during development, contributing to the defects in brain development associated with these deficiencies. To test this hypothesis, pregnant rat dams were rendered Cu deficient (CuD), FeD, or TH deficient from early gestation through weaning. Serum thyroxine (T4) and triiodothyronine (T3), and brain T3 levels, were subsequently measured in postnatal d 12 (P12) pups. Cu deficiency reduced serum total T3 by 48%, serum total T4 by 21%, and whole-brain T3 by 10% at P12. Fe deficiency reduced serum total T3 by 43%, serum total T4 by 67%, and whole-brain T3 by 25% at P12. Brain mRNA analysis revealed that expression of several TH-responsive genes were altered in CuD or FeD neonates, suggesting that reduced TH concentrations were sensed by the FeD and CuD neonatal brain. These results indicate that at least some of the brain defects associated with neonatal Fe and Cu deficiencies are mediated through reductions in circulating and brain TH levels. PMID:20573724

  14. Neonatal Bisphenol A exposure alters sexually dimorphic gene expression in the postnatal rat hypothalamus.

    PubMed

    Cao, Jinyan; Mickens, Jillian A; McCaffrey, Katherine A; Leyrer, Stephanie M; Patisaul, Heather B

    2012-01-01

    Developmental exposure to Bisphenol A (BPA), a component of polycarbonate and epoxy resins, has been purported to adversely impact reproductive function in female rodents. Because neonatal life is a critical window for the sexual dimorphic organization of the hypothalamic-pituitary-gonadal (HPG) axis, interference with this process could underlie compromised adult reproductive physiology. The goal of the present study was to determine if neonatal BPA exposure interferes with sex specific gene expression of estrogen receptor alpha (ERα), ER beta (ERβ) and kisspeptin (Kiss1) in the anterior and mediobasal hypothalamus. Long Evans (LE) neonatal rats were exposed to vehicle, 10μg estradiol benzoate (EB), 50mg/kg BPA or 50μg/kg BPA by subcutaneous injection daily from postnatal day 0 (PND 0) to PND 2. Gene expression was assessed by in situ hybridization on PNDs 4 and 10. Within the anterior hypothalamus ERα expression was augmented by BPA in PND 4 females, then fell to male-typical levels by PND 10. ERβ expression was not altered by BPA on PND 4, but significantly decreased or eliminated in both sexes by PND 10. Kiss1 expression was diminished by BPA in the anterior hypothalamus, especially in females. There were no significant impacts of BPA in the mediobasal hypothalamus. Collectively, BPA effects did not mirror those of EB. The results show that neonatal hypothalamic ER and Kiss1 expression is sensitive to BPA exposure. This disruption may alter sexually dimorphic hypothalamic organization and underlie adult reproductive deficiencies. Additionally, the discordant effects of EB and BPA indicate that BPA likely disrupts hypothalamic organization by a mechanism other than simply acting as an estrogen mimic.

  15. Susceptibility to Inhaled Flame-Generated Ultrafine Soot in Neonatal and Adult Rat Lungs

    PubMed Central

    Chan, Jackie K. W.; Fanucchi, Michelle V.; Anderson, Donald S.; Abid, Aamir D.; Wallis, Christopher D.; Dickinson, Dale A.; Kumfer, Benjamin M.; Kennedy, Ian M.; Wexler, Anthony S.; Van Winkle, Laura S.

    2011-01-01

    Over a quarter of the U.S. population is exposed to harmful levels of airborne particulate matter (PM) pollution, which has been linked to development and exacerbation of respiratory diseases leading to morbidity and mortality, especially in susceptible populations. Young children are especially susceptible to PM and can experience altered anatomic, physiologic, and biological responses. Current studies of ambient PM are confounded by the complex mixture of soot, metals, allergens, and organics present in the complex mixture as well as seasonal and temporal variance. We have developed a laboratory-based PM devoid of metals and allergens that can be replicated to study health effects of specific PM components in animal models. We exposed 7-day-old postnatal and adult rats to a single 6-h exposure of fuel-rich ultrafine premixed flame particles (PFPs) or filtered air. These particles are high in polycyclic aromatic hydrocarbons content. Pulmonary cytotoxicity, gene, and protein expression were evaluated at 2 and 24 h postexposure. Neonates were more susceptible to PFP, exhibiting increased lactate dehydrogenase activity in bronchoalveolar lavage fluid and ethidium homodimer-1 cellular staining in the lung in situ as an index of cytotoxicity. Basal gene expression between neonates and adults differed for a significant number of antioxidant, oxidative stress, and proliferation genes and was further altered by PFP exposure. PFP diminishes proliferation marker PCNA gene and protein expression in neonates but not adults. We conclude that neonates have an impaired ability to respond to environmental exposures that increases lung cytotoxicity and results in enhanced susceptibility to PFP, which may lead to abnormal airway growth. PMID:21914721

  16. Effects of neonatal treatment with two phytoestrogens on male rat sexual behavior and partner preference.

    PubMed

    Morales-Otal, Adriana; Ferreira-Nuño, Armando; Olayo-Lortia, Jesús; Barrios-González, Javier; Tarragó-Castellanos, Rosario

    2016-10-01

    The aim of this work was to compare the effect of neonatal treatment with the phytoestrogens coumestrol (COU) and genistein (GEN), administered in equimolecular doses, on the sexual behavior and partner preference of male rats. Four groups of male rats were injected daily from day 1 to 5 with 150 µg of GEN, an equivalent amount of COU, 1 µg of β-estradiol 3-benzoato (EB), or olive oil (VEH) (control). A fifth group remained intact. In the GEN group, intromission and ejaculation latencies decreased, whereas ejaculatory frequency increased. Contrasting results were observed in COU males. EB males could not ejaculate and their mount and intromission latencies increased significantly. To determine sexual-partner preferences, a multiple partner preference arena was used and two types of tests were performed, the first one without allowing contact test (CT) with the stimulus animals, followed by a CT. COU and GEN groups did not show preference for any stimulus animal, whereas the EB males preferred the expert male. When CT with the stimulus animals was allowed, GEN-males preferred the receptive female, unlike the COU and EB groups. It is concluded that neonatal treatment with COU and GEN induced opposite effects, the effects of COU being more estrogenic.

  17. Neonatal hypoxia-ischemia induces attention-deficit hyperactivity disorder-like behavior in rats.

    PubMed

    Miguel, Patrícia Maidana; Schuch, Clarissa Pedrini; Rojas, Joseane Jiménez; Carletti, Jaqueline Vieira; Deckmann, Iohanna; Martinato, Luísa Helena Machado; Pires, Augusto Viana; Bizarro, Lisiane; Pereira, Lenir Orlandi

    2015-06-01

    Attention-deficit hyperactivity disorder (ADHD) may be caused by genetic or environmental factors. Among environmental factors, perinatal complications are related, such as neonatal hypoxia-ischemia (HI). Thus, the aim of this study was to investigate whether HI contributes to the development of characteristics related to ADHD in adult rats, and to correlate the behavioral results with brain damage volume. Male Wistar rats were divided into 2 groups: HI and control. The HI procedure consisted of a permanent occlusion of the right common carotid artery followed by a period of hypoxia (90 min; 8% O₂ and 92% N₂) on the 7th postnatal day. Two months later, animals were evaluated in the open field test during a single 5-min session, and in the 5-choice serial reaction time task (5-CSRTT), over 25 weeks. Our results demonstrated that animals submitted to HI manifest cognitive impairments in task acquisition, deficits in sustained attention, and increases in impulsivity and compulsivity in response to task manipulation in the 5-CSRTT. Locomotor activity observed in open field did not differ between groups. Moreover, brain volume loss in the total hemisphere, cerebral cortex, white matter, hippocampus, and striatum were observed in HI animals, especially on the side ipsilateral to the lesion. From these results, we can infer that neonatal HI is an environmental factor that could contribute to the development of behavioral characteristics observed in ADHD that are associated with general brain atrophy. PMID:26030430

  18. Neuroprotective actions of taurine on hypoxic-ischemic brain damage in neonatal rats.

    PubMed

    Zhu, Xiao-Yun; Ma, Peng-Sheng; Wu, Wei; Zhou, Ru; Hao, Yin-Ju; Niu, Yang; Sun, Tao; Li, Yu-Xiang; Yu, Jian-Qiang

    2016-06-01

    Taurine is an abundant amino acid in the nervous system, which has been proved to possess antioxidation, osmoregulation and membrane stabilization. Previously it has been demonstrated that taurine exerts ischemic brain injury protective effect. This study was designed to investigate whether the protective effect of taurine has the possibility to be applied to treat neonatal hypoxic-ischemic brain damage. Seven-day-old Sprague-Dawley rats were treated with left carotid artery ligation followed by exposure to 8% oxygen to generate the experimental group. The cerebral damage area was measured after taurine post-treatment with 2,3,5-triphenyltetrazolium chloride (TTC) staining, Hematoxyline-Eosin (HE) staining and Nissl staining. The activities of superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GSH-Px), total antioxidant capacity (T-AOC), myeloperoxtidase (MPO), ATP and Lactic Acid productions were assayed with ipsilateral hemisphere homogenates. Western-blot and immunofluorescence assay were processed to detect the expressions of AIF, Cyt C, Bax, Bcl-2 in brain. We found that taurine significantly reduced brain infarct volume and ameliorated morphological injury obviously reversed the changes of SOD, MDA, GSH-Px, T-AOC, ATP, MPO, and Lactic Acid levels. Compared with hypoxic-ischemic group, it showed marked reduction of AIF, Cyt C and Bax expressions and increase of Bcl-2 after post-treatment. We conclude that taurine possesses an efficacious neuroprotective effect after cerebral hypoxic-ischemic damage in neonatal rats. PMID:27345710

  19. Prolactin and Prolactin Receptor Expression in Rat, Small Intestine, Intraepithelial Lymphocytes During Neonatal Developmen

    PubMed Central

    Urtishak, Sandra L.; Mckenna, Elizabeth A.; Mastro, Andrea M.

    2001-01-01

    Intraepithelial lymphocytes (IEL) are specialized T cells found between the epithelial cells of the small intestine. Because of their location, IEL are the first lymphocytes to contact intestinal bacteria and food antigens. In the neonate, IEL may be the first cells of the immune system to interact with milk-borne hormones including prolactin (PRL). PRL, an endocrine hormone abundant in breast milk, interacts with cells through surface receptors. PRL has been shown to function as an immunoregulator and may affect the development of the newborn's immune system. To determine if PRL plays a role in IEL development, small intestine IEL from rats of various ages were examined for the presence of surface prolactin receptor (PRL-R) and several lymphoid markers by flow cytometry. Between birth and 96 days of age about 80% of IEL were found to express PRL-R. These same cells also expressed the mRNA for PRL. Additionally, all of the IEL subpopulations examined were found to express PRL-R. Analysis of the normal development of rat IEL revealed an age related increase in total IEL, CD4 positive cells as well as a peak in interleukin-2 receptor (IL-2R) expression at weaning. In summary, the results indicate that IEL express PRL and PRL-R. In addition, an activation marker, IL-2R, changes in expression during neonatal development. PMID:11785680

  20. A Mathematical Model of Neonatal Rat Atrial Monolayers with Constitutively Active Acetylcholine-Mediated K+ Current.

    PubMed

    Majumder, Rupamanjari; Jangsangthong, Wanchana; Feola, Iolanda; Ypey, Dirk L; Pijnappels, Daniël A; Panfilov, Alexander V

    2016-06-01

    Atrial fibrillation (AF) is the most frequent form of arrhythmia occurring in the industrialized world. Because of its complex nature, each identified form of AF requires specialized treatment. Thus, an in-depth understanding of the bases of these arrhythmias is essential for therapeutic development. A variety of experimental studies aimed at understanding the mechanisms of AF are performed using primary cultures of neonatal rat atrial cardiomyocytes (NRAMs). Previously, we have shown that the distinct advantage of NRAM cultures is that they allow standardized, systematic, robust re-entry induction in the presence of a constitutively-active acetylcholine-mediated K+ current (IKACh-c). Experimental studies dedicated to mechanistic explorations of AF, using these cultures, often use computer models for detailed electrophysiological investigations. However, currently, no mathematical model for NRAMs is available. Therefore, in the present study we propose the first model for the action potential (AP) of a NRAM with constitutively-active acetylcholine-mediated K+ current (IKACh-c). The descriptions of the ionic currents were based on patch-clamp data obtained from neonatal rats. Our monolayer model closely mimics the action potential duration (APD) restitution and conduction velocity (CV) restitution curves presented in our previous in vitro studies. In addition, the model reproduces the experimentally observed dynamics of spiral wave rotation, in the absence and in the presence of drug interventions, and in the presence of localized myofibroblast heterogeneities. PMID:27332890

  1. Plasma levels of corticosterone and testosterone after sexual activity in male rats treated neonatally with clomipramine.

    PubMed

    Bonilla-Jaime, H; Retana-Márquez, S; Vazquez-Palacios, G; Velázquez-Moctezuma, J

    2003-07-01

    Neonatal treatment with clomipramine (CMI) in rats, induces alterations of pleasure-seeking behaviors during adulthood. Alterations of hormonal responses to stressful situations have also been reported. In this study, the levels of corticosterone and testosterone in response to sexual activity were assessed in rats treated neonatally with CMI. Male pups received subcutaneous injections of CMI (15 mg/kg, 0.1 ml), twice a day (09.00 hours and 18.00 hours) from 8 to 21 days of age. A control group received saline in the same number of injections. Four months after CMI treatment, subjects (Ss) were submitted to the forced swim test to verify the effect of CMI. Thereafter, they were tested to assess their spontaneous sexual activity. Plasma levels of corticosterone and testosterone were assessed under different conditions. Results of sexual behavior and the forced swim test corroborate the depressive-like effect of CMI. The sole presence of an estrogenized stimulus female caused an increase in plasma levels of testosterone in both control and CMI-treated Ss. The same was true for corticosterone; however, this increase was significantly lower in the CMI-treated group. There is a discrepancy between the normal hypothalamus-pituitary-gonadal (HPG) response and the decreased sexual behavior. The data suggest that CMI induces permanent changes in the reactivity of the hypothalamic-pituitary-adrenal axis.

  2. A Mathematical Model of Neonatal Rat Atrial Monolayers with Constitutively Active Acetylcholine-Mediated K+ Current

    PubMed Central

    Majumder, Rupamanjari; Jangsangthong, Wanchana; Feola, Iolanda; Ypey, Dirk L.; Pijnappels, Daniël A.; Panfilov, Alexander V.

    2016-01-01

    Atrial fibrillation (AF) is the most frequent form of arrhythmia occurring in the industrialized world. Because of its complex nature, each identified form of AF requires specialized treatment. Thus, an in-depth understanding of the bases of these arrhythmias is essential for therapeutic development. A variety of experimental studies aimed at understanding the mechanisms of AF are performed using primary cultures of neonatal rat atrial cardiomyocytes (NRAMs). Previously, we have shown that the distinct advantage of NRAM cultures is that they allow standardized, systematic, robust re-entry induction in the presence of a constitutively-active acetylcholine-mediated K+ current (IKACh-c). Experimental studies dedicated to mechanistic explorations of AF, using these cultures, often use computer models for detailed electrophysiological investigations. However, currently, no mathematical model for NRAMs is available. Therefore, in the present study we propose the first model for the action potential (AP) of a NRAM with constitutively-active acetylcholine-mediated K+ current (IKACh-c). The descriptions of the ionic currents were based on patch-clamp data obtained from neonatal rats. Our monolayer model closely mimics the action potential duration (APD) restitution and conduction velocity (CV) restitution curves presented in our previous in vitro studies. In addition, the model reproduces the experimentally observed dynamics of spiral wave rotation, in the absence and in the presence of drug interventions, and in the presence of localized myofibroblast heterogeneities. PMID:27332890

  3. Neonatal hypoxia-ischemia induces attention-deficit hyperactivity disorder-like behavior in rats.

    PubMed

    Miguel, Patrícia Maidana; Schuch, Clarissa Pedrini; Rojas, Joseane Jiménez; Carletti, Jaqueline Vieira; Deckmann, Iohanna; Martinato, Luísa Helena Machado; Pires, Augusto Viana; Bizarro, Lisiane; Pereira, Lenir Orlandi

    2015-06-01

    Attention-deficit hyperactivity disorder (ADHD) may be caused by genetic or environmental factors. Among environmental factors, perinatal complications are related, such as neonatal hypoxia-ischemia (HI). Thus, the aim of this study was to investigate whether HI contributes to the development of characteristics related to ADHD in adult rats, and to correlate the behavioral results with brain damage volume. Male Wistar rats were divided into 2 groups: HI and control. The HI procedure consisted of a permanent occlusion of the right common carotid artery followed by a period of hypoxia (90 min; 8% O₂ and 92% N₂) on the 7th postnatal day. Two months later, animals were evaluated in the open field test during a single 5-min session, and in the 5-choice serial reaction time task (5-CSRTT), over 25 weeks. Our results demonstrated that animals submitted to HI manifest cognitive impairments in task acquisition, deficits in sustained attention, and increases in impulsivity and compulsivity in response to task manipulation in the 5-CSRTT. Locomotor activity observed in open field did not differ between groups. Moreover, brain volume loss in the total hemisphere, cerebral cortex, white matter, hippocampus, and striatum were observed in HI animals, especially on the side ipsilateral to the lesion. From these results, we can infer that neonatal HI is an environmental factor that could contribute to the development of behavioral characteristics observed in ADHD that are associated with general brain atrophy.

  4. In situ morphology of the foramen ovale in the fetal and neonatal rat.

    PubMed

    Momma, K; Ito, T; Ando, M

    1992-12-01

    In situ cross-sectional morphology of the foramen ovale was studied after rapid whole-body freezing of the fetal and neonatal rat. In the fetus, the foramen ovale was open widely toward the left atrium with a thin, short primum septum. The opening area of the foramen ovale was 40% of the cross-section of the thoracic inferior vena cava, and the ratio of the long diameter to the short diameter was 2 to 1. After birth, the primum septum became longer, thicker, and straighter, with less leftward bowing. The opening of the foramen ovale diminished in the first 2 d and closed completely 3 d after birth. Postnatal thickening of the primum septum was very remarkable, increasing by 400% in the first 2d, while only minimal change was noticed in the right and the left atrial walls. The length of the primum septum was short and was only 90% of the diameter of the fossa ovalis in the fetus. It increased and reached 97% and 111% of the diameter of the fossa ovalis 1 and 2 d after birth, respectively. The septum secundum also grew rapidly after birth, and its length and width increased by 40% and 29% after 1 and 2 d, respectively. These observations indicate a sudden, explosive growth of the atrial septum in the early neonatal period in the rat. PMID:1287556

  5. Effects of neonatal treatment with two phytoestrogens on male rat sexual behavior and partner preference.

    PubMed

    Morales-Otal, Adriana; Ferreira-Nuño, Armando; Olayo-Lortia, Jesús; Barrios-González, Javier; Tarragó-Castellanos, Rosario

    2016-10-01

    The aim of this work was to compare the effect of neonatal treatment with the phytoestrogens coumestrol (COU) and genistein (GEN), administered in equimolecular doses, on the sexual behavior and partner preference of male rats. Four groups of male rats were injected daily from day 1 to 5 with 150 µg of GEN, an equivalent amount of COU, 1 µg of β-estradiol 3-benzoato (EB), or olive oil (VEH) (control). A fifth group remained intact. In the GEN group, intromission and ejaculation latencies decreased, whereas ejaculatory frequency increased. Contrasting results were observed in COU males. EB males could not ejaculate and their mount and intromission latencies increased significantly. To determine sexual-partner preferences, a multiple partner preference arena was used and two types of tests were performed, the first one without allowing contact test (CT) with the stimulus animals, followed by a CT. COU and GEN groups did not show preference for any stimulus animal, whereas the EB males preferred the expert male. When CT with the stimulus animals was allowed, GEN-males preferred the receptive female, unlike the COU and EB groups. It is concluded that neonatal treatment with COU and GEN induced opposite effects, the effects of COU being more estrogenic. PMID:27482864

  6. CXCR4 Blockade Attenuates Hyperoxia Induced Lung Injury in Neonatal Rats

    PubMed Central

    Drummond, Shelley; Ramachandran, Shalini; Torres, Eneida; Huang, Jian; Hehre, Dorothy; Suguihara, Cleide; Young, Karen C.

    2015-01-01

    Background Lung inflammation is a key factor in the pathogenesis of bronchopulmonary dysplasia (BPD). Stromal derived factor-1 (SDF-1) and its receptor chemokine receptor 4 (CXCR4) modulate the inflammatory response. Whether antagonism of CXCR4 will alleviate lung inflammation in neonatal hyperoxia-induced lung injury is unknown. Objective To determine whether CXCR4 antagonism would attenuate lung injury in rodents with experimental BPD by decreasing pulmonary inflammation. Methods Newborn rats exposed to normoxia (RA) or hyperoxia (FiO2=0.9) from postnatal day 2 (P2)-P16 were randomized to receive the CXCR4 antagonist, AMD3100 or placebo (PL) from P5 to P15. Lung alveolarization, angiogenesis, and inflammation were evaluated at P16. Results As compared to RA, hyperoxic-PL pups had a decrease in alveolarization, reduced lung vascular density and increased lung inflammation. In contrast, AMD3100-treated hyperoxic pups had improved alveolarization and increased angiogenesis. This improvement in lung structure was accompanied by a decrease in bronchoalveolar lavage fluid macrophage and neutrophil count and reduced lung myeloperoxidase activity. Conclusion CXCR4 antagonism decreases lung inflammation and improves alveolar as well as vascular structure in neonatal rats with experimental BPD. These findings suggest a novel therapeutic strategy to alleviate lung injury in preterm infants with BPD. PMID:25825119

  7. Effect of maternal exercise on biochemical parameters in rats submitted to neonatal hypoxia-ischemia.

    PubMed

    Marcelino, Thiago Beltram; de Lemos Rodrigues, Patrícia Idalina; Miguel, Patrícia Maidana; Netto, Carlos Alexandre; Pereira Silva, Lenir Orlandi; Matté, Cristiane

    2015-10-01

    Pregnancy is a critical period for brain metabolic programming, being affected by individual environment, such as nutrition, stress, and physical exercise. In this context, we previously reported a cerebral antioxidant upregulation and mitochondrial biogenesis in the offspring delivered from exercised mothers, which could provide neuroprotection against neonatal insults. Hypoxia-ischemia (HI) encephalopathy is one of the most studied models of neonatal brain injury; disrupting motor, cognitive, and learning abilities. Physiopathology includes oxidative stress, allied to mitochondria energy production failure, glutamatergic excitotoxicity, and cell death. In this study we evaluated the effect of maternal swimming during pregnancy on offspring׳s brain oxidative status evaluated fourteen days after HI stablishment. Swimming exercise was performed by female adult rats one week before and during pregnancy, in controlled environment. Their offspring was submitted to HI on postnatal day 7, and the brain samples for biochemical assays were obtained in the weaning. Contrary to our expectations, maternal exercise did not prevent the oxidative alterations observed in brain from HI-rats. In a general way, we found a positive modulation in the activities of antioxidant enzymes, measured two weeks after HI, in hippocampus, striatum, and cerebellum of pups delivered from exercised mothers. Reactive species levels were modulated differently in each structure evaluated. Considering the scenery presented, we concluded that HI elicited a neurometabolic adaptation in both brain hemispheres, particularly in hippocampus, parietal cortex, and cerebellum; while striatum appears to be most damaged. The protocol of aerobic maternal exercise was not enough to fully prevent HI-induced brain damages.

  8. Non-injurious neonatal hypoxia confers resistance to brain senescence in aged male rats.

    PubMed

    Martin, Nicolas; Bossenmeyer-Pourié, Carine; Koziel, Violette; Jazi, Rozat; Audonnet, Sandra; Vert, Paul; Guéant, Jean-Louis; Daval, Jean-Luc; Pourié, Grégory

    2012-01-01

    Whereas brief acute or intermittent episodes of hypoxia have been shown to exert a protective role in the central nervous system and to stimulate neurogenesis, other studies suggest that early hypoxia may constitute a risk factor that influences the future development of mental disorders. We therefore investigated the effects of a neonatal "conditioning-like" hypoxia (100% N₂, 5 min) on the brain and the cognitive outcomes of rats until 720 days of age (physiologic senescence). We confirmed that such a short hypoxia led to brain neurogenesis within the ensuing weeks, along with reduced apoptosis in the hippocampus involving activation of Erk1/2 and repression of p38 and death-associated protein (DAP) kinase. At 21 days of age, increased thicknesses and cell densities were recorded in various subregions, with strong synapsin activation. During aging, previous exposure to neonatal hypoxia was associated with enhanced memory retrieval scores specifically in males, better preservation of their brain integrity than controls, reduced age-related apoptosis, larger hippocampal cell layers, and higher expression of glutamatergic and GABAergic markers. These changes were accompanied with a marked expression of synapsin proteins, mainly of their phosphorylated active forms which constitute major players of synapse function and plasticity, and with increases of their key regulators, i.e. Erk1/2, the transcription factor EGR-1/Zif-268 and Src kinase. Moreover, the significantly higher interactions between PSD-95 scaffolding protein and NMDA receptors measured in the hippocampus of 720-day-old male animals strengthen the conclusion of increased synaptic functional activity and plasticity associated with neonatal hypoxia. Thus, early non-injurious hypoxia may trigger beneficial long term effects conferring higher resistance to senescence in aged male rats, with a better preservation of cognitive functions.

  9. Enriched rehabilitation promotes motor recovery in rats exposed to neonatal hypoxia-ischemia.

    PubMed

    Schuch, Clarissa Pedrini; Jeffers, Matthew Strider; Antonescu, Sabina; Nguemeni, Carine; Gomez-Smith, Mariana; Pereira, Lenir Orlandi; Morshead, Cindi M; Corbett, Dale

    2016-05-01

    Despite continuous improvement in neonatology there is no clinically effective treatment for perinatal hypoxia ischemia (HI). Therefore, development of a new therapeutic intervention to minimize the resulting neurological consequences is urgently needed. The immature brain is highly responsive to environmental stimuli, such as environmental enrichment but a more effective paradigm is enriched rehabilitation (ER), which combines environmental enrichment with daily reach training. Another neurorestorative strategy to promote tissue repair and functional recovery is cyclosporine A (CsA). However, potential benefits of CsA after neonatal HI have yet to be investigated. The aim of this study was to investigate the effects of a combinational therapy of CsA and ER in attempts to promote cognitive and motor recovery in a rat model of perinatal hypoxic-ischemic injury. Seven-day old rats were submitted to the HI procedure and divided into 4 groups: CsA+Rehabilitation; CsA+NoRehabilitation; Vehicle+Rehabilitation; Vehicle+NoRehabilitation. Behavioural parameters were evaluated pre (experiment 1) and post 4 weeks of combinational therapy (experiment 2). Results of experiment 1 demonstrated reduced open field activity of HI animals and increased foot faults relative to shams in the ladder rung walking test. In experiment 2, we showed that ER facilitated acquisition of a staircase skilled-reaching task, increased number of zone crosses in open-field exploration and enhanced coordinated limb use during locomotion on the ladder rung task. There were no evident deficits in novel object recognition testing. Delayed administration of CsA, had no effect on functional recovery after neonatal HI. There was a significant reduction of cortical and hemispherical volume and hippocampal area, ipsilateral to arterial occlusion in HI animals; combinational therapy had no effect on these morphological measurements. In conclusion, the present study demonstrated that ER, but not CsA was the main

  10. Enriched rehabilitation promotes motor recovery in rats exposed to neonatal hypoxia-ischemia.

    PubMed

    Schuch, Clarissa Pedrini; Jeffers, Matthew Strider; Antonescu, Sabina; Nguemeni, Carine; Gomez-Smith, Mariana; Pereira, Lenir Orlandi; Morshead, Cindi M; Corbett, Dale

    2016-05-01

    Despite continuous improvement in neonatology there is no clinically effective treatment for perinatal hypoxia ischemia (HI). Therefore, development of a new therapeutic intervention to minimize the resulting neurological consequences is urgently needed. The immature brain is highly responsive to environmental stimuli, such as environmental enrichment but a more effective paradigm is enriched rehabilitation (ER), which combines environmental enrichment with daily reach training. Another neurorestorative strategy to promote tissue repair and functional recovery is cyclosporine A (CsA). However, potential benefits of CsA after neonatal HI have yet to be investigated. The aim of this study was to investigate the effects of a combinational therapy of CsA and ER in attempts to promote cognitive and motor recovery in a rat model of perinatal hypoxic-ischemic injury. Seven-day old rats were submitted to the HI procedure and divided into 4 groups: CsA+Rehabilitation; CsA+NoRehabilitation; Vehicle+Rehabilitation; Vehicle+NoRehabilitation. Behavioural parameters were evaluated pre (experiment 1) and post 4 weeks of combinational therapy (experiment 2). Results of experiment 1 demonstrated reduced open field activity of HI animals and increased foot faults relative to shams in the ladder rung walking test. In experiment 2, we showed that ER facilitated acquisition of a staircase skilled-reaching task, increased number of zone crosses in open-field exploration and enhanced coordinated limb use during locomotion on the ladder rung task. There were no evident deficits in novel object recognition testing. Delayed administration of CsA, had no effect on functional recovery after neonatal HI. There was a significant reduction of cortical and hemispherical volume and hippocampal area, ipsilateral to arterial occlusion in HI animals; combinational therapy had no effect on these morphological measurements. In conclusion, the present study demonstrated that ER, but not CsA was the main

  11. Neonatal proinflammatory challenge in male Wistar rats: Effects on behavior, synaptic plasticity, and adrenocortical stress response.

    PubMed

    Tishkina, Anna; Stepanichev, Mikhail; Kudryashova, Irina; Freiman, Sofia; Onufriev, Mikhail; Lazareva, Natalia; Gulyaeva, Natalia

    2016-05-01

    Effects of neonatal proinflammatory stress (NPS) on the development of anxiety and depressive-like behavior, stress responsiveness, hippocampal plasticity and conditioned fear response were studied in adolescent and adult male Wistar rats. On PND 3 and PND 5, the pups were subcutaneously injected with bacterial lipopolysaccharide (LPS, 50 μg/kg). In the open field test, signs of increased anxiety were demonstrated in adolescent (PND 32), but not in adult (PND 101) rats. In the elevated plus maze, no changes could be detected in adolescent rats, however, in the adults the number of entries into the open arms decreased suggesting increased anxiety after NPS. Signs of "behavioral despair" in the forced swim test, expressed in adolescent rats as a trend, became significant in the adults indicating depression-like behavior. In the majority of brain slices from PND 19-PND 33 rats subjected to NPS, deficit of LTP in the hippocampal CA1 field was detected, this deficit being associated with the impaired mechanisms of LTP induction. In the adult rats, NPS enhanced fear conditioning promoting improved formation of the novel context-foot shock association in the contextual fear conditioning paradigm without effect on cued fear conditioning. NPS significantly impaired functioning of the hypothalamic-pituitary-adrenal axis (HPAA), resulting in an elevated corticosterone level maintained in the adolescents but not in the adults and in modified corticosterone response to behavioral sub-chronic stress in both adolescent and adult rats. Thus, NPS induces "perinatal malprogramming" resulting in development of depression-like behaviors, associated with abnormalities in functioning of the HPAA, impaired hippocampal neuroplasticity (LTP) and changes in hippocampus-dependent memory formation.

  12. Effect of neonatal MSG treatment on day-night alkaline phosphatase activity in the rat duodenum.

    PubMed

    Martinková, A; Lenhardt, L; Mozes, S

    2000-01-01

    The day-night variation of food intake and alkaline phosphatase (AP) activity was studied in the duodenum of rats neonatally treated with monosodium glutamate (MSG) and saline-treated (control) rats. The animals were kept under light-dark conditions (light phase from 09:00 h to 21:00 h) with free access to food. AP activity was cytophotometrically analyzed in the brush-border of enterocytes separated from the tip, middle and cryptal part of the villi every 6 h over a 24-hour period. In comparison with the controls, MSG-treated rats consumed about 40% less food during the dark period and their 24-hour food intake was thus significantly lowered (P<0.001). On the other hand, the nocturnal feeding habit showed a similar pattern: food consumption was high during the night (65% vs. 75%) and the lowest consumption was found during the light phase (35% vs. 25%) in MSG-treated and control rats, respectively. In agreement with the rhythm of food intake, the highest AP activity was observed during the dark phase and was lowest during the light phase in both groups of animals. These significant day-night variations showed nearly the same pattern in the enterocytes of all observed parts along the villus axis. In comparison with the controls, a permanent increase of AP activity was observed in neonatal MSG-treated rats. This increase was more expressive during the dark phase of the day in the cryptal (P<0.001) and middle part of the villus (P<0.01). From the viewpoint of feeding, this enzyme in MSG-treated rats was enhanced in an inverse relation to the amount of food eaten i.e. despite sustained hypophagia the mean AP activity in the enterocytes along the villus axis was higher than in the control animals during all investigated periods. The present results suggest that the increased AP activity in MSG-treated rats is probably not a consequence of actual day-night eating perturbations but could be a component of a more general effect of MSG. This information contributes to

  13. Evidence that FOXO3a is involved in oocyte apoptosis in the neonatal rat ovary.

    PubMed

    Sui, Xu-Xia; Luo, Li-Li; Xu, Jin-Jie; Fu, Yu-Cai

    2010-08-01

    Previous studies have proposed that the forkhead transcription factor FOXO3a is involved in cell cycle arrest and apoptosis and that it may also repress follicular development by inducing cell cycle arrest in ovaries. We have recently demonstrated that FOXO3a induces oocyte apoptosis of neonatal rat ovaries under in vitro conditions. In the present study, we evaluated the role of FOXO3a in oocyte apoptosis under in vivo conditions. Ovaries from rats were obtained from newborns on postnatal day (PD) 1, 2, 3, and 4. TUNEL assay results showed that oocyte apoptosis occurred mainly on PD 1 and 2. Immunohistochemical staining of FOXO3a, Bim, Fas ligand (FasL), p27KIP1, caspase-8, and caspase-3 showed that they were all expressed mainly in naked oocytes on PD 1 and 2. The percentage of positive FOXO3a staining of oocytes reached peak levels in the ovaries of 2-day-old rats, which was consistent with the rate of the apoptotic profiles determined by TUNEL. The percentage between TUNEL-positive and FOXO3a-positive oocytes in the nucleus showed no statistical differences within the 4-day-old rat ovaries. Furthermore, the positive oocyte percentage of the target factors of FOXO3a (Bim, p27KIP1, and FasL) and pro-apoptotic proteins (caspase-3 and caspase-8) also reached peak levels in the ovaries of 2-day-old rats, which was similar to the rate of FOXO3a-positive oocytes. These results suggest that FOXO3a in the oocyte nucleus is involved in oocyte apoptosis; that is, FOXO3a-positive oocytes may be the apoptotic cells. To verify this, rat oocytes were subjected to TUNEL and immunofluorescent double-labeling assays. We found that TUNEL-positive cells were also FOXO3a-, Bim-, or FasL-positive. To identify the downstream target of FOXO3a, double immunofluorescent staining with antibodies to Bim and FasL was performed. We found that FOXO3a-positive cells were also Bim- and FasL-positive. We conclude that the overexpression of FOXO3a in the oocyte nucleus of neonatal rat ovaries

  14. LEFT VENTRICULAR INFLOW OBSTRUCTION BY GIANT ATRIAL SEPTAL ANEURYSM IN A NEONATE WITH HYPOPLASTIC RIGHT HEART SYNDROME: CASE REPORT.

    PubMed

    Yuko-Jowi, C; Okello, C A

    2013-02-01

    Atrial septal aneurysm remains a rare congenital cardiac malformation. In the neonatal age group it can occur as an isolated cardiac malformation or in association with complex hypoplastic cardiac malformations of the right and left heart. In the adult population most aneurysms have been described in association with stroke. Baby H.N delivered on 10/05/2008 by C/S, was cyanosed at birth with systemic desaturation. Chest X-ray showed oligaemic lung fields while two dimensional echocardiograms showed tricuspid atresia with hypoplastic right ventricle, large secundum atrial septal defect, and highly mobile gigantic aneurysms of the atrial septum obstructing the inflow of the mitral valve and entering the left ventricle in diastole. Surgical intervention was not possible and child died on second day.

  15. Neonatally Induced Mild Diabetes in Rats and Its Effect on Maternal, Placental, and Fetal Parameters

    PubMed Central

    Sinzato, Yuri Karen; Volpato, Gustavo Tadeu; Iessi, Isabela Lovizutto; Bueno, Aline; Calderon, Iracema de Mattos Paranhos; Rudge, Marilza Vieira Cunha; Damasceno, Débora Cristina

    2012-01-01

    The aim of this study was to assess placental changes and reproductive outcomes in neonatally induced mild diabetic dams and fetal development in their offspring. At birth, female rats were assigned either to control or diabetic group (100 mg of streptozotocin/Kg, subcutaneously). At adulthood, the female rats were mated. During pregnancy, the blood glucose levels and glucose and insulin tolerance tests were performed. At term, maternal reproductive outcomes, fetal and placental weight, and placental morphology were analyzed. Diabetic rats had smaller number of living fetuses, implantations and corpora lutea, and increased rate of embryonic loss. Placenta showed morphometric alterations in decidua area. Our results showed that mild diabetes was sufficient to trigger alterations in maternal organism leading to impaired decidua development contributing to failure in embryonic implantation and early embryonic losses. Regardless placental decidua alteration, the labyrinth, which is responsible for the maternal-fetal exchanges, showed no morphometric changes contributing to an appropriate fetal development, which was able to maintain normal fetal weight at term in mild diabetic rats. Thus, this experimental model of diabetes induction at the day of birth was more effective to reproduce the reproductive alterations of diabetic women. PMID:22778712

  16. Rewarded associative and instrumental conditioning after neonatal ventral hippocampus lesions in rats.

    PubMed

    Macedo, Carlos Eduardo; Sandner, Guy; Angst, Marie-Josée; Guiberteau, Thierry

    2008-06-18

    Sprague Dawley rats were submitted to bilateral ventral hippocampus lesions 7 days after birth. This corresponds to the Lipska and Weinberger's procedure for modeling schizophrenia. The aim of the present work was to test the learning capacity of such rats with an associative Pavlovian and an instrumental learning paradigm, both methods using reward outcome (food, sucrose or polycose). The associative paradigm comprised also a second learning test with reversed learning contingencies. The instrumental conditioning comprised an extinction test under outcome devaluation conditions. Neonatally lesioned rats, once adults (over 60 days of age), showed a conditioning deficit in the associative paradigm but not in the instrumental one. Lesioned rats remained able to adapt as readily as controls to the reversed learning contingency and were as sensitive as controls to the devaluation of outcome. Such observations indicate that the active access (instrumental learning) to a reward could have compensated for the deficit observed under the "passive" stimulus-reward associative learning condition. This feature is compared to the memory management impairments observed in clinical patients.

  17. Neonatal Maternal Separation Augments Carotid Body Response to Hypoxia in Adult Males but Not Female Rats

    PubMed Central

    Soliz, Jorge; Tam, Rose; Kinkead, Richard

    2016-01-01

    Perinatal exposure to adverse experiences disrupts brain development, including the brainstem network that regulates breathing. At adulthood, rats previously subjected to stress (in the form of neonatal maternal separation; NMS) display features reported in patients suffering from sleep disordered breathing, including an increased hypoxic ventilatory response and hypertension. This effect is also sex-specific (males only). Based on these observations, we hypothesized that NMS augments the carotid body's O2-chemosensitivity. Using an isolated and perfused ex vivo carotid body preparation from adult rats we compared carotid sinus nerve (CSN) responses to hypoxia and hypercapnia in carotid bodies harvested from adult rats that either experienced control conditions (no experimental manipulation) or were subjected to NMS (3 h/day from postnatal days 3 to 12). In males, the CSN response to hypoxia measured in preparations from NMS males was 1.5 fold higher than controls. In control rats, the female's response was similar to that of males; however, the increase in CSN activity measured in NMS females was 3.0 times lower than controls. The CSN response to hypercapnia was not influenced by stress or sex. We conclude that NMS is sufficient to have persistent and sex-specific effects on the carotid body's response to hypoxia. Because NMS also has sex-specific effects on the neuroendocrine response to stress, we propose that carotid body function is influenced by stress hormones. This, in turn, leads to a predisposition toward cardio-respiratory disorders. PMID:27729873

  18. Effects of neonatal exposure to a glyphosate-based herbicide on female rat reproduction.

    PubMed

    Ingaramo, Paola I; Varayoud, Jorgelina; Milesi, María M; Schimpf, Marlise Guerrero; Muñoz-de-Toro, Mónica; Luque, Enrique H

    2016-11-01

    In this study, we investigated whether neonatal exposure to a glyphosate-based herbicide (GBH) alters the reproductive performance and the molecular mechanisms involved in the decidualization process in adult rats. Newborn female rats received vehicle or 2 mg/kg/day of a GBH on postnatal days (PND) 1, 3, 5 and 7. On PND90, the rats were mated to evaluate (i) the reproductive performance on gestational day (GD) 19 and (ii) the ovarian steroid levels, uterine morphology, endometrial cell proliferation, apoptosis and cell cycle regulators, and endocrine pathways that regulate uterine decidualization (steroid receptors/COUP-TFII/Bmp2/Hoxa10) at the implantation sites (IS) on GD9. The GBH-exposed group showed a significant increase in the number of resorption sites on GD19, associated with an altered decidualization response. In fact, on GD9, the GBH-treated rats showed morphological changes at the IS, associated with a decreased expression of estrogen and progesterone receptors, a downregulation of COUP-TFII (Nr2f2) and Bmp2 mRNA and an increased expression of HOXA10 and the proliferation marker Ki67(Mki67) at the IS. We concluded that alterations in endometrial decidualization might be the mechanism of GBH-induced post-implantation embryo loss. PMID:27486271

  19. In vivo constriction of the fetal and neonatal ductus arteriosus by a prostanoid EP4-receptor antagonist in rats.

    PubMed

    Momma, Kazuo; Toyoshima, Katsuaki; Takeuchi, Daiji; Imamura, Shinichiro; Nakanishi, Toshio

    2005-11-01

    Indomethacin is used to constrict the patent ductus arteriosus in premature infants. To clarify possible prostanoid receptor antagonists that can constrict the ductus, we studied in vivo constriction of the fetal and neonatal ductus arteriosus by AE3-208, a prostanoid EP4-receptor antagonist, in rats. Following quick cesarean section of near-term pregnant rats (21 d), neonates were incubated in room air at 33 degrees C. The inner diameter of the ductus was measured with a microscope and a micrometer following rapid whole-body freezing of the fetus and neonate, and sectioning of the thorax in the frontal plane on a freezing microtome. In the control, the ductus arteriosus constricted quickly after birth, and the inner diameter was 0.80 mm in the fetus and 0.06 mm at 90 min after birth. AE3-208, administered orogastrically to the dam, constricted the fetal ductus dose dependently. Maximal ductal constriction was observed 4 h after administration, and the ductal diameters were 0.06 mm and 0.26 mm after administration of 10 mg/kg and 10 ng/kg of AE3-208, respectively. In neonatal rats, AE3-208 injected subcutaneously at 30 min after birth, inhibited dilatation of the ductus by PGE1 dose dependently. PGE1 (10 microg/kg) was injected subcutaneously to the 1-h-old neonatal rat, and the ductal diameters were 0.53 mm and 0.19 mm without and with pretreatment of AE3-208 (10 microg/kg), respectively. These results indicate the major role of EP4 in the fetal and neonatal ductus and show that an EP4 antagonist can be used to constrict the patent ductus of premature infants.

  20. Chronic hydrogen-rich saline treatment reduces oxidative stress and attenuates left ventricular hypertrophy in spontaneous hypertensive rats.

    PubMed

    Yu, Yong-Sheng; Zheng, Hao

    2012-06-01

    In hypertensive animals and patients, oxidative stress represents the primary risk factor for progression of left ventricular hypertrophy. Recently, it has been demonstrated that hydrogen, as a novel antioxidant, can selectively reduce hydroxyl radicals and peroxynitrite anion to exert therapeutic antioxidant activity. In the current study, we explored the effect of chronic treatment with hydrogen-rich saline (HRS) on left ventricular hypertrophy in spontaneously hypertensive rats (SHR). The 8-week-old male SHR and age-matched Wistar-Kyoto rats (WKY) were randomized into HRS-treated (6 ml/kg/day for 3 months, i.p.) and vehicle-treated groups. HRS treatment had no significant effect on blood pressure, but it effectively attenuated left ventricular hypertrophy in SHR. HRS treatment abated oxidative stress, restored the activity of antioxidant enzymes including GPx, GST, catalase, and SOD, suppressed NADPH oxidase activity and downregulated Nox2 and Nox4 expression in left ventricles of SHR. HRS treatment suppressed pro-inflammatory cytokines including IL-1β, IL-6, TNF-α, and MCP-1, and inhibited NF-κB activation through preventing IκBα degradation in left ventricles of SHR. HRS treatment preserved mitochondrial function through restoring electron transport chain enzyme activity, repressing ROS formation, and enhancing ATP production in left ventricles of SHR. Moreover, HRS treatment suppressed ACE expression and locally reduced angiotensin II generation in left ventricles of SHR. In conclusion, HRS treatment attenuates left ventricular hypertrophy through abating oxidative stress, suppressing inflammatory process, preserving mitochondrial function, in which suppression of HRS on angiotensin II in left ventricles locally might be involved.

  1. [Effect of allitridum on remodeling of the transient outward potassium current of ventricular myocytes of spontaneously hypertensive rats].

    PubMed

    Dan, Qing; Zhao, Ying; Wu, Zhi-juan; Zhu, Chao; Liu, Li; Xu, Bin; Liu, Yu-qi; Chen, Qi; Li, Yang

    2015-01-01

    We aimed to study the effect of allitridum (All) on the transient outward potassium current (Ito) of ventricular myocytes of spontaneously hypertensive rats (SHR). Totally 30 male SHRs were randomly divided into three groups: low-dose All group (7.5 mg·kg(-1)), high-dose All group (15.0 mg·kg(-1)) and normal saline group. The other 10 sex and age matched Wistar-kyoto rats (WKY) were also taken as control group (WKY group). All animals received i.p. administration for 8 weeks. The dual enzymatic method was used to separate single ventricular myocyte from animals. Patch-clamp technique was used to record Ito and analyze the effect of All on the current. It was shown that the left ventricular hypertrophy of SHR was reversed significantly by All. Furthermore, the density of Ito was recovered in both high and low dose All groups. The peak current densities of Ito were enhanced from 18.23±3.64 to 25.17±2.86 pA/pF (P<0.01) and 36.47±5.42 pA/pF (P<0.01) at +50 mV by All 7.5 mg·kg(-1) and 15.0 mg·kg(-1), respectively, which was not significantly different with WKY group. The effect was associated with positive shift of the steady-state, close-state inactivation, and shortened recovery from inactivation of Ito. It is concluded that All decreases the remodeling of Ito of ventricular hypertrophic myocytes of SHR. PMID:25924473

  2. Overexpression of VEGF-C attenuates chronic high salt intake-induced left ventricular maladaptive remodeling in spontaneously hypertensive rats.

    PubMed

    Yang, Guo-Hong; Zhou, Xin; Ji, Wen-Jie; Zeng, Shan; Dong, Yan; Tian, Lu; Bi, Ying; Guo, Zhao-Zeng; Gao, Fei; Chen, Hong; Jiang, Tie-Min; Li, Yu-Ming

    2014-02-15

    Recent studies have shown that the tonicity-responsive enhancer binding protein (TonEBP)/vascular endothelial growth factor-C (VEGF-C) signaling pathway-induced lymphangiogenesis provides a buffering mechanism for high salt (HS) intake-induced elevation of blood pressure (BP). Moreover, blocking of TonEBP/VEGF-C signaling by mononuclear phagocyte depletion can induce salt-sensitive hypertension in rats. We hypothesized that HS intake could have an impact on cardiac lymphangiogenesis, and regulation of VEGF-C bioactivity, which is largely through the main receptor for VEGFR-3, may modulate HS intake-induced left ventricular remodeling. We demonstrated upregulation of TonEBP, increased macrophage infiltration, and enhanced lymphangiogenesis in the left ventricles of spontaneously hypertensive rats (SHR) that were fed a HS diet (8.0% NaCl). Then, retrovirus vectors capable of overexpression (ΔNΔC/VEGF-C/Cys152Ser, used for overexpressing VEGF-C) and blocking (VEGFR-3-Rg, used for trapping of bioactive VEGF-C) of VEGF-C and control vector (pLPCX) were intravenously administered to SHR from week 9 of a 12-wk HS loading period. At the end of the HS challenge, overexpression of VEGF-C led to enhanced cardiac lymphangiogenesis, decreased myocardial fibrosis, and macrophage infiltration, preserved left ventricular functions, as well as decreased blood pressure level compared with the HS group and the control vector-treated HS group. In contrast, systemic blocking of VEGF-C was associated with elevation of blood pressure level and an exacerbation of hypertensive left ventricular remodeling, as indicated by increased fibrosis and macrophage infiltration, and diminished lymphangiogenesis. Hence, our findings highlight that VEGF-C/VEGFR-3 is a promising therapeutic target to attenuate hypertensive left ventricular remodeling induced by HS intake, presumably via blood pressure-dependent and -independent mechanisms. PMID:24337460

  3. Fetal transplants rescue axial muscle representations in M1 cortex of neonatally transected rats that develop weight support.

    PubMed

    Giszter, S F; Kargo, W J; Davies, M; Shibayama, M

    1998-12-01

    Fetal transplants rescue axial muscle representations in M1 cortex of neonatally transected rats that develop weight support. J. Neurophysiol. 80: 3021-3030, 1998. Intraspinal transplants of fetal spinal tissue partly alleviate motor deficits caused by spinal cord injury. How transplants modify body representation and muscle recruitment by motor cortex is currently largely unknown. We compared electromyographic responses from motor cortex stimulation in normal adult rats, adult rats that received complete spinal cord transection at the T8-T10 segmental level as neonates (TX rats), and similarly transected rats receiving transplants of embryonic spinal cord (TP rats). Rats were also compared among treatments for level of weight support and motor performance. Sixty percent of TP rats showed unassisted weight-supported locomotion as adults, whereas approximately 30% of TX rats with no intervention showed unassisted weight-supported locomotion. In the weight-supporting animals we found that the transplants enabled motor responses to be evoked by microstimulation of areas of motor cortex that normally represent the lumbar axial muscles in rats. These same regions were silent in all TX rats with transections but no transplants, even those exhibiting locomotion with weight support. In weight-supporting TX rats low axial muscles could be recruited from the rostral cortical axial representation, which normally represents the neck and upper trunk. No operated animal, even those with well-integrated transplants and good weight-supported locomotion, had a hindlimb motor representation in cortex. The data demonstrate that spinal transplants allow the development of some functional interactions between areas of motor cortex and spinal cord that are not available to the rat lacking the intervention. The data also suggest that operated rats that achieve weight support may primarily use the axial muscles to steer the pelvis and hindlimbs indirectly rather than use explicit hindlimb

  4. Early neonatal 192 IgG saporin induces learning impairments and disrupts cortical morphogenesis in rats.

    PubMed

    Ricceri, Laura; Hohmann, Christine; Berger-Sweeney, Joanne

    2002-11-01

    We have shown previously that neonatal intraventricular injections of the selective cholinergic immunotoxin 192 IgG saporin on postnatal day 7 (pnd 7) induce marked cholinergic loss in hippocampus and neocortex and a learning impairment on pnd 15. In the present study, we analysed the behavioural, morphological and neurochemical effects of earlier intraventricular injection of the immunotoxin 192 IgG saporin (pnd 1 and 3). We hypothesised that these earlier lesions would interrupt a critical stage in neocortical maturation, and impair behavior more profoundly than the later lesions. Passive avoidance (PA) learning and locomotor activity during the PA test were assessed on pnd 15. Retention of the PA task was assessed on pnd 16. Reactivity to spatial and object novelty was assessed on pnd 180 in a spatial open field test with five objects. Choline acetyltransferase (ChAT) activity was measured in basal forebrain targets on pnd 20 and pnd 180. Neonatal administration of 192 IgG saporin resulted in a slower acquisition of the PA task in females; retention and locomotor activity were not affected. On pnd 180, reaction to spatial novelty was mildly impaired in lesioned rats of both sexes. There was a marked reduction of ChAT in the hippocampus and neocortex of lesioned rats of both sexes, at both ages. Morphological analysis of the somatosensory cortex of lesioned rats revealed alterations in cortical development with sex specific variations in total cortical thickness. These results suggest that interrupting cholinergic basal forebrain innervation of neocortex and hippocampus during the first postnatal days affects the development of cognitive behaviour, neurochemistry and cortical organisation in a sex specific manner. Furthermore, the alterations in cortical organization are more profound than those noted after a lesion later in postnatal development. These behavioural and morphological abnormalities could be considered a model for several neurodevelopmental

  5. CyPA-CD147-ERK1/2-cyclin D2 signaling pathway is upregulated during rat left ventricular hypertrophy.

    PubMed

    Tang, Fu-Cai; Wang, Hong-Yan; Ma, Ming-Ming; Guan, Tian-Wang; Pan, Long; Yao, Dun-Chen; Chen, Ya-Lan; Chen, Wei-Bei; Tu, Yong-Sheng; Fu, Xiao-Dong

    2015-08-25

    The changes of serum cyclophilin A (CyPA), its receptor CD147 and the downstream signaling pathway during the process of cardiac hypertrophy remain unknown. The present study aims to investigate the relationships between CyPA-CD147-ERK1/2-cyclin D2 signaling pathway and the development of cardiac hypertrophy. Left ventricular hypertrophy was prepared by 2-kidney, 2-clip in Sprague-Dawley rats and observed for 1 week, 4 and 8 weeks. Left ventricular hypertrophy was evaluated by ratio of left ventricular heart weight to body weight (LVW/BW) and cardiomyocyte cross sectional area (CSA). CyPA levels in serum were determined with a rat CyPA ELISA kit. Expressions of CyPA, CD147, phospho-ERK1/2 and cyclin D2 in left ventricular myocytes were determined by Western blot and immunostaining. Compared with sham groups, systolic blood pressure reached hypertensive levels at 4 weeks in 2K2C groups. LVW/BW and CSA in 2K2C groups were significantly increased at 4 and 8 weeks after clipping. ELISA results indicated a prominent increase in serum CyPA level associated with the degree of left ventricular hypertrophy. Western blot revealed that the expressions of CyPA, CD147, phospho-ERK1/2 and cyclin D2 in left ventricular tissues were also remarkably increased as the cardiac hypertrophy developed. The results of the present study demonstrates that serum CyPA and CyPA-CD147-ERK1/2-cyclin D2 signaling pathway in ventricular tissues are time-dependently upregulated and activated with the process of left ventricular hypertrophy. These data suggest that CyPA-CD147 signaling cascade might play a role in the pathogenesis of left ventricular hypertrophy, and CyPA might be a prognosticator of the degree of left ventricular hypertrophy. PMID:26300251

  6. Dual effects of tetracaine on spontaneous calcium release in rat ventricular myocytes.

    PubMed Central

    Györke, S; Lukyanenko, V; Györke, I

    1997-01-01

    1. Confocal microfluorometry was used to study the effects of tetracaine on spontaneous Ca2+ release from the sarcoplasmic reticulum (SR) in isolated rat ventricular myocytes. 2. At low concentrations (0.25-1.25 mM), tetracaine caused an initial inhibition of spontaneous release events (Ca2+ sparks) and Ca2+ waves, which was followed by a gradual increase in Ca2+ release activity. The frequency and magnitude of sparks were first decreased and then increased with respect to control levels. At high concentrations (> 1.25 mM), tetracaine abolished all forms of spontaneous release. 3. Exposure of the myocytes to tetracaine resulted in a gradual increase in the SR Ca2+ load as indexed by changes in the magnitude of caffeine-induced Ca2+ transients. 4. In cardiac SR Ca(2+)-release channels incorporated into lipid bilayers, tetracaine (> 0.25 mM) induced a steady inhibition of channel activity. Addition of millimolar Ca2+ to the luminal side of the channel caused an increase in channel open probability under control conditions as well as in the presence of various concentrations of tetracaine. 5. We conclude that the primary effect of tetracaine on SR Ca(2+)-release channels is inhibition of channel activity both in vitro and in situ. The ability of tetracaine to reduce spark magnitude suggests that these events are not due to activation of single channels or non-reducible clusters of channels and, therefore, supports the multichannel origin of sparks. We propose that the paradoxical late potentiation of release by submaximal concentrations of tetracaine is caused by a gradual increase in SR Ca2+ load and subsequent activation of the Ca(2+)-release channels by Ca2+ inside the SR. Images Figure 1 Figure 2 Figure 4 PMID:9147318

  7. Analysis of Cav1.2 and Ryanodine Receptor Clusters in Rat Ventricular Myocytes

    PubMed Central

    Scriven, David R.L.; Asghari, Parisa; Schulson, Meredith N.; Moore, Edwin D.W.

    2010-01-01

    We analyzed the distribution of ryanodine receptor (RyR) and Cav1.2 clusters in adult rat ventricular myocytes using three-dimensional object-based colocalization metrics. We found that ∼75% of the Cav1.2 clusters and 65% of the RyR clusters were within couplons, and both were roughly two and a half times larger than their extradyadic counterparts. Within a couplon, Cav1.2 was concentrated near the center of the underlying RyR cluster and accounted for ∼67% of its size. These data, together with previous findings from binding studies, enable us to estimate that a couplon contains 74 RyR tetramers and 10 copies of the α-subunit of Cav1.2. Extradyadic clusters of RyR contained ∼30 tetramers, whereas the extradyadic Cav1.2 clusters contained, on average, only four channels. Between 80% and 85% of both RyR and Cav1.2 molecules are within couplons. RyR clusters were in the closest proximity, with a median nearest-neighbor distance of 552 nm; comparable values for Cav1.2 clusters and couplons were 619 nm and 735 nm, respectively. Extradyadic RyR clusters were significantly closer together (624 nm) and closer to the couplons (674 nm) than the couplons were to each other. In contrast, the extradyadic clusters of Cav1.2 showed no preferential localization and were broadly distributed. These results provide a wealth of morphometric data that are essential for understanding intracellular Ca2+ regulation and modeling Ca2+ dynamics. PMID:21156134

  8. Fetal and Neonatal Iron Deficiency Reduces Thyroid Hormone-Responsive Gene mRNA Levels in the Neonatal Rat Hippocampus and Cerebral Cortex

    PubMed Central

    Bastian, Thomas W.; Anderson, Jeremy A.; Fretham, Stephanie J.; Prohaska, Joseph R.; Georgieff, Michael K.

    2012-01-01

    Copper (Cu), iron (Fe), and thyroid hormone (TH) deficiencies produce similar defects in late brain development including hypomyelination of axons and impaired synapse formation and function, suggesting that these micronutrient deficiencies share a common mechanism contributing to these derangements. We previously demonstrated that fetal/neonatal Cu and Fe deficiencies lower circulating TH concentrations in neonatal rats. Fe deficiency also reduces whole-brain T3 content, suggesting impaired TH action in the developing Fe-deficient brain. We hypothesized that fetal/neonatal Cu and Fe deficiencies will produce mild or moderate TH deficiencies and will impair TH-responsive gene expression in the neonatal cerebral cortex and hippocampus. To test this hypothesis, we rendered pregnant Sprague Dawley rats Cu-, Fe-, or TH-deficient from early gestation through postnatal d 10 (P10). Mild and moderate TH deficiencies were induced by 1 and 3 ppm propylthiouracil treatment, respectively. Cu deficiency did not significantly alter serum or tissue TH concentrations or TH-responsive brain mRNA expression. Fe deficiency significantly lowered P10 serum total T3 (45%), serum total T4 (52%), whole brain T3 (14%), and hippocampal T3 (18%) concentrations, producing a mild TH deficiency similar to 1 ppm propylthiouracil treatment. Fe deficiency lowered Pvalb, Enpp6, and Mbp mRNA levels in the P10 hippocampus. Fe deficiency also altered Hairless, Dbm, and Dio2 mRNA levels in the P10 cerebral cortex. These results suggest that some of the brain defects associated with Fe deficiency may be mediated through altered thyroidal status and the concomitant alterations in TH-responsive gene transcription. PMID:23054056

  9. Pentaerythritol Tetranitrate Targeting Myocardial Reactive Oxygen Species Production Improves Left Ventricular Remodeling and Function in Rats With Ischemic Heart Failure.

    PubMed

    Fraccarollo, Daniela; Galuppo, Paolo; Neuser, Jonas; Bauersachs, Johann; Widder, Julian D

    2015-11-01

    Reduced nitric oxide bioavailability contributes to progression of cardiac dysfunction and remodeling in ischemic heart failure. Clinical use of organic nitrates as nitric oxide donors is limited by development of nitrate tolerance and reactive oxygen species formation. We investigated the effects of long-term therapy with pentaerythritol tetranitrate (PETN), an organic nitrate devoid of tolerance, in rats with congestive heart failure after extensive myocardial infarction. Seven days after coronary artery ligation, rats were randomly allocated to treatment with PETN (80 mg/kg BID) or placebo for 9 weeks. Long-term PETN therapy prevented the progressive left ventricular dilatation and improved left ventricular contractile function and relaxation in rats with congestive heart failure. Mitochondrial superoxide anion production was markedly increased in the failing left ventricular myocardium and nearly normalized by PETN treatment. Gene set enrichment analysis revealed that PETN beneficially modulated the dysregulation of mitochondrial genes involved in energy metabolism, paralleled by prevention of uncoupling protein-3, thioredoxin-2, and superoxide dismutase-2 downregulation. Moreover, PETN provided a remarkable protective effect against reactive fibrosis in chronically failing hearts. Mechanistically, induction of heme oxygenase-1 by PETN prevented mitochondrial superoxide generation, NOX4 upregulation, and ensuing formation of extracellular matrix proteins in fibroblasts from failing hearts. In summary, PETN targeting reactive oxygen species generation prevented the changes of mitochondrial antioxidant enzymes and progressive fibrotic remodeling, leading to amelioration of cardiac functional performance. Therefore, PETN might be a promising therapeutic option in the treatment of ischemic heart diseases involving oxidative stress and impairment in nitric oxide bioactivity.

  10. Effects of neonatal fluoxetine exposure on behavior across development in rats selectively bred for an infantile affective trait.

    PubMed

    Zimmerberg, Betty; Germeyan, Sierra C

    2015-03-01

    Infants born to women with depressive symptoms are at higher risk for insecure attachment and behavioral problems. Thus current medical practice is to continue psychotropic medication of pregnant women with depression despite concerns about its behavioral teratology. There are few animal studies focused on long-term behavioral effects of prenatal antidepressant exposure; in addition, studies have not looked at individual differences in baseline affective state as a source of response variability. In this study, fluoxetine, a selective serotonin reuptake inhibitor (SSRI), was administered to male and female rat pups from postnatal days 2-7 to model exposure to antidepressants in the human third trimester. Four behavioral measures were conducted from the neonatal to adult age periods in Low and High lines selectively bred for their rate of ultrasonic vocalizations after brief maternal separation. Neonatal fluoxetine administration decreased distress calls in both lines, but to a greater extent in High line rats than Low line. Neonatal fluoxetine also impaired motor coordination in neonates. Neonatal fluoxetine administration decreased social behavior in both juvenile and adult subjects. Fluoxetine-related reductions in anxiety behavior were not observed at the two older ages. As expected, High line subjects displayed more anxiety behavior than Low line subjects at all three test ages. These results suggest that there are may be significant behavioral consequences of antidepressant use during late pregnancy on offspring maternal attachment and social behavior, with implications for increased risk of autism spectrum disorders.

  11. Effects of neonatal fluoxetine exposure on behavior across development in rats selectively bred for an infantile affective trait.

    PubMed

    Zimmerberg, Betty; Germeyan, Sierra C

    2015-03-01

    Infants born to women with depressive symptoms are at higher risk for insecure attachment and behavioral problems. Thus current medical practice is to continue psychotropic medication of pregnant women with depression despite concerns about its behavioral teratology. There are few animal studies focused on long-term behavioral effects of prenatal antidepressant exposure; in addition, studies have not looked at individual differences in baseline affective state as a source of response variability. In this study, fluoxetine, a selective serotonin reuptake inhibitor (SSRI), was administered to male and female rat pups from postnatal days 2-7 to model exposure to antidepressants in the human third trimester. Four behavioral measures were conducted from the neonatal to adult age periods in Low and High lines selectively bred for their rate of ultrasonic vocalizations after brief maternal separation. Neonatal fluoxetine administration decreased distress calls in both lines, but to a greater extent in High line rats than Low line. Neonatal fluoxetine also impaired motor coordination in neonates. Neonatal fluoxetine administration decreased social behavior in both juvenile and adult subjects. Fluoxetine-related reductions in anxiety behavior were not observed at the two older ages. As expected, High line subjects displayed more anxiety behavior than Low line subjects at all three test ages. These results suggest that there are may be significant behavioral consequences of antidepressant use during late pregnancy on offspring maternal attachment and social behavior, with implications for increased risk of autism spectrum disorders. PMID:25503615

  12. Distribution of bisphenol A into tissues of adult, neonatal, and fetal Sprague-Dawley rats

    SciTech Connect

    Doerge, Daniel R.; Twaddle, Nathan C.; Vanlandingham, Michelle; Brown, Ronald P.; Fisher, Jeffrey W.

    2011-09-15

    Bisphenol A (BPA) is an important industrial chemical used in the manufacture of polycarbonate plastic products and epoxy resin-based food can liners. The presence of BPA metabolites in urine of > 90% of Americans aged 6-60 suggests ubiquitous and frequent exposure in the range of 0.02-0.2 {mu}g/kg bw/d (25th-95th percentiles). The current study used LC/MS/MS to measure placental transfer and concentrations of aglycone (receptor-active) and conjugated (inactive) BPA in tissues from Sprague-Dawley rats administered deuterated BPA (100 {mu}g/kg bw) by oral and IV routes. In adult female rat tissues, the tissue/serum concentration ratios for aglycone BPA ranged from 0.7 in liver to 5 in adipose tissue, reflecting differences in tissue perfusion, composition, and metabolic capacity. Following IV administration to dams, placental transfer was observed for aglycone BPA into fetuses at several gestational days (GD), with fetal/maternal serum ratios of 2.7 at GD 12, 1.2 at GD 16, and 0.4 at GD 20; the corresponding ratios for conjugated BPA were 0.43, 0.65, and 3.7. These ratios were within the ranges observed in adult tissues and were not indicative of preferential accumulation of aglycone BPA or hydrolysis of conjugates in fetal tissue in vivo. Concentrations of aglycone BPA in GD 20 fetal brain were higher than in liver or serum. Oral administration of the same dose did not produce measurable levels of aglycone BPA in fetal tissues. Amniotic fluid consistently contained levels of BPA at or below those in maternal serum. Concentrations of aglycone BPA in tissues of neonatal rats decreased with age in a manner consistent with the corresponding circulating levels. Phase II metabolism of BPA increased with fetal age such that near-term fetus was similar to early post-natal rats. These results show that concentrations of aglycone BPA in fetal tissues are similar to those in other maternal and neonatal tissues and that maternal Phase II metabolism, especially following oral

  13. Alterations to prepulse inhibition magnitude and latency in adult rats following neonatal treatment with domoic acid and social isolation rearing.

    PubMed

    Marriott, Amber L; Tasker, R Andrew; Ryan, Catherine L; Doucette, Tracy A

    2016-02-01

    Deficits in perceptual, informational, and attentional processing are consistently identified as a core feature in schizophrenia and related neuropsychiatric disorders. Neonatal injections of low doses of the AMPA/kainate agonist domoic acid (DOM) have previously been shown to alter various aspects of perceptual and attentional processing in adult rats. The current study investigated the effects of combined neonatal DOM treatment with isolation rearing on prepulse inhibition behaviour and relevant neurochemical measures, to assess the usefulness of these paradigms in modeling neurodevelopmental disorders. Daily subcutaneous injections of DOM (20 μg/kg) or saline were administered to male and female rat pups from postnatal days (PND) 8-14. After weaning, rats were either housed alone or in groups of 4. Both the magnitude and latency of prepulse inhibition were determined in adulthood (approximately 4.5 months of age) and post-mortem brain tissue was assayed using Western blot. Social isolation alone significantly lowered PPI magnitude in male (but not female) rats while DOM treatment appeared to make animals refractory to this effect. Combining social isolation and DOM treatment caused an additive decrease in PPI startle latency. No statistically significant differences were found in the expression of D1, D2, TH, GAD65 or GAD67 protein in either the prefrontal cortex or hippocampus, although some tendencies toward differences were noted. We conclude that both neonatal low-dose DOM and social isolation affect prepulse inhibition in rats but that each paradigm exerts these effects through different neuronal signalling systems.

  14. Neurotranscriptomics: The Effects of Neonatal Stimulus Deprivation on the Rat Pineal Transcriptome

    PubMed Central

    Hartley, Stephen W.; Coon, Steven L.; Savastano, Luis E.; Mullikin, James C.; Fu, Cong; Klein, David C.

    2015-01-01

    The term neurotranscriptomics is used here to describe genome-wide analysis of neural control of transcriptomes. In this report, next-generation RNA sequencing was using to analyze the effects of neonatal (5-days-of-age) surgical stimulus deprivation on the adult rat pineal transcriptome. In intact animals, more than 3000 coding genes were found to exhibit differential expression (adjusted-p < 0.001) on a night/day basis in the pineal gland (70% of these increased at night, 376 genes changed more than 4-fold in either direction). Of these, more than two thousand genes were not previously known to be differentially expressed on a night/day basis. The night/day changes in expression were almost completely eliminated by neonatal removal (SCGX) or decentralization (DCN) of the superior cervical ganglia (SCG), which innervate the pineal gland. Other than the loss of rhythmic variation, surgical stimulus deprivation had little impact on the abundance of most genes; of particular interest, expression levels of the melatonin-synthesis-related genes Tph1, Gch1, and Asmt displayed little change (less than 35%) following DCN or SCGX. However, strong and consistent changes were observed in the expression of a small number of genes including the gene encoding Serpina1, a secreted protease inhibitor that might influence extracellular architecture. Many of the genes that exhibited night/day differential expression in intact animals also exhibited similar changes following in vitro treatment with norepinephrine, a superior cervical ganglia transmitter, or with an analog of cyclic AMP, a norepinephrine second messenger in this tissue. These findings are of significance in that they establish that the pineal-defining transcriptome is established prior to the neonatal period. Further, this work expands our knowledge of the biological process under neural control in this tissue and underlines the value of RNA sequencing in revealing how neurotransmission influences cell biology. PMID

  15. Intranasal administration of IGF-1 attenuates hypoxic-ischemic brain injury in neonatal rats

    PubMed Central

    Lin, Shuying; Fan, Lir-Wan; Rhodes, Philip G.; Cai, Zhengwei

    2009-01-01

    To determine whether intranasal administration (iN) of recombinant human insulin-like growth factor-1 (rhIGF-1) provides neuroprotection to the neonatal rat brain following cerebral hypoxia-ischemia (HI), two doses of rhIGF-1 (50 μg at a 1 h interval) were infused into the right naris of postnatal day 7 (P7) rat pups with or without a prior HI insult (right common carotid artery ligation, followed by an exposure to 8% oxygen for 2 h). Our result showed that rhIGF-1 administered via iN was successfully delivered into the brain 30 min after the second dose. In the following studies rhIGF-1 was administered to P7 rat pups at 0, 1 or 2 h after HI at the dose described above. Pups in the control group received cerebral HI and vehicle treatment. Pups that underwent sham operation and vehicle treatment served as the sham group. Brain pathological changes were evaluated 2 and 15 d after HI. Our results showed that rhIGF-1 treatment up to 1 hr after cerebral HI effectively reduced brain injury as compared to that in the vehicle-treated rats. Moreover, rhIGF-1 treatment improved neurobehavioral performance (tested on P5-P21) in juvenile rats subjected to HI. Our results further showed that rhIGF-1 inhibited apoptotic cell death, possibly through activating the Akt signal transduction pathway. rhIGF-1 enhanced proliferation of neuronal and oligodendroglial progenitors after cerebral HI as well. These data suggest that iN administration of IGF-1 has the potential to be used for clinical treatment. PMID:19332057

  16. Development of UDP-glucuronosyltransferase activity toward digitoxigenin-monodigitoxoside in neonatal rats.

    PubMed

    Watkins, J B; Klaassen, C D

    1985-01-01

    Glucuronidation is low or undetectable in embryonic and early fetal tissues and changes to adult levels at rates depending on the acceptor, tissue, and species. Because other data indicate there may be a specific UDP-glucuronosyltransferase (GT) in the liver of adult rats that glucuronidates digitoxigenin-monodigitoxoside (DIG), the development of GT activity in neonatal rats toward DIG was compared with that of other acceptors. Conjugation of p-nitrophenol and 1-naphthol was higher at birth and decreased to adult levels by 20 days of age. Glucuronidation of chloramphenicol, morphine, valproic acid, and bilirubin increased from birth to adult activity by 20 days of age. Conjugation of phenolphthalein, estrone, and diethylstilbestrol was low in 1-day-old rats and higher than adult in 20-day-old animals. In contrast, glucuronidation of DIG was barely detectable (9% of adult) in 20-day-old rats. The concentration of UDP-glucuronic acid was 50% of adult levels at birth and increased to adult values by 10 days of age. Administration of 3-methylcholanthrene on days 6 to 9 after birth significantly stimulated GT activity toward 1-naphthol, p-nitrophenol, and morphine, whereas phenobarbital precociously increased conjugation of chloramphenicol, valproic acid, morphine, and diethylstilbestrol. Pregnenolone-16 alpha-carbonitrile enhanced the development of GT activity toward morphine, chloramphenicol, valproic acid, bilirubin, diethylstilbestrol, and estrone. Glucuronidation of DIG was not increased after 3-methylcholanthrene or phenobarbital, but could be induced after pregnenolone-16 alpha-carbonitrile to 7% of adult values in 10-day-old rats.(ABSTRACT TRUNCATED AT 250 WORDS)

  17. Neonatal handling reduces angiotensin II receptor density in the medial preoptic area and paraventricular nucleus but not in arcuate nucleus and locus coeruleus of female rats.

    PubMed

    Gomes, Cármen Marilei; Donadio, Márcio Vinícius Fagundes; Franskoviaki, Inélia; Anselmo-Franci, Janete A; Franci, Celso Rodrigues; Lucion, Aldo Bolten; Sanvitto, Gilberto Luiz

    2006-01-01

    Neonatal handling alters the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitary-gonads axis (HPG) in adult animals, and angiotensin II (Ang II) modulates the functions in these axes. We tested whether neonatal handling could change the density of Ang II receptors in some central areas in female rats. Results showed decreased density of the Ang II receptors in the medial preoptic area (MPOA) and hypothalamic paraventricular nucleus (PVN) of the neonatal handled group.

  18. Neonatal finasteride administration decreases dopamine release in nucleus accumbens after alcohol and food presentation in adult male rats.

    PubMed

    Llidó, Anna; Bartolomé, Iris; Darbra, Sònia; Pallarès, Marc

    2016-08-01

    Endogenous levels of the neurosteroid (NS) allopregnanolone (AlloP) during neonatal stages are crucial for the correct development of the central nervous system (CNS). In a recent work we reported that the neonatal administration of AlloP or finasteride (Finas), an inhibitor of the enzyme 5α-reductase needed for AlloP synthesis, altered the voluntary consumption of ethanol and the ventrostriatal dopamine (DA) levels in adulthood, suggesting that neonatal NS manipulations can increase alcohol abuse vulnerability in adulthood. Moreover, other authors have associated neonatal NS alterations with diverse dopaminergic (DAergic) alterations. Thus, the aim of the present work is to analyse if manipulations of neonatal AlloP alter the DAergic response in the nucleus accumbens (NAcc) during alcohol intake in rats. We administered AlloP or Finas from postnatal day (PND) 5 to PND9. At PND98, we measured alcohol consumption using a two-bottle free-choice model (ethanol 10% (v/v)+glucose 3% (w/v), and glucose 3% (w/v)) for 12 days. On the last day of consumption, we measured the DA and 3,4-dihydroxyphenylacetic acid (DOPAC) release in NAcc in response to ethanol intake. The samples were obtained by means of in vivo microdialysis in freely moving rats, and DA and DOPAC levels were determined by means of high-performance liquid chromatography analysis (HPLC). The results revealed that neonatal Finas increased ethanol consumption in some days of the consumption phase, and decreased the DA release in the NAcc in response to solutions (ethanol+glucose) and food presentation. Taken together, these results suggest that neonatal NS alterations can affect alcohol rewarding properties. PMID:27139934

  19. Neonatal finasteride administration decreases dopamine release in nucleus accumbens after alcohol and food presentation in adult male rats.

    PubMed

    Llidó, Anna; Bartolomé, Iris; Darbra, Sònia; Pallarès, Marc

    2016-08-01

    Endogenous levels of the neurosteroid (NS) allopregnanolone (AlloP) during neonatal stages are crucial for the correct development of the central nervous system (CNS). In a recent work we reported that the neonatal administration of AlloP or finasteride (Finas), an inhibitor of the enzyme 5α-reductase needed for AlloP synthesis, altered the voluntary consumption of ethanol and the ventrostriatal dopamine (DA) levels in adulthood, suggesting that neonatal NS manipulations can increase alcohol abuse vulnerability in adulthood. Moreover, other authors have associated neonatal NS alterations with diverse dopaminergic (DAergic) alterations. Thus, the aim of the present work is to analyse if manipulations of neonatal AlloP alter the DAergic response in the nucleus accumbens (NAcc) during alcohol intake in rats. We administered AlloP or Finas from postnatal day (PND) 5 to PND9. At PND98, we measured alcohol consumption using a two-bottle free-choice model (ethanol 10% (v/v)+glucose 3% (w/v), and glucose 3% (w/v)) for 12 days. On the last day of consumption, we measured the DA and 3,4-dihydroxyphenylacetic acid (DOPAC) release in NAcc in response to ethanol intake. The samples were obtained by means of in vivo microdialysis in freely moving rats, and DA and DOPAC levels were determined by means of high-performance liquid chromatography analysis (HPLC). The results revealed that neonatal Finas increased ethanol consumption in some days of the consumption phase, and decreased the DA release in the NAcc in response to solutions (ethanol+glucose) and food presentation. Taken together, these results suggest that neonatal NS alterations can affect alcohol rewarding properties.

  20. The role of the sarcoplasmic reticulum in neonatal uterine smooth muscle: enhanced role compared to adult rat

    PubMed Central

    Noble, Karen; Wray, Susan

    2002-01-01

    Little is known about contractile activity, response to agonists or excitation-contraction coupling in neonatal smooth muscle. We have therefore investigated 10-day rat uterus to better understand these processes, and compared it to adult uterus to elucidate how control of contractility develops. Spontaneous contractions are present in the 10-day neonatal uterus, although they are not as large or as regular as those present in adult tissues. External Ca2+ entry via L-type Ca2+ channels is the sole source of Ca2+ and is essential for the spontaneous activity. The neonatal uterus was responsive to carbachol or prostaglandin F2α application; it showed a marked stimulation and a clear dissociation between the force and Ca2+ changes. Such sensitization was not apparent in adult rat myometrium. The sarcoplasmic reticulum (SR) had more releasable Ca2+ and contributed more to the response to agonists in neonatal compared to adult tissues. Thus, Ca2+ entry as opposed to SR Ca2+ release contributed much less to the uterine response to agonists in the neonatal, compared to adult tissues. Inhibition of the SR by cyclopiazonic acid also caused a more vigorous increase in Ca2+ and contractile activity, particularly frequency, in the neonatal compared to the adult uterus. Taken together these data suggest that: (1) spontaneous activity is already present by day 10, (2) receptor-coupling and excitation-contraction signalling pathways are functional, (3) the SR and Ca2+ sensitization mechanisms play a more prominent role in the neonate, and (4) there is a shift to a greater reliance on Ca2+ entry and excitability with development of the myometrium. PMID:12456834

  1. Ileal Immunoglobulin Binding by the Neonatal Fc Receptor: A Previously Unrecognized Mechanism of Protection in the Neonatal Rat Model of Necrotizing Enterocolitis?

    PubMed Central

    Swanson, Jonathan R.; Jilling, Tamas; Lu, Jing; Landseadel, Jessica B.; Marcinkiewicz, Marek; Gordon, Phillip V.

    2013-01-01

    Background Mucosal apoptosis is the initiating event in models of necrotizing enterocolitis (NEC) within rodents. It is possible there are species-specific differences that make apoptosis a more prominent feature of NEC in rodents than in humans. Hypothesis A lower threshold for mucosal apoptosis in the rodent distal intestine might have evolutionary advantages (via enhanced opsonization with the neonatal Fc receptor [FcRn]), since many short-gestation mammals are comparatively premature (histomorphologically) but are protected from NEC by breast milk. Methods We utilized a rat intestinal epithelial cell (IEC-18) model to determine if cell death alters FcRn – IgG binding, and rodent models of NEC to determine if cell death results in increased opsonization of IgG. Cultured IEC-18 cells were treated with H2O2 and analyzed. Neonatal Sprague-Dawley rats were cold and hypoxia stressed and intestinal sections were frozen for analysis. Results IgG binding was increased in H2O2-treated cells. Co-incubation of treated cells with either insulin-like growth factor or tunicamycin decreased IgG binding. Sprague-Dawley rats formula fed with exogenous bacteria showed a significant decrease in intestinal FcRn mRNA but increased ileal IgG binding. Conclusions We speculate that FcRn plays a role in passive opsonization and subsequent bacterial pathogen clearance, making rodents resistant to NEC. PMID:25105063

  2. The HDAC Inhibitor Phenylbutyrate Reverses Effects of Neonatal Ventral Hippocampal Lesion in Rats

    PubMed Central

    Sandner, Guy; Host, Lionel; Angst, Marie-Josée; Guiberteau, Thierry; Guignard, Blandine; Zwiller, Jean

    2011-01-01

    Recent evidence suggests that epigenetic mechanisms play a role in psychiatric diseases. In this study, we considered rats with neonatal ventral hippocampal lesions (NVHL) that are currently used for modeling neurodevelopmental aspects of schizophrenia. Contribution of epigenetic regulation to the effects of the lesion was investigated, using a histone deacetylase (HDAC) inhibitor. Lesioned or sham-operated rats were treated with the general HDAC inhibitor phenylbutyrate, which was injected daily from the day after surgery until adulthood. Changes in the volume of the lesion were monitored by magnetic resonance imaging (MRI). Anxiety was analyzed in the Plus Maze Test. Hypersensitivity of the dopaminergic system was evaluated by measuring the locomotor response to apomorphine. An associative conditioning test rewarded with food was used to evaluate learning abilities. The volume of the lesions expanded long after surgery, independently of the treatment, as assessed by MRI. Removal of the ventral hippocampus reduced anxiety, and this remained unchanged when animals were treated with phenylbutyrate. In contrast, NVHL rats’ hypersensitivity to apomorphine and deterioration of the associative learning were reduced by the treatment. Global HDAC activity, which was increased in the prefrontal cortex of lesioned non-treated rats, was found to be reversed by HDAC inhibition. The study provides evidence that chromatin remodeling may be useful for limiting behavioral consequences due to lesioning of the ventral hippocampus at an early age. This represents a novel approach for treating disorders resulting from insults occurring during brain development. PMID:21423460

  3. Non-clinical safety assessment of gadoterate meglumine (Dotarem(®)) in neonatal and juvenile rats.

    PubMed

    Giorgi, Hervé; Ammerman, Jennifer; Briffaux, Jean-Paul; Fretellier, Nathalie; Corot, Claire; Bourrinet, Philippe

    2015-12-01

    The purpose of this study was to assess the safety of gadoterate meglumine, a gadolinium-based contrast agent used in magnetic resonance imaging, in neonatal and juvenile rats. Rats received a single intravenous administration on postnatal day (PND) 10 or 6 administrations (from PND 10 to 30), at doses of 0, 0.6, 1.25, and 2.5 mmol/kg/administration, i.e. equivalent to approximately 1, 2 and 4-times the usual human dose. The animals were sacrificed at the end of the treatment period or after a 60-day treatment-free period. No mortality and no significant treatment-related effect on clinical signs, macroscopic and histopathological findings, development, behavior, sexual maturation and hematology parameters were observed. Minor non-adverse changes were observed in clinical biochemistry and urinary parameters. Based on AUC0-t, gadoterate meglumine was more rapidly eliminated at PND 30 vs. PND 10, reflecting maturation of kidney function. At the end of the treatment period, Gd was measurable in all organs sampled after single or repeated dosing and levels were dose-dependent as expected, the highest ones being found in kidneys. The total Gd concentrations were similar in all the organs following a single or repeated dosing. At the end of the treatment-free period, only traces of gadolinium were quantifiable, almost exclusively in kidneys, reflecting the excretory function of this organ. In conclusion, single or repeated administration of gadoterate meglumine to juvenile rats was well tolerated.

  4. Noradrenergic Modulation of Intrinsic and Synaptic Properties of Lumbar Motoneurons in the Neonatal Rat Spinal Cord

    PubMed Central

    Tartas, Maylis; Morin, France; Barrière, Grégory; Goillandeau, Michel; Lacaille, Jean-Claude; Cazalets, Jean-René; Bertrand, Sandrine S.

    2009-01-01

    Although it is known that noradrenaline (NA) powerfully controls spinal motor networks, few data are available regarding the noradrenergic (NAergic) modulation of intrinsic and synaptic properties of neurons in motor networks. Our work explores the cellular basis of NAergic modulation in the rat motor spinal cord. We first show that lumbar motoneurons express the three classes of adrenergic receptors at birth. Using patch-clamp recordings in the newborn rat spinal cord preparation, we characterized the effects of NA and of specific agonists of the three classes of adrenoreceptors on motoneuron membrane properties. NA increases the motoneuron excitability partly via the inhibition of a KIR like current. Methoxamine (α1), clonidine (α2) and isoproterenol (β) differentially modulate the motoneuron membrane potential but also increase motoneuron excitability, these effects being respectively inhibited by the antagonists prazosin (α1), yohimbine (α2) and propranolol (β). We show that the glutamatergic synaptic drive arising from the T13-L2 network is enhanced in motoneurons by NA, methoxamine and isoproterenol. On the other hand, NA, isoproterenol and clonidine inhibit both the frequency and amplitude of miniature glutamatergic EPSCs while methoxamine increases their frequency. The T13-L2 synaptic drive is thereby differentially modulated from the other glutamatergic synapses converging onto motoneurons and enhanced by presynaptic α1 and β receptor activation. Our data thus show that the NAergic system exerts a powerful and complex neuromodulation of lumbar motor networks in the neonatal rat spinal cord. PMID:20300468

  5. Identification and characterization of somatostatin receptors in neonatal rat long bones.

    PubMed Central

    Bruns, C; Dietl, M M; Palacios, J M; Pless, J

    1990-01-01

    Somatostatin (somatotropin release inhibiting factor; SRIF) has widespread functions as a modulator of neural activity as well as of endocrine and exocrine secretion. In the present paper, the binding characteristics of somatostatin receptors have been investigated in rat long bones using the stable analogue, 125I-SDZ 204-090, as a ligand. Binding studies revealed the presence of a single class of high-affinity binding sites for 125I-SDZ 204-090 on cells prepared from neonatal rat long bones with an equilibrium dissociation constant (KD) of 70.1 +/- 8.2 pM (n = 3). An excellent correlation was found between the ability of various somatostatin analogues to inhibit growth hormone in pituitary cells and to displace the binding of 125I-SDZ 204-090 to the bone cell preparation, indicating that the receptors are very similar, if not identical. The localization of the somatostatin-binding sites was examined by autoradiography after labelling in vitro and in vivo. The binding sites were shown by both procedures to be selectively localized to the metaphysis of rat long bones. The labelling experiments in vivo indicate that these receptors can be reached in the living animal by circulating somatostatin analogues. In addition, the analogue SMS 201-995 inhibited the forskolin-stimulated adenylate cyclase activity in bone cell suspensions. These results suggest that somatostatin could be an important regulatory factor in bone metabolism. Images Fig. 5. PMID:1967933

  6. Partial purification and characterization of a peroxidase from neonatal rat skin

    SciTech Connect

    Strohm, B.H.

    1987-01-01

    Peroxidase activity was partially purified from neonatal CFN rat skin. The membrane-bound peroxidase activity was extracted with 0.5 M calcium chloride and was monitored spectrophotometrically at 470 nm with 2-methoxyphenol and hydrogen peroxide as substrates. Subcellular distribution studies indicated the specific activity to be highest and comparable in the 800 {times} g and 8000 {times} g pellets, lowest in the 100,000 {times} g pellet, and absent in the 100,000 {times} g supernatant. The peroxidase activity was partially purified by affinity chromatography on concanavaline-A-sepharose 4-B and by gel filtration using Bio-gel P-150. The apparent molecular weight of the native enzyme as determined by Bio-gel P-200 gel filtration was approximately 42,500 {plus minus} 2,300 daltons. Peroxidase activity increased linearly with increases in protein concentration, time, and guaiacol concentration. Activity was inhibited approximately 75% by 0.1 mM potassium cyanide or 0.05 mM sodium azide. Pyrogallol, hydroquinone, p-cresol, catechol, benzidine, 3,3{prime}-dimethoxybenzidine, tetramethylbenzidine, and p-phenylenediamine were active as substrates for rat skin peroxidase. Rat skin peroxidase was also shown to mediate non-extractable binding of ({sup 3}H)-benzo(a)pyrene-7,8-dihydrodiol and ({sup 3}H)-2-aminofluorene to DNA and protein.

  7. PKA, Rap1, ERK1/2, and p90RSK mediate PGE2 and EP4 signaling in neonatal ventricular myocytes.

    PubMed

    He, Quan; Harding, Pamela; LaPointe, Margot C

    2010-01-01

    We have previously reported that 1) inhibition of cyclooxygenase-2 and PGE(2) production reduces hypertrophy after myocardial infarction in mice and 2) PGE(2) acting through its EP4 receptor causes hypertrophy of neonatal ventricular myocytes (NVMs) via ERK1/2. It is known that EP4 couples to adenylate cyclase, cAMP, and PKA. The present study was designed to determine interactions between the cAMP-PKA pathway and ERK1/2 and to further characterize events downstream of ERK1/2. We hypothesized that PKA and the small GTPase Rap are upstream of ERK1/2 and that 90-kDa ribosomal S6 kinase (p90RSK) is activated downstream. Treatment of NVMs with PGE(2) activated Rap, and this activation was inhibited in part by an EP4 antagonist and PKA inhibition. Transfection of a dominant negative mutant of Rap reduced PGE(2) activation of ERK1/2. PGE(2) activation of p90RSK was also dependent on EP4, PKA, and Rap. We also tested the involvement of Rap, ERK1/2, and p90RSK in PGE(2) regulation of gene expression. PGE(2) stimulation of brain natriuretic peptide promoter activity was blocked by either ERK1/2 inhibition or a dominant negative mutation of p90RSK. PGE(2) stimulation of c-Fos was dependent on EP4, PKA, ERK1/2, and p90RSK, whereas only the latter two kinases were involved in PGE(2) regulation of early growth response-1. Finally, we tested the involvement of EP4-dependent signaling in the NVM growth response and found that the overexpression of EP4 increased NVM cell size. We conclude that EP4-dependent signaling in NVMs in part involves PKA, Rap, ERK1/2, and p90RSK and results in the increased expression of brain natriuretic peptide and c-Fos.

  8. Neonatal exposure to monosodium glutamate induces morphological alterations in suprachiasmatic nucleus of adult rat.

    PubMed

    Rojas-Castañeda, Julio César; Vigueras-Villaseñor, Rosa María; Chávez-Saldaña, Margarita; Rojas, Patricia; Gutiérrez-Pérez, Oscar; Rojas, Carolina; Arteaga-Silva, Marcela

    2016-02-01

    Neonatal exposure to monosodium glutamate (MSG) induces circadian disorders in several physiological and behavioural processes regulated by the suprachiasmatic nucleus (SCN). The objective of this study was to evaluate the effects of neonatal exposure to MSG on locomotor activity, and on morphology, cellular density and expression of proteins, as evaluated by optical density (OD), of vasopressin (VP)-, vasoactive intestinal polypeptide (VIP)- and glial fibrillary acidic protein (GFAP)-immunoreactive cells in the SCN. Male Wistar rats were used: the MSG group was subcutaneously treated from 3 to 10 days of age with 3.5 mg/g/day. Locomotor activity was evaluated at 90 days of age using 'open-field' test, and the brains were processed for immunohistochemical studies. MSG exposure induced a significant decrease in locomotor activity. VP- and VIP-immunoreactive neuronal densities showed a significant decrease, while the somatic OD showed an increase. Major axes and somatic area were significantly increased in VIP neurons. The cellular and optical densities of GFAP-immunoreactive sections of SCN were significantly increased. These results demonstrated that newborn exposure to MSG induced morphological alterations in SCN cells, an alteration that could be the basis for behavioural disorders observed in the animals.

  9. The serotonin reuptake inhibitor citalopram suppresses activity in the neonatal rat barrel cortex in vivo.

    PubMed

    Akhmetshina, Dinara; Zakharov, Andrei; Vinokurova, Daria; Nasretdinov, Azat; Valeeva, Guzel; Khazipov, Roustem

    2016-06-01

    Inhibition of serotonin uptake, which causes an increase in extracellular serotonin levels, disrupts the development of thalamocortical barrel maps in neonatal rodents. Previous in vitro studies have suggested that the disruptive effect of excessive serotonin on barrel map formation involves a depression at thalamocortical synapses. However, the effects of serotonin uptake inhibitors on the early thalamocortical activity patterns in the developing barrel cortex in vivo remain largely unknown. Here, using extracellular recordings of the local field potentials and multiple unit activity (MUA) we explored the effects of the selective serotonin reuptake inhibitor (SSRI) citalopram (10-20mg/kg, intraperitoneally) on sensory evoked activity in the barrel cortex of neonatal (postnatal days P2-5) rats in vivo. We show that administration of citalopram suppresses the amplitude and prolongs the delay of the sensory evoked potentials, reduces the power and frequency of the early gamma oscillations, and suppresses sensory evoked and spontaneous neuronal firing. In the adolescent P21-29 animals, citalopram affected neither sensory evoked nor spontaneous activity in barrel cortex. We suggest that suppression of the early thalamocortical activity patterns contributes to the disruption of the barrel map development caused by SSRIs and other conditions elevating extracellular serotonin levels. PMID:27016034

  10. Enhanced sympathetic nerve activity induced by neonatal colon inflammation induces gastric hypersensitivity and anxiety-like behavior in adult rats.

    PubMed

    Winston, John H; Sarna, Sushil K

    2016-07-01

    Gastric hypersensitivity (GHS) and anxiety are prevalent in functional dyspepsia patients; their underlying mechanisms remain unknown largely because of lack of availability of live visceral tissues from human subjects. Recently, we demonstrated in a preclinical model that rats subjected to neonatal colon inflammation show increased basal plasma norepinephrine (NE), which contributes to GHS through the upregulation of nerve growth factor (NGF) expression in the gastric fundus. We tested the hypothesis that neonatal colon inflammation increases anxiety-like behavior and sympathetic nervous system activity, which upregulates the expression of NGF to induce GHS in adult life. Chemical sympathectomy, but not adrenalectomy, suppressed the elevated NGF expression in the fundus muscularis externa and GHS. The measurement of heart rate variability showed a significant increase in the low frequency-to-high frequency ratio in GHS vs. the control rats. Stimulus-evoked release of NE from the fundus muscularis externa strips was significantly greater in GHS than in the control rats. Tyrosine hydroxylase expression was increased in the celiac ganglia of the GHS vs. the control rats. We found an increase in trait but not stress-induced anxiety-like behavior in GHS rats in an elevated plus maze. We concluded that neonatal programming triggered by colon inflammation upregulates tyrosine hydroxylase in the celiac ganglia, which upregulates the release of NE in the gastric fundus muscularis externa. The increase of NE release from the sympathetic nerve terminals concentration dependently upregulates NGF, which proportionately increases the visceromotor response to gastric distention. Neonatal programming concurrently increases anxiety-like behavior in GHS rats. PMID:27151940

  11. Use of High Resolution 3D Diffusion Tensor Imaging to Study Brain White Matter Development in Live Neonatal Rats

    PubMed Central

    Cai, Yu; McMurray, Matthew S.; Oguz, Ipek; Yuan, Hong; Styner, Martin A.; Lin, Weili; Johns, Josephine M.; An, Hongyu

    2011-01-01

    High resolution diffusion tensor imaging (DTI) can provide important information on brain development, yet it is challenging in live neonatal rats due to the small size of neonatal brain and motion-sensitive nature of DTI. Imaging in live neonatal rats has clear advantages over fixed brain scans, as longitudinal and functional studies would be feasible to understand neuro-developmental abnormalities. In this study, we developed imaging strategies that can be used to obtain high resolution 3D DTI images in live neonatal rats at postnatal day 5 (PND5) and PND14, using only 3 h of imaging acquisition time. An optimized 3D DTI pulse sequence and appropriate animal setup to minimize physiological motion artifacts are the keys to successful high resolution 3D DTI imaging. Thus, a 3D rapid acquisition relaxation enhancement DTI sequence with twin navigator echoes was implemented to accelerate imaging acquisition time and minimize motion artifacts. It has been suggested that neonatal mammals possess a unique ability to tolerate mild-to-moderate hypothermia and hypoxia without long term impact. Thus, we additionally utilized this ability to minimize motion artifacts in magnetic resonance images by carefully suppressing the respiratory rate to around 15/min for PND5 and 30/min for PND14 using mild-to-moderate hypothermia. These imaging strategies have been successfully implemented to study how the effect of cocaine exposure in dams might affect brain development in their rat pups. Image quality resulting from this in vivo DTI study was comparable to ex vivo scans. fractional anisotropy values were also similar between the live and fixed brain scans. The capability of acquiring high quality in vivo DTI imaging offers a valuable opportunity to study many neurological disorders in brain development in an authentic living environment. PMID:22013426

  12. Developmental responses to opioids reveals a lack of effect on stress-induced corticosterone levels in neonatal rats.

    PubMed Central

    Bailey, C. C.; Kitchen, I.

    1987-01-01

    The neonate has an unusual capacity for survival and the possibility exists that mechanisms for controlling stress responses may differ in the developing animal. In adults both endogenous and exogenous opioids can modulate the corticosterone responses to stress. We have studied this effect in neonatal rats and found that opioid modulation is absent in early postnatal development. Neonatal rats of either sex were injected with morphine (5-50 mg kg-1), fentanyl (10-100 micrograms kg-1), buprenorphine (0.1-30 mg kg-1) or naloxone (0.1-10 mg kg-1) and plasma corticosterone measured fluorimetrically 15 or 20 min later. In addition naloxone reversibility studies (1 mg kg-1, co-administered) were carried out for the opioid agonists. In adult rats, elevations in plasma corticosterone caused by injection stress were potentiated by morphine, fentanyl and buprenorphine. In neonates, though injection stress-induced rises in plasma corticosterone were absent at 10 days, elevations were observed at 21 days and later. However, significant potentiation of this corticosterone response by fentanyl was absent at 21 days and at later ages (30 and 40 days) for morphine and buprenorphine. The potentiating effect of all three agonists did not become fully effective until day 45. In addition, in animals acclimatized to injection stress by 7 day injection pretreatment, fentanyl did not significantly alter corticosterone levels in 30 day old neonates. High doses of naloxone (10 mg kg-1) significantly increased the corticosterone response to injection stress in adult rats but this effect was absent in 30 day old animals.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3594070

  13. Postweaning housing conditions and partner preference and sexual behavior of neonatally ATD-treated male rats.

    PubMed

    Bakker, J; van Ophemert, J; Slob, A K

    1995-01-01

    Male rats were neonatally treated with cholesterol or a substance that blocks the aromatization of testosterone to estradiol (1,4,6-androstatriene-3,17-dione: ATD). At weaning (21 days) they were either housed alone or in small groups (2-3 animals) and tested for partner preference behavior (PPB) in adulthood. Choice was between an estrous female and an active male (Part I) and between an estrous female and an ATD-male (Part II). Tests were carried out in a 3-compartment box. Social isolation did not have major effects on PPB except when sexual interaction with the stimulus animals was prevented (Part I). In this case, isolates (ATD and control) showed higher preference scores (PS) for the estrous female and spent less time in the empty middle compartment. When the choice was between an estrous female and an ATD-male, partner PS decreased in all males, most clearly in ATD-males. The latter animals spent more time with the stimulus ATD-male than they had done in previous PPB tests with the normal stimulus male. In contrast to partner preference behaviors, sexual behavior was clearly affected by social isolation. Isolates (ATD and control) displayed lower frequencies of mounts and intromissions. These effects persisted over consecutive tests. Ejaculation was not affected. In conclusion, the present results confirm earlier findings about the significance of neonatal endocrine conditions for the organization of adult PPB in male rats. The presence or absence of social conspecifics after weaning appears to have little influence on adult PPB.

  14. Maternal Oxytocin Administration Before Birth Influences the Effects of Birth Anoxia on the Neonatal Rat Brain.

    PubMed

    Boksa, Patricia; Zhang, Ying; Nouel, Dominique

    2015-08-01

    Ineffective contractions and prolonged labor are common birth complications in primiparous women, and oxytocin is the most common agent given for induction or augmentation of labor. Clinical studies in humans suggest oxytocin might adversely affect the CNS response to hypoxia at birth. In this study, we used a rat model of global anoxia during Cesarean section birth to test if administering oxytocin to pregnant dams prior to birth affects the acute neonatal CNS response to birth anoxia. Anoxic pups born from dams pre-treated with intravenous injections or infusions of oxytocin before birth showed significantly increased brain lactate, a metabolic indicator of CNS hypoxia, compared to anoxic pups from dams pre-treated with saline. Anoxic pups born from dams given oxytocin before birth also showed decreased brain ATP compared to anoxic pups from saline dams. Direct injection of oxytocin to postnatal day 2 rat pups followed by exposure to anoxia also resulted in increased brain lactate and decreased brain ATP, compared to anoxia exposure alone. Oxytocin pre-treatment of the dam decreased brain malondialdehyde, a marker of lipid peroxidation, as well as protein kinase C activity, both in anoxic pups and controls, suggesting oxytocin may reduce aspects of oxidative stress. Finally, when dams were pretreated with indomethacin, a cyclooxygenase (COX) inhibitor, maternal oxytocin no longer potentiated effects of anoxia on neonatal brain lactate, suggesting this effect of oxytocin may be mediated via prostaglandin production or other COX-derived products. The results indicate that maternal oxytocin administration may have multiple acute effects on CNS metabolic responses to anoxia at birth.

  15. Transient expression of somatostatin messenger RNA and peptide in the hypoglossal nucleus of the neonatal rat.

    PubMed

    Seroogy, K B; Bayliss, D A; Szymeczek, C L; Hökfelt, T; Millhorn, D E

    1991-06-21

    The postnatal developmental expression of somatostatin mRNA and peptide in the rat hypoglossal nucleus was analyzed using immunocytochemical and in situ hybridization techniques. Both the neuropeptide and its cognate mRNA were found to be transiently present within a subpopulation of hypoglossal motoneurons during the neonatal period. At the day of birth, a large population of perikarya situated in caudal, ventral regions of the hypoglossal nucleus expressed somatostatin. By postnatal day 7, the number of hypoglossal somata which expressed somatostatin had diminished considerably, and by 2 weeks postnatal, only few such cell bodies were found. By 3-4 weeks postnatal, somatostatin peptide- and mRNA-containing hypoglossal motoneurons were rarely observed, and in the adult, they were never detected, despite the use of colchicine. A double-labeling co-localization technique was used to demonstrate that somatostatin, when present perinatally, always coexisted with calcitonin gene-related peptide in hypoglossal motoneurons. The latter peptide, in contrast to somatostatin, was expressed in large numbers of somata throughout the entire hypoglossal nucleus and persisted within the motoneurons throughout development into adulthood. These results demonstrate that somatostatin is transiently expressed in motoneurons of the caudal, ventral tier of the hypoglossal nucleus in the neonatal rat. The developmental disappearance of somatostatin is most likely not due to cell death; hypoglossal somata continue to express calcitonin gene-related peptide, with which somatostatin coexisted perinatally, a high levels throughout development. Thus, it appears that the regulation of somatostatin expression in hypoglossal neurons occurs at the level of gene transcription or mRNA stability/degradation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1680035

  16. Episodic hypoxia evokes long-term facilitation of genioglossus muscle activity in neonatal rats

    PubMed Central

    McKay, Leanne C; Janczewski, Wiktor A; Feldman, Jack L

    2004-01-01

    The aim of this study was to determine if episodic hypoxia evokes persistent increases of genioglossus muscle (GG) activity, termed long-term facilitation (LTF), in neonatal rats in vivo. Experiments were performed on anaesthetized, spontaneously breathing, intubated neonatal rats (postnatal days (P) 3–7), divided into three groups. The first group (n = 8) was subjected to three 5-min periods of hypoxia (5% O2–95% N2) alternating with 5 min periods of room air. The second group (n = 8) was exposed to 15 min of continuous hypoxia. The third (n = 4) group was not exposed to hypoxia and served as a control. GG EMG activity and airflow were recorded before, during and for 60 min after episodic and continuous hypoxic exposure. During hypoxia, GG EMG burst amplitude and tidal volume (VT) significantly increased compared to baseline levels (episodic protocol: mean ±s.e.m.; 324 ± 59% of control and 0.13 ± 0.007 versus 0.09 ± 0.005 ml, respectively; continuous protocol: 259 ± 30% of control and 0.16 ± 0.005 versus 0.09 ± 0.007 ml, respectively; P < 0.05). After the episodic protocol, GG EMG burst amplitude transiently returned to baseline; over the next 60 min, burst amplitude progressively increased to levels significantly greater than baseline (238 ± 40% at 60 min; P < 0.05), without any significant increase in VT and respiratory frequency (P> 0.05). After the continuous protocol, there was no lasting increase in GG EMG burst amplitude. We conclude that LTF of upper airway muscles is an adaptive respiratory behaviour present from birth. PMID:15047768

  17. Involvement of enzymatic degradation in the inactivation of tachykinin neurotransmitters in neonatal rat spinal cord.

    PubMed Central

    Suzuki, H; Yoshioka, K; Yanagisawa, M; Urayama, O; Kurihara, T; Hosoki, R; Saito, K; Otsuka, M

    1994-01-01

    1. The possible involvement of enzymatic degradation in the inactivation of tachykinin neurotransmitters was examined in the spinal cord of the neonatal rat. 2. The magnitude of substance P (SP)- or neurokinin A (NKA)-evoked depolarization of a lumbar ventral root in the isolated spinal cord preparation was increased by a mixture of peptidase inhibitors, consisting of actinonin (6 microM), arphamenine B (6 microM), bestatin (10 microM), captopril (10 microM) and thiorphan (0.3 microM). The mixture augmented the response to NKA more markedly than that to SP. 3. In the isolated spinal cord-cutaneous nerve preparation, the saphenous nerve-evoked slow depolarization of the L3 ventral root was augmented by the mixture of peptidase inhibitors in the presence of naloxone (0.5 microM) but not in the presence of both naloxone and a tachykinin receptor antagonist, GR71251 (5 microM). 4. Application of capsaicin (0.5 microM) for 6 min to the spinal cord evoked an increase in the release of SP from the spinal cord. The amount of SP released was significantly augmented by the mixture of peptidase inhibitors. 5. Synaptic membrane fractions were prepared from neonatal rat spinal cords. These fractions showed degrading activities for SP and NKA and the activities were inhibited by the mixture of peptidase inhibitors. The degrading activity for NKA was higher than that for SP and the inhibitory effect of the mixture for NKA was more marked than that for SP. Although some other fractions obtained from homogenates of spinal cords showed higher degrading activities for SP, these activities were insensitive to the mixture of peptidase inhibitors.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7529113

  18. Impaired glucose homeostasis after a transient intermittent hypoxic exposure in neonatal rats.

    PubMed

    Pae, Eung-Kwon; Ahuja, Bhoomika; Kim, Marieyerie; Kim, Gyuyoup

    2013-11-22

    This initial report presents a neonatal rat model with exposure to a transient intermittent hypoxia (IH), which results in a persisting diabetes-like condition in the young rats. Twenty-five male pups were treated at postnatal day 1 with IH exposure by alternating the level of oxygen between 10.3% and 20.8% for 5h. The treated animals were then maintained in normal ambient oxygen condition for 3 week and compared to age-matched controls. The IH treated animals exhibited a significantly higher fasting glucose level than the control animals (237.00 ± 19.66 mg/dL vs. 167.25 ± 2.95 mg/dL; P=0.003); and a significantly lower insulin level than the control (807.0 ± 72.5 pg/mL vs. 1839.8 ± 377.6 pg/mL; P=0.023). There was no difference in the mass or the number of insulin producing beta cells as well as no indicative of inflammatory changes; however, glucose tolerance tests showed a significantly disturbed glucose homeostasis. In addition, the amount of C-peptide secreted from the islets harvested from the IH animals were decreased significantly (from 914 pM in control to 809 pM in IH; P=0.0006) as well. These observations demonstrate that the neonatal exposure to the IH regimen initiates the development of deregulation in glucose homeostasis without infiltration of inflammatory cells. PMID:24183722

  19. The human milk oligosaccharide disialyllacto-N-tetraose prevents necrotising enterocolitis in neonatal rats

    PubMed Central

    Jantscher-Krenn, Evelyn; Zherebtsov, Monica; Nissan, Caroline; Goth, Kerstin; Guner, Yigit S; Naidu, Natasha; Choudhury, Biswa; Grishin, Anatoly V; Ford, Henri R; Bode, Lars

    2014-01-01

    Background Necrotising enterocolitis (NEC) is one of the most common and fatal intestinal disorders in preterm infants. Breast-fed infants are at lower risk for NEC than formula-fed infants, but the protective components in human milk have not been identified. In contrast to formula, human milk contains high amounts of complex glycans. Objective To test the hypothesis that human milk oligosaccharides (HMO) contribute to the protection from NEC. Methods Since human intervention studies are unfeasible due to limited availability of HMO, a neonatal rat NEC model was used. Pups were orally gavaged with formula without and with HMO and exposed to hypoxia episodes. Ileum sections were scored blindly for signs of NEC. Two-dimensional chromatography was used to determine the most effective HMO, and sequential exoglycosidase digestions and linkage analysis was used to determine its structure. Results Compared to formula alone, pooled HMO significantly improved 96-hour survival from 73.1% to 95.0% and reduced pathology scores from 1.98±1.11 to 0.44±0.30 (p<0.001). Within the pooled HMO, a specific isomer of disialyllacto-N-tetraose (DSLNT) was identified to be protective. Galacto-oligosaccharides, currently added to formula to mimic some of the effects of HMO, had no effect. Conclusion HMO reduce NEC in neonatal rats and the effects are highly structure specific. If these results translate to NEC in humans, DSLNT could be used to prevent or treat NEC in formula-fed infants, and its concentration in the mother’s milk could serve as a biomarker to identify breast-fed infants at risk of developing this disorder. PMID:22138535

  20. Effect of maternal exercise on biochemical parameters in rats submitted to neonatal hypoxia-ischemia.

    PubMed

    Marcelino, Thiago Beltram; de Lemos Rodrigues, Patrícia Idalina; Miguel, Patrícia Maidana; Netto, Carlos Alexandre; Pereira Silva, Lenir Orlandi; Matté, Cristiane

    2015-10-01

    Pregnancy is a critical period for brain metabolic programming, being affected by individual environment, such as nutrition, stress, and physical exercise. In this context, we previously reported a cerebral antioxidant upregulation and mitochondrial biogenesis in the offspring delivered from exercised mothers, which could provide neuroprotection against neonatal insults. Hypoxia-ischemia (HI) encephalopathy is one of the most studied models of neonatal brain injury; disrupting motor, cognitive, and learning abilities. Physiopathology includes oxidative stress, allied to mitochondria energy production failure, glutamatergic excitotoxicity, and cell death. In this study we evaluated the effect of maternal swimming during pregnancy on offspring׳s brain oxidative status evaluated fourteen days after HI stablishment. Swimming exercise was performed by female adult rats one week before and during pregnancy, in controlled environment. Their offspring was submitted to HI on postnatal day 7, and the brain samples for biochemical assays were obtained in the weaning. Contrary to our expectations, maternal exercise did not prevent the oxidative alterations observed in brain from HI-rats. In a general way, we found a positive modulation in the activities of antioxidant enzymes, measured two weeks after HI, in hippocampus, striatum, and cerebellum of pups delivered from exercised mothers. Reactive species levels were modulated differently in each structure evaluated. Considering the scenery presented, we concluded that HI elicited a neurometabolic adaptation in both brain hemispheres, particularly in hippocampus, parietal cortex, and cerebellum; while striatum appears to be most damaged. The protocol of aerobic maternal exercise was not enough to fully prevent HI-induced brain damages. PMID:26119914

  1. Intramembrane charge movement in guinea-pig and rat ventricular myocytes.

    PubMed Central

    Hadley, R W; Lederer, W J

    1989-01-01

    1. Non-linear capacitative current (charge movement) was studied in isolated guinea-pig and rat ventricular myocytes. Linear capacitance was subtracted using standard procedures. Most of the experiments were done with guinea-pig myocytes, while rat myocytes were used for comparison. 2. When a myocyte was held at -100 mV, depolarizing clamp steps produced a rapid outward current transient, which was followed by an inward current transient upon repolarization. This current was identified as the movement of charged particles in the cell membrane, rather than ionic movement across the membrane, for the following reasons: (1) the current saturated at membrane potentials positive to +20 mV; (2) the current was capacitative in nature, having no reversal potential; (3) in general, the charge moved during depolarization (Qon) approximated the charge moved during repolarization (Qoff). 3. Qoff was significantly less than Qon for a depolarization from -100 mV to 0 mV. However, the Qoff/Qon ratio approached unity if the cell was instead repolarized to -140 mV. This was interpreted as being due to the immobilization of a fraction of the charge during the depolarization, which recovered rapidly enough to be measured at -140 mV, but recovered too slowly at -100 mV. 4. Charge movement in these cells had a sigmoidal dependence on the membrane potential, which could be empirically described by the two-state Boltzmann equation Q = Qmax/(1 + exp[-(V-V*)/kappa]), where Q is the charge movement at potential V, Qmax is the maximum charge, V* is the membrane potential at Q = Qmax/2, and kappa is a slope factor. Qmax was 11.7 nC/microF, V* was -18 mV and kappa was 16 mV in guinea-pig myocytes held at -100 mV, while the values in rat myocytes were 10.9 nC/microF, -32 mV and 13 mV. 5. The charge movement could be partially immobilized by a prior depolarization. This effect developed over a broad voltage range, from -120 to +20 mV. The fraction of charge that could be immobilized by a 10 s

  2. Ionic mechanism of the effects of hydrogen peroxide in rat ventricular myocytes.

    PubMed

    Ward, C A; Giles, W R

    1997-05-01

    1. Whole-cell and amphotericin-perforated patch-clamp techniques have been used to study the effects of hydrogen peroxide (H2O2) on action potentials and underlying ionic currents in single myocytes from the ventricles of adult rat hearts. 2. The results obtained differed markedly depending on the recording method utilized. Conventional whole-cell recordings, in which the myoplasm is dialysed with the contents of the pipette, failed to show any significant effects of H2O2 on the action potential or cell shortening. In contrast, when action potentials were recorded with the amphotericin-perforated patch method, H2O2 (50-200 microM) produced a marked prolongation of the action potential and an increase in cell shortening. 3. Voltage-clamp recordings with the amphotericin-perforated patch method showed that H2O2 caused no significant changes in either the Ca(2+)-independent transient outward K+ current (Ito) or the inwardly rectifying K+ current (IK1). 4. Application of tetrodotoxin (TTX; 8 x 10(-6) M), a Na+ channel blocker, largely inhibited the effects of H2O2 on the action potential. Moreover, anthopleurin A (4 x 10 (-7) M), which augments Na+ current (INa) by slowing its inactivation, mimicked the effects of H2O2 on the action potential of ventricular myocytes. These effects on INa were also blocked almost completely by TTX. 5. The hypothesis that H2O2 can augment INa by slowing its kinetics of inactivation was tested directly using ensemble recordings from cell-attached macropatches. These results demonstrated a significant enhancement of late opening events when H2O2 (200 microM) was included in the recording pipette. A corresponding slowing of inactivation of the ensemble INa was observed. 6. The possibility that protein kinase C (PKC) is an intracellular second messenger for the observed effects of H2O2 was examined using the blocker bisindolylmaelimide (BIS; 10(-7) M). Bath application of BIS prior to H2O2 exposure significantly delayed and also attenuated

  3. Feeding of Nigella sativa during neonatal and juvenile growth improves learning and memory of rats

    PubMed Central

    Beheshti, Farimah; Hosseini, Mahmoud; Vafaee, Farzaneh; Shafei, Mohammad Naser; Soukhtanloo, Mohammad

    2015-01-01

    The positive roles of antioxidants on brain development and learning and memory have been suggested. Nigella sativa (NS) has been suggested to have antioxidant and neuroprotective effects. This study was done to investigate the effects of feeding by the hydro-alcoholic extract of NS during neonatal and juvenile growth on learning and memory of rats. The pregnant rats were kept in separate cages. After delivery, they were randomly divided into four Groups including: (1) control; (2) NS 100 mg/kg (NS 100); (3) NS 200 mg/kg (NS 200); and (4) NS 400 mg/kg (NS 400). Rats in the control group (Group 1) received normal drinking water, whereas Groups 2, 3, and 4 received the same drinking water supplemented with the hydro-alcoholic extract of NS (100 mg/kg, 200 mg/kg, and 400 mg/kg, respectively) from the 1st day after birth through the first 8 weeks of life. After 8 weeks, 10 male offspring from each group were randomly selected and tested in the Morris water maze (MWM) and passive avoidance (PA) test. Finally, the brains were removed and total thiol groups and malondialdehyde (MDA) concentrations were determined. In the MWM, treatment by 400 mg/kg extract reduced both the time latency and the distance traveled to reach the platform compared to the control group (p < 0.05–p < 0.01). Both 200 mg/kg and 400 mg/kg of the extract increased the time spent in the target quadrant (p < 0.05–p < 0.01). In the PA test, the treatment of the animals by 200 mg/kg and 400 mg/kg of NS extract significantly increased the time latency for entering the dark compartment (p < 0.05–p < 0.001). Pretreatment of the animals with 400 mg/kg of NS extract decreased the MDA concentration in hippocampal tissues whereas it increased the thiol content compared to the control group (p < 0.001). These results allow us to propose that feeding of the rats by the hydro-alcoholic extract of NS during neonatal and juvenile growth has positive effects on learning and memory. The

  4. Feeding of Nigella sativa during neonatal and juvenile growth improves learning and memory of rats.

    PubMed

    Beheshti, Farimah; Hosseini, Mahmoud; Vafaee, Farzaneh; Shafei, Mohammad Naser; Soukhtanloo, Mohammad

    2016-04-01

    The positive roles of antioxidants on brain development and learning and memory have been suggested. Nigella sativa (NS) has been suggested to have antioxidant and neuroprotective effects. This study was done to investigate the effects of feeding by the hydro-alcoholic extract of NS during neonatal and juvenile growth on learning and memory of rats. The pregnant rats were kept in separate cages. After delivery, they were randomly divided into four Groups including: (1) control; (2) NS 100 mg/kg (NS 100); (3) NS 200 mg/kg (NS 200); and (4) NS 400 mg/kg (NS 400). Rats in the control group (Group 1) received normal drinking water, whereas Groups 2, 3, and 4 received the same drinking water supplemented with the hydro-alcoholic extract of NS (100 mg/kg, 200 mg/kg, and 400 mg/kg, respectively) from the 1st day after birth through the first 8 weeks of life. After 8 weeks, 10 male offspring from each group were randomly selected and tested in the Morris water maze (MWM) and passive avoidance (PA) test. Finally, the brains were removed and total thiol groups and malondialdehyde (MDA) concentrations were determined. In the MWM, treatment by 400 mg/kg extract reduced both the time latency and the distance traveled to reach the platform compared to the control group (p < 0.05-p < 0.01). Both 200 mg/kg and 400 mg/kg of the extract increased the time spent in the target quadrant (p < 0.05-p < 0.01). In the PA test, the treatment of the animals by 200 mg/kg and 400 mg/kg of NS extract significantly increased the time latency for entering the dark compartment (p < 0.05-p < 0.001). Pretreatment of the animals with 400 mg/kg of NS extract decreased the MDA concentration in hippocampal tissues whereas it increased the thiol content compared to the control group (p < 0.001). These results allow us to propose that feeding of the rats by the hydro-alcoholic extract of NS during neonatal and juvenile growth has positive effects on learning and memory. The

  5. Sitagliptin decreases ventricular arrhythmias by attenuated glucose-dependent insulinotropic polypeptide (GIP)-dependent resistin signalling in infarcted rats

    PubMed Central

    Lee, Tsung-Ming; Chen, Wei-Ting; Chang, Nen-Chung

    2016-01-01

    Myocardial infarction (MI) was associated with insulin resistance, in which resistin acts as a critical mediator. We aimed to determine whether sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, can attenuate arrhythmias by regulating resistin-dependent nerve growth factor (NGF) expression in postinfarcted rats. Normoglycaemic male Wistar rats after ligating coronary artery were randomized to either vehicle or sitagliptin for 4 weeks starting 24 h after operation. Post-infarction was associated with increased myocardial noradrenaline [norepinephrine (NE)] levels and sympathetic hyperinnervation. Compared with vehicle, sympathetic innervation was blunted after administering sitagliptin, as assessed by immunofluorescent analysis of tyrosine hydroxylase, growth-associated factor 43 and neurofilament and western blotting and real-time quantitative RT-PCR of NGF. Arrhythmic scores in the sitagliptin-treated infarcted rats were significantly lower than those in vehicle. Furthermore, sitagliptin was associated with reduced resistin expression and increased Akt activity. Ex vivo studies showed that glucose-dependent insulinotropic polypeptide (GIP) infusion, but not glucagon-like peptide-1 (GLP-1), produced similar reduction in resistin levels to sitagliptin in postinfarcted rats. Furthermore, the attenuated effects of sitagliptin on NGF levels can be reversed by wortmannin (a phosphatidylinositol 3-kinase antagonist) and exogenous resistin infusion. Sitagliptin protects ventricular arrhythmias by attenuating sympathetic innervation in the non-diabetic infarcted rats. Sitagliptin attenuated resistin expression via the GIP-dependent pathway, which inhibited sympathetic innervation through a signalling pathway involving phosphatidylinositol 3-kinase (PI3K) and Akt protein. PMID:26811539

  6. Sitagliptin decreases ventricular arrhythmias by attenuated glucose-dependent insulinotropic polypeptide (GIP)-dependent resistin signalling in infarcted rats.

    PubMed

    Lee, Tsung-Ming; Chen, Wei-Ting; Chang, Nen-Chung

    2016-01-01

    Myocardial infarction (MI) was associated with insulin resistance, in which resistin acts as a critical mediator. We aimed to determine whether sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, can attenuate arrhythmias by regulating resistin-dependent nerve growth factor (NGF) expression in postinfarcted rats. Normoglycaemic male Wistar rats after ligating coronary artery were randomized to either vehicle or sitagliptin for 4 weeks starting 24 h after operation. Post-infarction was associated with increased myocardial noradrenaline [norepinephrine (NE)] levels and sympathetic hyperinnervation. Compared with vehicle, sympathetic innervation was blunted after administering sitagliptin, as assessed by immunofluorescent analysis of tyrosine hydroxylase, growth-associated factor 43 and neurofilament and western blotting and real-time quantitative RT-PCR of NGF. Arrhythmic scores in the sitagliptin-treated infarcted rats were significantly lower than those in vehicle. Furthermore, sitagliptin was associated with reduced resistin expression and increased Akt activity. Ex vivo studies showed that glucose-dependent insulinotropic polypeptide (GIP) infusion, but not glucagon-like peptide-1 (GLP-1), produced similar reduction in resistin levels to sitagliptin in postinfarcted rats. Furthermore, the attenuated effects of sitagliptin on NGF levels can be reversed by wortmannin (a phosphatidylinositol 3-kinase antagonist) and exogenous resistin infusion. Sitagliptin protects ventricular arrhythmias by attenuating sympathetic innervation in the non-diabetic infarcted rats. Sitagliptin attenuated resistin expression via the GIP-dependent pathway, which inhibited sympathetic innervation through a signalling pathway involving phosphatidylinositol 3-kinase (PI3K) and Akt protein. PMID:26811539

  7. Protective effect of polydatin on learning and memory impairments in neonatal rats with hypoxic‑ischemic brain injury by up‑regulating brain‑derived neurotrophic factor.

    PubMed

    Sun, Jin; Qu, Yunxia; He, Huiming; Fan, Xiaolei; Qin, Yuanhua; Mao, Weifeng; Xu, Lixin

    2014-12-01

    Polydatin is a key component of Polygonum cuspidatum, a herb with medical and nutritional value. The present study investigated the protective effect of polydatin against learning and memory impairment in neonatal rats with hypoxic‑ischemic brain injury (HIBI). The unilateral common carotid artery ligation method was used to generate neonatal HIBI rats. Y‑maze testing revealed that rats with HIBI exhibited memory impairment, while rats with HIBI treated with polydatin displayed enhanced long‑term learning and memory. Of note, polydatin was found to upregulate the expression of hippocampal brain‑derived neurotrophic factor (BDNF) in rats with HIBI. BDNF has a role in protecting HIBI‑induced brain tissue injury and alleviating memory impairment. These findings showed that polydatin had a protective effect against learning and memory impairment in neonatal rats with HIBI and that the protective effect may be mediated through the upregulation of BDNF.

  8. Protective effect of polydatin on learning and memory impairments in neonatal rats with hypoxic‑ischemic brain injury by up‑regulating brain‑derived neurotrophic factor.

    PubMed

    Sun, Jin; Qu, Yunxia; He, Huiming; Fan, Xiaolei; Qin, Yuanhua; Mao, Weifeng; Xu, Lixin

    2014-12-01

    Polydatin is a key component of Polygonum cuspidatum, a herb with medical and nutritional value. The present study investigated the protective effect of polydatin against learning and memory impairment in neonatal rats with hypoxic‑ischemic brain injury (HIBI). The unilateral common carotid artery ligation method was used to generate neonatal HIBI rats. Y‑maze testing revealed that rats with HIBI exhibited memory impairment, while rats with HIBI treated with polydatin displayed enhanced long‑term learning and memory. Of note, polydatin was found to upregulate the expression of hippocampal brain‑derived neurotrophic factor (BDNF) in rats with HIBI. BDNF has a role in protecting HIBI‑induced brain tissue injury and alleviating memory impairment. These findings showed that polydatin had a protective effect against learning and memory impairment in neonatal rats with HIBI and that the protective effect may be mediated through the upregulation of BDNF. PMID:25241777

  9. Altered ventricular torsion and transmural patterns of myocyte relaxation precede heart failure in aging F344 rats.

    PubMed

    Campbell, Stuart G; Haynes, Premi; Kelsey Snapp, W; Nava, Kristofer E; Campbell, Kenneth S

    2013-09-01

    The purpose of this study was to identify and explain changes in ventricular and cellular function that contribute to aging-associated cardiovascular disease in aging F344 rats. Three groups of female F344 rats, aged 6, 18, and 22 mo, were studied. Echocardiographic measurements in isoflurane-anesthetized animals showed an increase in peak left ventricular torsion between the 6- and the 18-mo-old groups that was partially reversed in the 22-mo-old animals (P < 0.05). Epicardial, midmyocardial, and endocardial myocytes were subsequently isolated from the left ventricles of each group of rats. Unloaded sarcomere shortening and Ca(2+) transients were then measured in these cells (n = >75 cells for each of the nine age-region groups). The decay time of the Ca(2+) transient and the time required for 50% length relaxation both increased with age but not uniformly across the three regions (P < 0.02). Further analysis revealed a significant shift in the transmural distribution of these properties between 18 and 22 mo of age, with the largest changes occurring in epicardial myocytes. Computational modeling suggested that these changes were due in part to slower Ca(2+) dissociation from troponin in aging epicardial myocytes. Subsequent biochemical assays revealed a >50% reduction in troponin I phosphoprotein content in 22-mo-old epicardium relative to the other regions. These data suggest that between 18 and 22 mo of age (before the onset of heart failure), F344 rats display epicardial-specific myofilament-level modifications that 1) break from the progression observed between 6 and 18 mo and 2) coincide with aberrant patterns of cardiac torsion.

  10. Mechanical effects of liriodenine on the left ventricular-arterial coupling in Wistar rats: pressure-stroke volume analysis

    PubMed Central

    Chang, Kuo-Chu; Su, Ming-Jai; Peng, Ying-I; Shao, Ching-Chih; Wu, Yang-Chang; Tseng, Yung-Zu

    2001-01-01

    In a recent in vivo study, liriodenine, an aporphine alkaloid, has been identified as a prominent anti-arrhythmic agent that can prevent rats' sudden deaths, even at the dose as low as 10−7 g kg−1. The aim of this study was to determine whether liriodenine at its effective anti-arrhythmic dose of 10−7 g kg−1 had effects on the left ventricular (LV)-arterial coupling in Wistar rats. LV pressure and ascending aortic flow signals were recorded to construct the ventricular and arterial end-systolic pressure-stroke volume relationships to calculate LV end-systolic elastance (Ees) and effective arterial volume elastance (Ea), respectively. The optimal afterload (Qload) determined by the ratio of Ea to Ees was used to measure the optimality of energy transmission from the left ventricle to the arterial system. Liriodenine at the dose of 10−7 g kg−1 showed no significant changes in basal heart rate (HR), cardiac output (CO), LV end-systolic pressure (Pes), Ea, Ees, and Qload. By contrast, liriodenine at the dose of 10−6 g kg−1 produced a significant fall of 2.0% in HR and a significant rise of 5.8% in CO, but no significant change in Pes. Moreover, liriodenine administration of 10−6 g kg−1 to rats significantly decreased Ees by 8.5% and Ea by 10.6%, but did not change Qload. We conclude that liriodenine at the dose of 10−7 g kg−1 has no effects on the mechanical properties of the heart and the vasculature and the matching condition for the left ventricle coupled to its vasculature in rats. Even at 10 times the effective anti-arrhythmic dose, liriodenine shows no effects on the efficiency of energy transferred from the left ventricle to the arterial system. PMID:11325791

  11. Effect of dexamethasone and oxygen exposure on neonatal rat lung retinoic acid receptor proteins.

    PubMed

    McMenamy, K R; Anderson, M J; Zachman, R D

    1994-10-01

    Retinol deficiency in animal models results in histopathologic airway changes that appear similar to those found in human premature infants with bronchopulmonary dysplasia (BPD). Dexamethasone (DEX), a steroid now often used in the treatment of BPD, might potentially affect lung vitamin A homeostasis since it alters serum and liver retinoid stores in certain models. Our objective was to determine the effect of DEX on neonatal rat lung retinoid status and the binding of retinoic acid (RA) to cytosolic and nuclear receptor proteins. We examined this effect both in room air and when the animals breathed 95% oxygen (O2). Twenty-four 1-day-old rat pups received either 1 microgram/g DEX subcutaneously, an equal volume of normal saline (NS) subcutaneously at 0 (start experiment time), 24, and 48 hours, or no injection at all, and were sacrificed at 72 hours. Twelve rats in each treatment group were housed in room air and 12 in each group were exposed to > 95% O2 for the 3 day period. Lung and liver were analyzed for retinyl palmitate (RP). Nuclear retinoic acid receptor (RAR) and cellular retinoic acid binding protein (CRABP) were measured by specific binding assays. DEX decreased liver RP by 33-55% and rat pup lung RP by over 60%; it also decreased lung RAR binding (mean dpm/microgram protein +/- SEM) in both room air and oxygen groups: Air (11.2 +/- 1.0) vs. Air/DEX (4.6 +/- 1.3, n = 6; P < 0.01), and O2 (18.2 +/- 0.6) vs. O2/DEX (3.2 +/- 0.6, n = 6; P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7838622

  12. Destructive Effects of Prenatal WIN 55212-2 Exposure on Central Nervous System of Neonatal Rats

    PubMed Central

    Shabani, Mohammad; Divsalar, Kouros; Janahmadi, Mahyar

    2012-01-01

    Background Cannabinoid, particularly hashish and WIN 55212-2 (WIN), consumption during embryonic period may affect fetal growth, and the development of motor functioning, memory and cognitive functions. Therefore, the present study aimed to evaluate the effects of WIN 55212-2 during embryonic period on behavioral responses, as well as tissue and memory changes among neonatal rats. Methods WIN treated groups subcutaneously received daily doses of 0.5 or 1 mg/kg WIN suspended in 1% Tween-80-saline (1 ml/kg) from days 5 to 20 of pregnancy. The vehicle group received 1% Tween-80-saline from days 5 to 20 of pregnancy. Three, five and seven weeks after birth, the effects of maternal WIN consumption on infants' body weight, mortality, histological changes, motor functioning, and memory function were assessed. Findings Prenatal WIN consumption was associated with atrophy of cerebellum cortex in granular and Purkinje cells layers. WIN treatment of pregnant rats produced a significant decrease in the rearing frequency of the offspring, but significantly increased the grooming frequency at 22, 36 and 50 days of age. During the acquisition trials, approach latencies were not significantly different between all groups of rats (50 days old). When the trial was repeated 24 hours and seven days later (retention trial), the avoidance latencies of the WIN-exposed group were significantly shorter than those of the control and vehicle animals. The mortality percent was increased significantly and litter size was decreased significantly in WIN (1 mg/kg) treated rats compared to the control, vehicle and WIN (0.5 mg/kg) treatment groups. Conclusion These findings suggested that prenatal exposure to WIN probably induces long-term alterations in histological, motor functioning, and learning and memory parameters. PMID:24494131

  13. Ca exchange under non-perfusion-limited conditions in rat ventricular cells: Identification of subcellular compartments

    SciTech Connect

    Langer, G.A.; Rich, T.L.; Orner, F.B. )

    1990-08-01

    Freshly prepared ventricular myocytes from rat hearts, aliquots of which were tested for sarcolemmal integrity by La exposure, were labeled at high 45Ca specific activity. Isotope was subsequently washed out at a perfusion rate of 2.8 ml/s with washout solution sampled each 1 s. No initial unrecorded period of washout was imposed. Four compartments were distinguishable: (1) a rapid compartment (RC) containing 2.6 mmol Ca/kg dry wt of La-displaceable Ca, half time (t1/2) less than 1 s; (2) an intermediate compartment(s) (IC) containing 2.1 mmol, t1/2 = 3 and 19 s; (3) a slow compartment (SC) containing 1.6 mmol, t1/2 = 3.6 min; (4) an inexchangeable compartment that demonstrated no 45Ca uptake after 60-min labeling containing 1.2 mmol. Introduction of 10 mM caffeine as a probe for sarcoplasmic reticulum (SR) content at various times during the washouts caused an increased release of 45Ca. The net increased 45Ca release plotted as a function of time at which caffeine was introduced produced a biexponential curve with t1/2s of 2 and 22 s, very similar to the t1/2s of the IC. Ryanodine (1 microM) significantly reduced the caffeine-induced 45Ca release, confirming the SR locus of the IC. Cells were perfused with 10 mM NaH2PO4 to specifically increase mitochondrial 45Ca labeling. Subsequent removal of PO4 at various times during washouts produced large increases in effluent 45Ca. A plot of the net peak release of 45Ca vs. time of PO4 removal was monoexponential with t1/2 = 3.3 min, very similar to the SC t1/2. The large La-accessible RC remains unlocalized, but the rapidity of its exchange places it in the sarcolemma and/or at sites in rapid equilibrium with the sarcolemma.

  14. Prenatal ethanol exposure alters ventricular myocyte contractile function in the offspring of rats: influence of maternal Mg2+ supplementation.

    PubMed

    Wold, L E; Norby, F L; Hintz, K K; Colligan, P B; Epstein, P N; Ren, J

    2001-01-01

    Fetal alcohol syndrome (FAS) is often associated with cardiac hypertrophy and impaired ventricular function in a manner similar to postnatal chronic alcohol ingestion. Chronic alcoholism has been shown to lead to hypomagnesemia, and dietary Mg2+ supplementation was shown to ameliorate ethanol- induced cardiovascular dysfunction such as hypertension. However, the role of gestational Mg2+ supplementation on FAS-related cardiac dysfunction is unknown. This study was conducted to examine the influence of gestational dietary Mg2+ supplementation on prenatal ethanol exposure-induced cardiac contractile response at the ventricular myocyte level. Timed-pregnancy female rats were fed from gestation day 2 with liquid diets containing 0.13 g/L Mg2+ supplemented with ethanol (36%) or additional Mg2+ (0.52 g/L), or both. The pups were maintained on standard rat chow through adulthood, and ventricular myocytes were isolated and stimulated to contract at 0.5 Hz. Mechanical properties were evaluated using an IonOptix soft-edge system, and intracellular Ca2+ transients were measured as changes in fura-2 fluorescence intensity (Delta FFI). Offspring from all groups displayed similar growth curves. Myocytes from the ethanol group exhibited reduced cell length, enhanced peak shortening (PS), and shortened time to 90% relengthening (TR90) associated with a normal Delta FFI and time to PS (TPS). Mg2+ reverted the prenatal ethanol-induced alteration in PS and maximal velocity of relengthening. However, it shortened TPS and TR90, and altered the Delta FFI, as well as Ca2+ decay rate by itself. Additionally, myocytes from the ethanol group exhibited impaired responsiveness to increased extracellular Ca2+ or stimulating frequency, which were restored by gestational Mg2+ supplementation. These data suggest that although gestational Mg2+ supplementation may be beneficial to certain cardiac contractile dysfunctions in offspring of alcoholic mothers, caution must be taken, as Mg2

  15. CNS development under altered gravity: cerebellar glial and neuronal protein expression in rat neonates exposed to hypergravity

    NASA Astrophysics Data System (ADS)

    Nguon, K.; Li, G.-H.; Sajdel-Sulkowska, E. M.

    2004-01-01

    The future of space exploration depends on a solid understanding of the developmental process under microgravity, specifically in relation to the central nervous system (CNS). We have previously employed a hypergravity paradigm to assess the impact of altered gravity on the developing rat cerebellum [Exp. Biol. Med. 226 (2000) 790]. The present study addresses the molecular mechanisms involved in the cerebellar response to hypergravity. Specifically, the study focuses on the expression of selected glial and neuronal cerebellar proteins in rat neonates exposed to hypergravity (1.5 G) from embryonic day (E)11 to postnatal day (P)6 or P9 (the time of maximal cerebellar changes) comparing them against their expression in rat neonates developing under normal gravity. Proteins were analyzed by quantitative Western blots of cerebellar homogenates; RNA analysis was performed in the same samples using quantitative PCR. Densitometric analysis of Western blots suggested a reduction in glial (glial acidic protein, GFAP) and neuronal (neuronal cell adhesion moiecule, NCAM-L1, synaptophysin) proteins, but the changes in individual cerebellar proteins in hypergravity-exposed neonates appeared both age- and gender-specific. RNA analysis suggested a reduction in GFAP and synaptophysin mRNAs on P6. These data suggest that exposure to hypergravity may interfere with the expression of selected cerebellar proteins. These changes in protein expression may be involved in mediating the effect of hypergravity on the developing rat cerebellum.

  16. CNS development under altered gravity: cerebellar glial and neuronal protein expression in rat neonates exposed to hypergravity

    NASA Technical Reports Server (NTRS)

    Nguon, K.; Li, G-H; Sajdel-Sulkowska, E. M.

    2004-01-01

    The future of space exploration depends on a solid understanding of the developmental process under microgravity, specifically in relation to the central nervous system (CNS). We have previously employed a hypergravity paradigm to assess the impact of altered gravity on the developing rat cerebellum. The present study addresses the molecular mechanisms involved in the cerebellar response to hypergravity. Specifically, the study focuses on the expression of selected glial and neuronal cerebellar proteins in rat neonates exposed to hypergravity (1.5 G) from embryonic day (E)11 to postnatal day (P)6 or P9 (the time of maximal cerebellar changes) comparing them against their expression in rat neonates developing under normal gravity. Proteins were analyzed by quantitative Western blots of cerebellar homogenates; RNA analysis was performed in the same samples using quantitative PCR. Densitometric analysis of Western blots suggested a reduction in glial (glial acidic protein, GFAP) and neuronal (neuronal cell adhesion molecule, NCAM-L1, synaptophysin) proteins, but the changes in individual cerebellar proteins in hypergravity-exposed neonates appeared both age- and gender-specific. RNA analysis suggested a reduction in GFAP and synaptophysin mRNAs on P6. These data suggest that exposure to hypergravity may interfere with the expression of selected cerebellar proteins. These changes in protein expression may be involved in mediating the effect of hypergravity on the developing rat cerebellum. c2003 COSPAR. Published by Elsevier Ltd. All rights reserved.

  17. Low-dose sevoflurane promotes hippocampal neurogenesis and facilitates the development of dentate gyrus-dependent learning in neonatal rats.

    PubMed

    Chen, Chong; Shen, Feng-Yan; Zhao, Xuan; Zhou, Tao; Xu, Dao-Jie; Wang, Zhi-Ru; Wang, Ying-Wei

    2015-01-01

    Huge body of evidences demonstrated that volatile anesthetics affect the hippocampal neurogenesis and neurocognitive functions, and most of them showed impairment at anesthetic dose. Here, we investigated the effect of low dose (1.8%) sevoflurane on hippocampal neurogenesis and dentate gyrus-dependent learning. Neonatal rats at postnatal day 4 to 6 (P4-6) were treated with 1.8% sevoflurane for 6 hours. Neurogenesis was quantified by bromodeoxyuridine labeling and electrophysiology recording. Four and seven weeks after treatment, the Morris water maze and contextual-fear discrimination learning tests were performed to determine the influence on spatial learning and pattern separation. A 6-hour treatment with 1.8% sevoflurane promoted hippocampal neurogenesis and increased the survival of newborn cells and the proportion of immature granular cells in the dentate gyrus of neonatal rats. Sevoflurane-treated rats performed better during the training days of the Morris water maze test and in contextual-fear discrimination learning test. These results suggest that a subanesthetic dose of sevoflurane promotes hippocampal neurogenesis in neonatal rats and facilitates their performance in dentate gyrus-dependent learning tasks.

  18. Low vagally-mediated heart rate variability and increased susceptibility to ventricular arrhythmias in rats bred for high anxiety.

    PubMed

    Carnevali, Luca; Trombini, Mimosa; Graiani, Gallia; Madeddu, Denise; Quaini, Federico; Landgraf, Rainer; Neumann, Inga D; Nalivaiko, Eugene; Sgoifo, Andrea

    2014-04-10

    In humans, there is a documented association between anxiety disorders and cardiovascular disease. Putative underlying mechanisms may include an impairment of the autonomic nervous system control of cardiac function. The primary objective of the present study was to characterize cardiac autonomic modulation and susceptibility to arrhythmias in genetic lines of rats that differ largely in their anxiety level. To reach this goal, electrocardiographic recordings were performed in high-anxiety behavior (HAB, n=10) and low-anxiety behavior (LAB, n=10) rats at rest, during stressful stimuli and under autonomic pharmacological manipulations, and analyzed by means of time- and frequency-domain indexes of heart rate variability. During resting conditions, HAB rats displayed a reduced heart rate variability, mostly in terms of lower parasympathetic (vagal) modulation compared to LAB rats. In HAB rats, this relatively low cardiac vagal control was associated with smaller heart rate responsiveness to acute stressors compared to LAB counterparts. In addition, beta-adrenergic pharmacological stimulation induced a larger incidence of ventricular tachyarrhythmias in HABs compared to LABs. At sacrifice, a moderate increase in heart-body weight ratio was observed in HAB rats. We conclude that high levels of anxiety-related behavior in rats are associated with signs of i) impaired autonomic modulation of heart rate (low vagally-mediated heart rate variability), ii) poor adaptive heart rate responsiveness to stressful stimuli, iii) increased arrhythmia susceptibility, and iv) cardiac hypertrophy. These results highlight the utility of the HAB/LAB model for investigating the mechanistic basis of the comorbidity between anxiety disorders and cardiovascular disease.

  19. Oestrogenic effects of neonatal administration of raloxifene on hypothalamic-pituitary-gonadal axis in male and female rats.

    PubMed

    Pinilla, L; González, L C; Gaytán, F; Tena-Sempere, M; Aguilar, E

    2001-06-01

    Selective oestrogen receptor modulators constitute a family of drugs that are used increasingly in the management of oestrogen-associated pathology. Raloxifene is a selective oestrogen receptor modulator that is used to treat and prevent osteoporosis in post-menopausal women. The actions of raloxifene on bone, breast, uterus and serum cholesterol concentrations have been widely analysed, but very few studies have investigated the possible actions of this drug on the central nervous system. The central nervous system of the newborn rat is very sensitive to oestrogen action. In this study a series of experiments was conducted to analyse the effects of different doses of raloxifene (50, 100, 250 or 500 microg per rat per day) administered to neonatal rats on days 1-5 of age. Female rats treated with raloxifene showed decreased gonadotrophin secretion, hyperprolactinaemia, advanced vaginal opening, decreased body weight, persistent presence of cornified epithelial cells in vaginal smears, anovulation, inhibition of positive feedback between oestradiol and LH, and infertility. Male rats showed delayed balanopreputial separation, reduced body weight and hyperprolactinaemia. All these changes resemble those obtained after neonatal administration of oestradiol benzoate, thus indicating, for the first time, that raloxifene exerts an oestrogenic action on the hypothalamic-pituitary structures controlling reproductive function in rats.

  20. Withaferin A attenuates lipopolysaccharide-induced acute lung injury in neonatal rats.

    PubMed

    Gao, S; Li, H; Zhou, X-Q; You, J-B; Tu, D-N; Xia, G; Jiang, J-X; Xin, C

    2015-07-31

    Withaferin A (WFA) is an active compound from Withania somnifera and has been reported to exhibit a variety of pharmacological activities such as anti—inflammatory, immunomodulatory and anti—tumor properties. In the present study, we investigated the potential protective role of WFA on acute lung injury in neonatal rats induced by lipopolysaccharide (LPS). We found that WFA significantly attenuated the pathological changes of lungs induced by LPS injection. Administration with WFA obviously decreased pulmonary neutrophil infiltration accompanied with decreased MPO concentrations. WFA also reduced the expression of pro—inflammatory cytokines including MIP—2, TNF—α, IL—1β and IL—6. Meanwhile, the expression levels of anti—inflammatory mediators such as TGF—β1 and IL—10 were significantly increased following WFA administration. Moreover, WFA protected LPS—treated rats from oxidative damage via up—regulation of TBARS and H2O2 concentrations and down—regulation of ROS contents. Taken together, the present study demonstrated that WFA administration attenuated LPS—induced lung injury through inhibition of inflammatory responses and oxidative stress.

  1. Olfactory conditioning impairment following posttraining NMDA receptor blockade in neonatal rats.

    PubMed

    Weldon, D A; Fedorcik, G G; LoRusso, C M; Tiburzi, M J; Lenoci, J M

    1997-01-01

    Six-day-old Sprague-Dawley rat pups were exposed to peppermint odor paired with tactile stimulation (stroking the skin with a paint brush) for twenty 10-s conditioning trials, and their olfactory preference was tested the next day. In Experiment 1, pups that had received an injection of the noncompetitive N-methyl-D-aspartate receptor antagonist MK-801 (0.1 mg/kg, i.p.) either 30 min before or immediately after conditioning spent less time over the conditioned odor than saline-treated controls. In Experiment 2, pups received an injection of either MK-801 or saline 0, 30, or 60 min after the training period. There was a reduction in the preference for the conditioned odor in the animals receiving MK-801 immediately following training, but treatment with the drug at the other intervals did not produce a performance impairment. The impairment following immediate posttraining injection occurred with either 0.05 or 0.1, but not with 0.01 mg/kg of MK-801 (Experiment 3). Experiment 4 provided control data to confirm that pups that had experienced the procedures used in Experiments 1-3 showed greater preference for the conditioned odor than did naive pups or those receiving exposure to the odor without stroking. The data indicate that immediate posttraining activation of N-methyl-D-aspartate receptors is required for normal olfactory learning in neonatal rats. PMID:9013499

  2. Bimodal Respiratory-Locomotor Neurons in the Neonatal Rat Spinal Cord.

    PubMed

    Le Gal, Jean-Patrick; Juvin, Laurent; Cardoit, Laura; Morin, Didier

    2016-01-20

    Neural networks that can generate rhythmic motor output in the absence of sensory feedback, commonly called central pattern generators (CPGs), are involved in many vital functions such as locomotion or respiration. In certain circumstances, these neural networks must interact to produce coordinated motor behavior adapted to environmental constraints and to satisfy the basic needs of an organism. In this context, we recently reported the existence of an ascending excitatory influence from lumbar locomotor CPG circuitry to the medullary respiratory networks that is able to depolarize neurons of the parafacial respiratory group during fictive locomotion and to subsequently induce an increased respiratory rhythmicity (Le Gal et al., 2014b). Here, using an isolated in vitro brainstem-spinal cord preparation from neonatal rat in which the respiratory and the locomotor networks remain intact, we show that during fictive locomotion induced either pharmacologically or by sacrocaudal afferent stimulation, the activity of both thoracolumbar expiratory motoneurons and interneurons is rhythmically modulated with the locomotor activity. Completely absent in spinal inspiratory cells, this rhythmic pattern is highly correlated with the hindlimb ipsilateral flexor activities. Furthermore, silencing brainstem neural circuits by pharmacological manipulation revealed that this locomotor-related drive to expiratory motoneurons is solely dependent on propriospinal pathways. Together these data provide the first evidence in the newborn rat spinal cord for the existence of bimodal respiratory-locomotor motoneurons and interneurons onto which both central efferent expiratory and locomotor drives converge, presumably facilitating the coordination between the rhythmogenic networks responsible for two different motor functions. Significance statement: In freely moving animals, distant regions of the brain and spinal cord controlling distinct motor acts must interact to produce the best

  3. Comparison of Macitentan and Bosentan on Right Ventricular Remodeling in a Rat Model of Non-vasoreactive Pulmonary Hypertension

    PubMed Central

    Landskroner, Kyle; Bauer, Yasmina; Vercauteren, Magali; Rey, Markus; Renault, Berengère; Studer, Rolf; Vezzali, Enrico; Freti, Diego; Hadana, Hakim; Schläpfer, Manuela; Cattaneo, Christophe; Bortolamiol, Céline; Weber, Edgar; Whitby, Brian R.; Delahaye, Stéphane; Wanner, Daniel; Steiner, Pauline; Nayler, Oliver; Hess, Patrick; Clozel, Martine

    2015-01-01

    Aims: We compared the efficacy of macitentan, a novel dual endothelin A/endothelin B receptor antagonist, with that of another dual endothelin receptor antagonist, bosentan, in a rat model of non-vasoreactive pulmonary hypertension (PH) with particular emphasis on right ventricular (RV) remodeling. Methods and Results: Unlike monocrotaline or hypoxic/sugen rats, bleomycin-treated rats presented a non-vasoreactive PH characterized by the absence of pulmonary dilatation to adenosine. We therefore chose the bleomycin rat model to compare the effects of the maximally effective doses of macitentan and bosentan on pulmonary vascular and RV remodeling. Macitentan (100 mg·kg−1·d−1), but not bosentan (300 mg·kg−1·d−1), significantly prevented pulmonary vascular remodeling, RV hypertrophy, and cardiomyocyte diameter increase. Cardiac protection by macitentan was associated with a significant attenuation of genes related to cell hypertrophy and extracellular matrix remodeling. Microautoradiography and high performance liquid chromatography analysis showed greater distribution of macitentan than bosentan in the RV and pulmonary tissue. Conclusions: Macitentan was more efficacious than bosentan in preventing the development of pulmonary and RV hypertrophies in a model of non-vasoreactive PH. Greater ability to distribute into the tissue could contribute to the greater structural improvement by macitentan compared with bosentan. PMID:26230396

  4. Activation of soluble guanylyl cyclase by YC-1 in aortic smooth muscle but not in ventricular myocardium from rat

    PubMed Central

    Wegener, Jörg W; Gath, Ingolf; Förstermann, Ulrich; Nawrath, Hermann

    1997-01-01

    The effects of YC-1 (3-(5′-hydroxymethyl-2′-furyl)-1-benzyl indazole), an activator of soluble guanylyl cyclase, on tension, levels of cyclic GMP and cyclic AMP, and cardiac L-type Ca2+-current (ICa(L)) were investigated in aortic smooth muscle and ventricular heart muscle from rat.YC-1 (0.1–30 μM) induced a concentration-dependent relaxation in aortic rings precontracted with phenylephrine (3 μM). The relaxant effects of YC-1 were reversed by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (30 μM; ODQ), potentiated by zaprinast (10 μM) and antagonized by Rp-8-Br-cGMPS (100 μM).In ventricular heart muscle strips, YC-1 (30 μM) exhibited no effects on force of contraction (Fc) in the absence or presence of either zaprinast (10 μM) or 3-isobutyl-1-methylxanthine (30 μM). Fc was slightly increased by YC-1 (30 μM) in the presence of isoprenaline (100 nM), but this effect was not influenced by ODQ (30 μM).Cardiac ICa(L) was not significantly affected by YC-1 (30 μM), either in the absence or presence of isoprenaline (30 nM).In aortic rings, cyclic GMP levels were increased almost 3 fold by YC-1 (30 μM); this effect was abolished by ODQ (30 μM). In isolated ventricular cardiomyocytes, cyclic GMP levels were not affected by YC-1 (30 μM) but almost doubled by activation of particular guanylyl cyclase with atriopeptin II (100 nM).YC-1 (30 μM) did not increase cyclic AMP levels either in aortic rings or in ventricular cardiomyocytes. In contrast, isoprenaline (3 μM) increased cyclic AMP levels about two fold in both tissues. In cardiomyocytes, the effect of isoprenaline (3 μM) was slightly enhanced by YC-1 (30 μM).It is concluded that relaxation of smooth muscle preparations by YC-1 is mediated mainly by activation of soluble guanylyl cyclase and subsequent increase in cyclic GMP levels. The failure of YC-1 to affect cardiac Fc, levels of cyclic GMP, and ICa(L) suggests that soluble guanylyl cyclase is not

  5. PDE2 activity differs in right and left rat ventricular myocardium and differentially regulates β2 adrenoceptor-mediated effects

    PubMed Central

    Soler, Fernando; Fernández-Belda, Francisco; Pérez-Schindler, Joaquín; Handschin, Christoph; Fuente, Teodomiro

    2015-01-01

    The important regulator of cardiac function, cAMP, is hydrolyzed by different cyclic nucleotide phosphodiesterases (PDEs), whose expression and activity are not uniform throughout the heart. Of these enzymes, PDE2 shapes β1 adrenoceptor-dependent cardiac cAMP signaling, both in the right and left ventricular myocardium, but its role in regulating β2 adrenoceptor-mediated responses is less well known. Our aim was to investigate possible differences in PDE2 transcription and activity between right (RV) and left (LV) rat ventricular myocardium, as well as its role in regulating β2 adrenoceptor effects. The free walls of the RV and the LV were obtained from Sprague–Dawley rat hearts. Relative mRNA for PDE2 (quantified by qPCR) and PDE2 activity (evaluated by a colorimetric procedure and using the PDE2 inhibitor EHNA) were determined in RV and LV. Also, β2 adrenoceptor-mediated effects (β2-adrenoceptor agonist salbutamol + β1 adrenoceptor antagonist CGP-20712A) on contractility and cAMP concentrations, in the absence or presence of EHNA, were studied in the RV and LV. PDE2 transcript levels were less abundant in RV than in LV and the contribution of PDE2 to the total PDE activity was around 25% lower in the microsomal fraction of the RV compared with the LV. β2 adrenoceptor activation increased inotropy and cAMP levels in the LV when measured in the presence of EHNA, but no such effects were observed in the RV, either in the presence or absence of EHNA. These results indicate interventricular differences in PDE2 transcript and activity levels, which may distinctly regulate β2 adrenoceptor-mediated contractility and cAMP concentrations in the RV and in the LV of the rat heart. PMID:25432985

  6. Neonatal maternal separation up-regulates protein signalling for cell survival in rat hypothalamus.

    PubMed

    Irles, Claudine; Nava-Kopp, Alicia T; Morán, Julio; Zhang, Limei

    2014-05-01

    We have previously reported that in response to early life stress, such as maternal hyperthyroidism and maternal separation (MS), the rat hypothalamic vasopressinergic system becomes up-regulated, showing enlarged nuclear volume and cell number, with stress hyperresponsivity and high anxiety during adulthood. The detailed signaling pathways involving cell death/survival, modified by adverse experiences in this developmental window remains unknown. Here, we report the effects of MS on cellular density and time-dependent fluctuations of the expression of pro- and anti-apoptotic factors during the development of the hypothalamus. Neonatal male rats were exposed to 3 h-daily MS from postnatal days 2 to 15 (PND 2-15). Cellular density was assessed in the hypothalamus at PND 21 using methylene blue staining, and neuronal nuclear specific protein and glial fibrillary acidic protein immunostaining at PND 36. Expression of factors related to apoptosis and cell survival in the hypothalamus was examined at PND 1, 3, 6, 9, 12, 15, 20 and 43 by Western blot. Rats subjected to MS exhibited greater cell-density and increased neuronal density in all hypothalamic regions assessed. The time course of protein expression in the postnatal brain showed: (1) decreased expression of active caspase 3; (2) increased Bcl-2/Bax ratio; (3) increased activation of ERK1/2, Akt and inactivation of Bad; PND 15 and PND 20 were the most prominent time-points. These data indicate that MS can induce hypothalamic structural reorganization by promoting survival, suppressing cell death pathways, increasing cellular density which may alter the contribution of these modified regions to homeostasis.

  7. Repeated Neonatal Propofol Administration Induces Sex-Dependent Long-Term Impairments on Spatial and Recognition Memory in Rats

    PubMed Central

    Gonzales, Edson Luck T.; Yang, Sung Min; Choi, Chang Soon; Mabunga, Darine Froy N.; Kim, Hee Jin; Cheong, Jae Hoon; Ryu, Jong Hoon; Koo, Bon-Nyeo; Shin, Chan Young

    2015-01-01

    Propofol is an anesthetic agent that gained wide use because of its fast induction of anesthesia and rapid recovery post-anesthesia. However, previous studies have reported immediate neurodegeneration and long-term impairment in spatial learning and memory from repeated neonatal propofol administration in animals. Yet, none of those studies has explored the sex-specific long-term physical changes and behavioral alterations such as social (sociability and social preference), emotional (anxiety), and other cognitive functions (spatial working, recognition, and avoidance memory) after neonatal propofol treatment. Seven-day-old Wistar-Kyoto (WKY) rats underwent repeated daily intraperitoneal injections of propofol or normal saline for 7 days. Starting fourth week of age and onwards, rats were subjected to behavior tests including open-field, elevated-plus-maze, Y-maze, 3-chamber social interaction, novel-object-recognition, passive-avoidance, and rotarod. Rats were sacrificed at 9 weeks and hippocampal protein expressions were analyzed by Western blot. Results revealed long-term body weight gain alterations in the growing rats and sex-specific impairments in spatial (female) and recognition (male) learning and memory paradigms. A markedly decreased expression of hippocampal NMDA receptor GluN1 subunit in female- and increased expression of AMPA GluR1 subunit protein expression in male rats were also found. Other aspects of behaviors such as locomotor activity and coordination, anxiety, sociability, social preference and avoidance learning and memory were not generally affected. These results suggest that neonatal repeated propofol administration disrupts normal growth and some aspects of neurodevelopment in rats in a sex-specific manner. PMID:25995824

  8. Hyperbaric oxygen treatment promotes neural stem cell proliferation in the subventricular zone of neonatal rats with hypoxic-ischemic brain damage.

    PubMed

    Feng, Zhichun; Liu, Jing; Ju, Rong

    2013-05-01

    Hyperbaric oxygen therapy for the treatment of neonatal hypoxic-ischemic brain damage has been used clinically for many years, but its effectiveness remains controversial. In addition, the mechanism of this potential neuroprotective effect remains unclear. This study aimed to investigate the influence of hyperbaric oxygen on the proliferation of neural stem cells in the subventricular zone of neonatal Sprague-Dawley rats (7 days old) subjected to hypoxic-ischemic brain damage. Six hours after modeling, rats were treated with hyperbaric oxygen once daily for 7 days. Immunohistochemistry revealed that the number of 5-bromo-2'-deoxyuridine positive and nestin positive cells in the subventricular zone of neonatal rats increased at day 3 after hypoxic-ischemic brain damage and peaked at day 5. After hyperbaric oxygen treatment, the number of 5-bromo-2'-deoxyuridine positive and nestin positive cells began to increase at day 1, and was significantly higher than that in normal rats and model rats until day 21. Hematoxylin-eosin staining showed that hyperbaric oxygen treatment could attenuate pathological changes to brain tissue in neonatal rats, and reduce the number of degenerating and necrotic nerve cells. Our experimental findings indicate that hyperbaric oxygen treatment enhances the proliferation of neural stem cells in the subventricular zone of neonatal rats with hypoxic-ischemic brain damage, and has therapeutic potential for promoting neurological recovery following brain injury.

  9. Repeated sauna therapy attenuates ventricular remodeling after myocardial infarction in rats by increasing coronary vascularity of noninfarcted myocardium.

    PubMed

    Sobajima, Mitsuo; Nozawa, Takashi; Shida, Takuya; Ohori, Takashi; Suzuki, Takayuki; Matsuki, Akira; Inoue, Hiroshi

    2011-08-01

    Repeated sauna therapy (ST) increases endothelial nitric oxide synthase (eNOS) activity and improves cardiac function in heart failure as well as peripheral blood flow in ischemic limbs. The present study investigates whether ST can increase coronary vascularity and thus attenuate cardiac remodeling after myocardial infarction (MI). We induced MI by ligating the left coronary artery of Wistar rats. The rats were placed in a far-infrared dry sauna at 41°C for 15 min and then at 34°C for 20 min once daily for 4 wk. Cardiac hemodynamic, histopathological, and gene analyses were performed. Despite the similar sizes of MI between the ST and non-ST groups (51.4 ± 0.3 vs. 51.1 ± 0.2%), ST reduced left ventricular (LV) end-diastolic (9.7 ± 0.4 vs. 10.7 ± 0.5 mm, P < 0.01) and end-systolic (8.6 ± 0.5 vs. 9.6 ± 0.6 mm, P < 0.01) dimensions and attenuated MI-induced increases in LV end-diastolic pressure. Cross-sectional areas of cardiomyocytes were smaller in ST rats and associated with a significant reduction in myocardial atrial natriuretic peptide mRNA levels. Vascular density was reduced in the noninfarcted myocardium of non-ST rats, and the density of cells positive for CD31 and for α-smooth muscle actin was decreased. These decreases were attenuated in ST rats compared with non-ST rats and associated with increases in myocardial eNOS and vascular endothelial growth factor mRNA levels. In conclusion, ST attenuates cardiac remodeling after MI, at least in part, through improving coronary vascularity in the noninfarcted myocardium. Repeated ST might serve as a novel noninvasive therapy for patients with MI.

  10. Neonatal binge alcohol exposure increases microglial activation in the developing rat hippocampus.

    PubMed

    Boschen, K E; Ruggiero, M J; Klintsova, A Y

    2016-06-01

    Aberrant activation of the developing immune system can have long-term negative consequences on cognition and behavior. Teratogens, such as alcohol, activate microglia, the brain's resident immune cells, which could contribute to the lifelong deficits in learning and memory observed in humans with Fetal Alcohol Spectrum Disorders (FASD) and in rodent models of FASD. The current study investigates the microglial response of the brain 24 h following neonatal alcohol exposure (postnatal days (PDs) 4-9, 5.25 g/kg/day). On PD10, microglial cell counts and area of cell territory were assessed using unbiased stereology in the hippocampal subfields CA1, CA3 and dentate gyrus (DG), and hippocampal expression of pro- and anti-inflammatory genes was analyzed. A significant decrease in microglial cell counts in CA1 and DG was found in alcohol-exposed and sham-intubated (SI) animals compared to undisturbed suckle controls (SCs), suggesting overlapping effects of alcohol exposure and intubation alone on the neuroimmune response. Cell territory was decreased in alcohol-exposed animals in CA1, CA3, and DG compared to controls, suggesting the microglia have shifted to a more activated state following alcohol treatment. Furthermore, both alcohol-exposed and SI animals had increased levels of pro-inflammatory cytokines IL-1β, TNF-α, CD11b, and CCL4; in addition, CCL4 was significantly increased in alcohol-exposed animals compared to SI as well. Alcohol-exposed animals also showed increased levels of anti-inflammatory cytokine TGF-β compared to both SI and SCs. In summary, the number and activation of microglia in the neonatal hippocampus are both affected in a rat model of FASD, along with increased gene expression of pro- and anti-inflammatory cytokines. This study shows that alcohol exposure during development induces a neuroimmune response, potentially contributing to long-term alcohol-related changes to cognition, behavior and immune function. PMID:26996510

  11. Sex-dependent mitophagy and neuronal death following rat neonatal hypoxia-ischemia.

    PubMed

    Demarest, T G; Waite, E L; Kristian, T; Puche, A C; Waddell, J; McKenna, M C; Fiskum, G

    2016-10-29

    Males are more susceptible than females to long-term cognitive deficits following neonatal hypoxic-ischemic encephalopathy (HIE). Mitochondrial dysfunction is implicated in the pathophysiology of cerebral hypoxia-ischemia (HI), but the influence of sex on mitochondrial quality control (MQC) after HI is unknown. Therefore, we tested the hypothesis that mitophagy is sexually dimorphic and neuroprotective 20-24h following the Rice-Vannucci model of rat neonatal HI at postnatal day 7 (PN7). Mitochondrial and lysosomal morphology and degree of co-localization were determined by immunofluorescence in the cerebral cortex. No difference in mitochondrial abundance was detected in the cortex after HI. However, net mitochondrial fission increased in both hemispheres of female brain, but was most extensive in the ipsilateral hemisphere of male brain following HI. Basal autophagy, assessed by immunoblot for the autophagosome marker LC3BI/II, was greater in males suggesting less intrinsic reserve capacity for autophagy following HI. Autophagosome formation, lysosome size, and TOM20/LAMP2 co-localization were increased in the contralateral hemisphere following HI in female, but not male brain. An accumulation of ubiquitinated mitochondrial protein was observed in male, but not female brain following HI. Moreover, neuronal cell death with NeuN/TUNEL co-staining occurred in both hemispheres of male brain, but only in the ipsilateral hemisphere of female brain after HI. In summary, mitophagy induction and neuronal cell death are sex dependent following HI. The deficit in elimination of damaged/dysfunctional mitochondria in the male brain following HI may contribute to male vulnerability to neuronal death and long-term neurobehavioral deficits following HIE.

  12. Neonatal injury rapidly alters markers of pain and stress in rat pups.

    PubMed

    Victoria, Nicole C; Karom, Mary C; Eichenbaum, Hila; Murphy, Anne Z

    2014-01-01

    Less than 60% of infants undergoing invasive procedures in the neonatal intensive care unit receive analgesic therapy. These infants show long-term decreases in pain sensitivity and cortisol reactivity. In rats, we have previously shown that inflammatory pain experienced on the day of birth significantly decreases adult somatosensory thresholds and responses to anxiety- and stress-provoking stimuli. These long-term changes in pain and stress responsiveness are accompanied by two-fold increases in central met-enkephalin and β-endorphin expression. However, the time course over which these changes in central opioid peptide expression occur, relative to the time of injury, are not known. The present studies were conducted to determine whether the observed changes in adult opioid peptide expression were present within the first postnatal week following injury. The impact of neonatal inflammation on plasma corticosterone, a marker for stress reactivity, was also determined. Brain, spinal cord, and trunk blood were harvested at 24 h, 48 h, and 7 d following intraplantar administration of the inflammatory agent carrageenan on the day of birth. Radioimmunoassay was used to determine plasma corticosterone and met-enkephalin and β-endorphin levels within the forebrain, cortex, midbrain, and spinal cord. Within 24 h of injury, met-enkephalin levels were significantly increased in the midbrain, but decreased in the spinal cord and cortex; forebrain β-endorphin levels were significantly increased as a result of early life pain. Corticosterone levels were also significantly increased. At 7 d post-injury, opioid peptides remained elevated relative to controls, suggesting a time point by which injury-induced changes become programmed and permanent. PMID:24022912

  13. The effect of human milk on DNA synthesis of neonatal rat hepatocytes in primary culture.

    PubMed

    Kohno, Y; Shiraki, K; Mura, T

    1991-03-01

    We studied the effect of human milk on DNA synthesis of neonatal hepatocytes to elucidate the physiologic role of human milk in growth of the liver. Neonatal hepatocytes were isolated from 5-d-old rats and cultured in serum-free medium. Human milk stimulated DNA synthesis of these hepatocytes in a concentration-dependent manner. The stimulatory activity of 7.5% (vol/vol) human milk plus 0.1 mumol/L insulin was five times that of control and was almost the same as that of 20 micrograms/L human epidermal growth factor (hEGF) plus insulin. The effect of human milk was additive with treatment with hEGF and insulin. The milk associated with prolonged jaundice of infants was significantly more active than the milk that was not associated with jaundice, although the concentration of hEGF was not different between the two types of milk. The mitogenic activity of milk was heat-labile, inactivated by DTT and stable after treatment with trypsin. Three peaks of the activity were detected in milk by gel filtration and the fraction containing proteins of molecular weight between 36,000 and 76,000 showed the highest activity. Anti-hEGF antibody did not inhibit this activity completely. These results suggested the presence of mitogens other than hEGF or a more active form of hEGF in human milk. The milk associated with breast-milk jaundice exerts a different influence on cell growth and may affect maturation of the liver function related to bilirubin metabolism. The mitogenic activity of milk might be important for growth and development of the liver in infants.

  14. Parabens inhibit the early phase of folliculogenesis and steroidogenesis in the ovaries of neonatal rats.

    PubMed

    Ahn, Hyo-Jin; An, Beum-Soo; Jung, Eui-Man; Yang, Hyun; Choi, Kyung-Chul; Jeung, Eui-Bae

    2012-09-01

    Parabens are widely used as anti-microbial agents in the cosmetic and pharmaceutical industries. Recently, parabens have been shown to act as xenoestrogens, a class of endocrine disruptors. In the present study, 55 female pups were given daily subcutaneous injections of methyl-, propyl-, and butyl-paraben or 17beta-estradiol (E2) during neonatal Day 1-7. The ovaries were excised on postnatal Day 8, then fixed and stained with hematoxylin and eosin for histological analysis. The follicles were counted and classified as being in the primordial, early primary, or primary stages. The number of primordial follicles increased while early primary follicles decreased at the high doses of propyl- and butyl-paraben. The levels of anti-Mullerian hormone (AMH) and Foxl2 mRNA increased by propyl- and butyl-parabens whereas kit ligand/stem cell factor (KITL) expression was up regulated only by butyl-paraben. The mRNA levels of StAR and Cyp11a1 were significantly decreased after treatment with methyl-, propyl-, and butyl-parabens. Consistent with its use as a positive control, E2 regulated the expression of KITL, StAR, and Cyp11a1 genes, but surprisingly did not affect AMH and Foxl2 levels. Thus, E2 and parabens had different effects on the regulation of folliculogenic and steroidogenic genes, demonstrating the estrogenic and nonestrogenic properties of parabens in the ovary. Taken together, our data show that parabens stimulated AMH mRNA expression and consequently inhibited the early phase of folliculogenesis in the ovaries of neonatal female rat. The levels of steroidogenic enzymes, indicators of follicle differentiation, appeared to be regulated by parabens through inhibition of their transcriptional repressor, Foxl2.

  15. Alternative Splicing Generates a Novel Truncated Cav1.2 Channel in Neonatal Rat Heart*

    PubMed Central

    Liao, Ping; Yu, Dejie; Hu, Zhenyu; Liang, Mui Cheng; Wang, Jue Jin; Yu, Chye Yun; Ng, Gandi; Yong, Tan Fong; Soon, Jia Lin; Chua, Yeow Leng; Soong, Tuck Wah

    2015-01-01

    L-type Cav1.2 Ca2+ channel undergoes extensive alternative splicing, generating functionally different channels. Alternatively spliced Cav1.2 Ca2+ channels have been found to be expressed in a tissue-specific manner or under pathological conditions. To provide a more comprehensive understanding of alternative splicing in Cav1.2 channel, we systematically investigated the splicing patterns in the neonatal and adult rat hearts. The neonatal heart expresses a novel 104-bp exon 33L at the IVS3-4 linker that is generated by the use of an alternative acceptor site. Inclusion of exon 33L causes frameshift and C-terminal truncation. Whole-cell electrophysiological recordings of Cav1.233L channels expressed in HEK 293 cells did not detect any current. However, when co-expressed with wild type Cav1.2 channels, Cav1.233L channels reduced the current density and altered the electrophysiological properties of the wild type Cav1.2 channels. Interestingly, the truncated 3.5-domain Cav1.233L channels also yielded a dominant negative effect on Cav1.3 channels, but not on Cav3.2 channels, suggesting that Cavβ subunits is required for Cav1.233L regulation. A biochemical study provided evidence that Cav1.233L channels enhanced protein degradation of wild type channels via the ubiquitin-proteasome system. Although the physiological significance of the Cav1.233L channels in neonatal heart is still unknown, our report demonstrates the ability of this novel truncated channel to modulate the activity of the functional Cav1.2 channels. Moreover, the human Cav1.2 channel also contains exon 33L that is developmentally regulated in heart. Unexpectedly, human exon 33L has a one-nucleotide insertion that allowed in-frame translation of a full Cav1.2 channel. An electrophysiological study showed that human Cav1.233L channel is a functional channel but conducts Ca2+ ions at a much lower level. PMID:25694430

  16. Alterations in cortical GABAB receptors in neonatal rats exposed to hypoxic stress: role of glucose, oxygen, and epinephrine resuscitation.

    PubMed

    Anju, T R; Abraham, Pretty Mary; Antony, Sherin; Paulose, C S

    2010-10-01

    Hypoxia in neonates can cause permanent brain damage by gene and receptor level alterations mediated through changes in neurotransmitters. The present study evaluated GABA(B) receptor alterations, gene expression changes in glutamate decarboxylase and hypoxia-inducible factor 1A in the cerebral cortex of hypoxic neonatal rats and the resuscitation groups with glucose, oxygen, and epinephrine. Under hypoxic stress, a significant decrease in total GABA and GABA(B) receptors, GABA(B) and GAD gene expression was observed in the cerebral cortex, which accounts for the respiratory inhibition. Hypoxia-inducible factor 1A was upregulated under hypoxia to maintain body homeostasis. Hypoxic rats supplemented with glucose alone and with oxygen showed a reversal of the receptor alterations and changes in GAD and HIF-1A to near control. Being a source of immediate energy, glucose can reduce the ATP-depletion-induced changes in GABA and oxygenation, which helps in encountering hypoxia. Resuscitation with oxygen alone and epinephrine was less effective in reversing the receptor alterations. Thus, our study suggests that reduction in the GABA(B) receptors functional regulation during hypoxia plays an important role in cortical damage. Resuscitation with glucose alone and glucose and oxygen to hypoxic neonatal rats helps in protecting the brain from severe hypoxic damage.

  17. Differential microglial and astrocytic response to bacterial and viral infection in the developing hippocampus of neonatal rats.

    PubMed

    Patro, Nisha; Singh, Kavita; Patro, Ishan

    2013-08-01

    Polyinosinic:polycytidylic acid (Poly I:C; 5 mg/kg body weight, ip) and lipopolysaccharide (LPS; 0.3 mg/kg body weight, ip) induced microglial and astrocytic activation in Sprague Dawley rats. Higher microglial and astrocytic activities were noticed in Poly I:C infused rats throughout the hippocampus till postnatal day 21 with a comparatively weaker response in LPS group. However, LPS induced inflammation persisted even after postnatal day 21, indicating thereby, that the Poly I:C (viral mimic) produces an acute inflammation, while LPS (bacterial endotoxin) produces chronic inflammation when exposed during early neonatal life.

  18. Neonatal capsaicin treatment in rats affects TRPV1-related noxious heat sensation and circadian body temperature rhythm.

    PubMed

    Jeong, Keun-Yeong; Seong, Jinsil

    2014-06-15

    The transient receptor potential vanilloid 1 (TRPV1) is a cation channel that serves as a polymodal detector of noxious stimuli such as capsaicin. Therefore, capsaicin treatment has been used to investigate the physiological function of TRPV1. Here, we report physiological changes induced by treating neonatal rats with capsaicin. Capsaicin (50mg/kg) (cap-treated) or vehicle (vehicle-treated) was systemically administered to newborn SD rat pups within 48 h after birth. TRPV1 expression, intake volume of capsaicin water, and noxious heat sensation were measured 6 weeks after capsaicin treatment. Circadian body temperature and locomotion were recorded by biotelemetry. Expression of Per1, Per2, Bmal1 and Hsf1 (clock genes) was also investigated. Neonatal capsaicin treatment not only decreased TRPV1 expression but also induced desensitization to noxious heat stimuli. Circadian body temperature of cap-treated rats increased significantly compared with that of vehicle-treated rats. Additionally, the amplitude of the circadian body temperature was reversed in cap-treated rats. Expression of the hypothalamic Hsf1 and liver Per2 clock genes followed a similar trend. Therefore, we suggest that these findings will be useful in studying various physiological mechanisms related to TRPV1.

  19. Animal Models of Human Disease: Severe and Mild Lead Encephalopathy in the Neonatal Rat*

    PubMed Central

    Michaelson, I. Arthur; Sauerhoff, Mitchell W.

    1974-01-01

    Inorganic lead produces cerebral dysfunction and clinically definable encephalopathies in man. To date there have been few studies on the biochemical changes in brain following exposure to inorganic lead. Studies correlating toxicity with behavioral and brain neurochemical changes following lead exposure have been hindered because adult laboratory animals are resistant to the central nervous system effects of lead poisoning. Such studies have been impeded by lack of suitable experimental models until Pentschew and Garro showed that brain lesions develop in neonatal rats when a pregnant rat newly delivered of her litter is placed on a 4% lead carbonate containing diet. Lead passes into the developing sucklings via maternal milk. Lead-poisoned new-borns have pronounced retardation of growth and during the fourth week of ilfe develop the severe signs of lead encephalopathy, namely, extensive histological lesions of the cerebellum, brain edema, and paraplegia. There is an approximate 85-fold increase in the lead concentration of both the cerebellum and cerebral cortex relative to controls, but edema and gross vascular changes are confined to the cerebellum. Ingested lead had little effect on RNA, DNA, and protein concentrations of developing rat cerebellum and cerebral cortex. However, there was a reduction of between 10 and 20% in the DNA content of the cerebellum around 3 weeks of age in the lead-exposed sucklings. This suggests a failure of cell multiplication in this part of the brain. A critical evaluation of this experimental approach indicated that under similar dietary conditions experimental lactating rats eat 30% less food than controls resulting in: (a) sustained loss in body weight of nursing mothers and that (b) offsprings who develop paraplegia and cerebellar damage do so after gaining access to lead containing diet. We have studied mothers' food consumption and body weight changes and blood, milk, and brain lead content; and newborns' body and brain

  20. Metabolic Inhibition Strongly Inhibits Na+-Dependent Mg2+ Efflux in Rat Ventricular Myocytes

    PubMed Central

    Tashiro, Michiko; Inoue, Hana; Konishi, Masato

    2009-01-01

    Abstract We measured intracellular Mg2+ concentration ([Mg2+]i) in rat ventricular myocytes using the fluorescent indicator furaptra (25°C). In normally energized cells loaded with Mg2+, the introduction of extracellular Na+ induced a rapid decrease in [Mg2+]i: the initial rate of decrease in [Mg2+]i (initial Δ[Mg2+]i/Δt) is thought to represent the rate of Na+-dependent Mg2+ efflux (putative Na+/Mg2+ exchange). To determine whether Mg2+ efflux depends directly on energy derived from cellular metabolism, in addition to the transmembrane Na+ gradient, we estimated the initial Δ[Mg2+]i/Δt after metabolic inhibition. In the absence of extracellular Na+ and Ca2+, treatment of the cells with 1 μM carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone, an uncoupler of mitochondria, caused a large increase in [Mg2+]i from ∼0.9 mM to ∼2.5 mM in a period of 5–8 min (probably because of breakdown of MgATP and release of Mg2+) and cell shortening to ∼50% of the initial length (probably because of formation of rigor cross-bridges). Similar increases in [Mg2+]i and cell shortening were observed after application of 5 mM potassium cyanide (KCN) (an inhibitor of respiration) for ≥90 min. The initial Δ[Mg2+]i/Δt was diminished, on average, by 90% in carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone-treated cells and 92% in KCN-treated cells. When the cells were treated with 5 mM KCN for shorter times (59–85 min), a significant decrease in the initial Δ[Mg2+]i/Δt (on average by 59%) was observed with only a slight shortening of the cell length. Intracellular Na+ concentration ([Na+]i) estimated with a Na+ indicator sodium-binding benzofuran isophthalate was, on average, 5.0–10.5 mM during the time required for the initial Δ[Mg2+]i/Δt measurements, which is well below the [Na+]i level for half inhibition of the Mg2+ efflux (∼40 mM). Normalization of intracellular pH using 10 μM nigericin, a H+ ionophore, did not reverse the inhibition of the Mg2+ efflux

  1. Long-term cognitive impairments in adult rats treated neonatally with beta-N-Methylamino-L-Alanine.

    PubMed

    Karlsson, Oskar; Roman, Erika; Brittebo, Eva B

    2009-11-01

    Most cyanobacteria (blue-green algae) can produce the neurotoxin beta-N-methylamino-L-alanine (BMAA). Dietary exposure to BMAA has been suggested to be involved in the etiology of the neurodegenerative disease amyotrophic lateral sclerosis/Parkinsonism-dementia complex (ALS/PDC). Little is known about BMAA-induced neurotoxicity following neonatal administration. Our previous studies have revealed an uptake of BMAA in the hippocampus and striatum of neonatal mice. Furthermore, rats treated with BMAA during the neonatal period displayed acute but transient motoric disturbances and failed to show habituation at juvenile age suggesting impairments in learning functions. In the present study, the aim was to investigate long-term behavioral effects of BMAA administration in neonatal rats. BMAA was administered on postnatal days 9-10 (200 or 600 mg/kg; subcutaneous injection). Spatial learning and memory was investigated in adulthood using the radial arm maze test. The results revealed impaired learning but not memory in BMAA-treated animals. The observed impairments were not due to alterations in motoric capacity, general activity, or behavioral profiles, as assessed in the multivariate concentric square field (MCSF) and open field tests. An aversive stimulus in the MCSF test revealed impairments in avoidance learning and/or memory. There was no difference in basal serum corticosterone levels in BMAA-treated animals, indicating that the observed long-term effects were not secondary to an altered basal hypothalamic-pituitary-adrenal axis function. The present data demonstrated long-term learning impairments following neonatal BMAA administration. Further studies on biochemical effects in various brain regions and subsequent behavioral alterations are needed to elucidate the mechanisms of BMAA-induced developmental neurotoxicity.

  2. A comparison of the apoptotic effect of Delta(9)-tetrahydrocannabinol in the neonatal and adult rat cerebral cortex.

    PubMed

    Downer, Eric J; Gowran, Aoife; Campbell, Veronica A

    2007-10-17

    The maternal use of cannabis during pregnancy results in a number of cognitive deficits in the offspring that persist into adulthood. The endocannabinoid system has a role to play in neurodevelopmental processes such as neurogenesis, migration and synaptogenesis. However, exposure to phytocannabinoids, such as Delta(9)-tetrahydrocannabinol, during gestation may interfere with these events to cause abnormal patterns of neuronal wiring and subsequent cognitive impairments. Aberrant cell death evoked by Delta(9)-tetrahydrocannabinol may also contribute to cognitive deficits and in cultured neurones Delta(9)-tetrahydrocannabinol induces apoptosis via the CB(1) cannabinoid receptor. In this study we report that Delta(9)-tetrahydrocannabinol (5-50 microM) activates the stress-activated protein kinase, c-jun N-terminal kinase, and the pro-apoptotic protease, caspase-3, in in vitro cerebral cortical slices obtained from the neonatal rat brain. The proclivity of Delta(9)-tetrahydrocannabinol to impact on these pro-apoptotic signalling molecules was not observed in in vitro cortical slices obtained from the adult rat brain. In vivo, subcutaneous administration of Delta(9)-tetrahydrocannabinol (1-30 mg/kg) activated c-jun N-terminal kinase, caspase-3 and cathepsin-D, and induced DNA fragmentation in the cerebral cortex of neonatal rats. In contrast, in vivo administration of Delta(9)-tetrahydrocannabinol to adult rats was not associated with the apoptotic pathway in the cerebral cortex. The data provide evidence which supports the hypothesis that the neonatal rat brain is more vulnerable to the neurotoxic influence of Delta(9)-tetrahydrocannabinol, suggesting that the cognitive deficits that are observed in humans exposed to marijuana during gestation may be due, in part, to abnormal engagement of the apoptotic cascade during brain development.

  3. Thymosin β4 inhibits microglia activation through microRNA 146a in neonatal rats following hypoxia injury.

    PubMed

    Zhou, Tian; Huang, Yan-xia; Song, Jian-wen; Ma, Qiao-mei

    2015-12-01

    Neuroinflammation mediated by activated microglia plays a pivotal role in the pathogenesis of neurological disorders, including hypoxic injury of the developing brain. Thymosin β4 (Tβ4), the major G-actin-sequestering molecule, has an anti-inflammatory effect and has been used to treat various neurological diseases. However, the effect of Tβ4 on hypoxia-induced microglia activation in the developing brain remains unclear. We investigate here the effect of Tβ4 on microglia activation of neonatal rats after hypoxia exposure. Tβ4 treatment was carried out on 1-day-old rats and BV-2 cells. Tβ4 expression in microglia was determined by quantitative real time-PCR, western blotting, and immunofluorescence staining. Secretion of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and nitric oxide (NO) was assessed by enzyme-linked immunosorbent assay and colorimetric assay. mRNA expression of TNF-α and IL-1β, and microRNA 146a expression was determined by quantitative real time-PCR. We showed that Tβ4 treatment significantly inhibited secretion of inflammatory mediators in the cerebellum of neonatal rats following hypoxia injury. Increased expression of endogenous Tβ4 in microglia was observed both in hypoxic rats and in BV-2 cells. Tβ4 treatment significantly inhibited the expression and secretion of hypoxia-induced TNF-α, IL-1β, and NO. Remarkably, microRNA 146a expression was found to have increased in Tβ4-treated BV-2 cells. We demonstrated the anti-inflammatory effect of Tβ4 in neonatal rats following hypoxic brain injury. More importantly, our data reveal, for the first time, that Tβ4 inhibits microglia activation in vitro. Therefore, this study contributes to understanding the role and mechanism of Tβ4 function in central nervous system diseases.

  4. Histological correlates of N40 auditory evoked potentials in adult rats after neonatal ventral hippocampal lesion: animal model of schizophrenia.

    PubMed

    Romero-Pimentel, A L; Vázquez-Roque, R A; Camacho-Abrego, I; Hoffman, K L; Linares, P; Flores, G; Manjarrez, E

    2014-11-01

    The neonatal ventral hippocampal lesion (NVHL) is an established neurodevelopmental rat model of schizophrenia. Rats with NVHL exhibit several behavioral, molecular and physiological abnormalities that are similar to those found in schizophrenics. Schizophrenia is a severe psychiatric illness characterized by profound disturbances of mental functions including neurophysiological deficits in brain information processing. These deficits can be assessed by auditory evoked potentials (AEPs), where schizophrenics exhibit abnormalities in amplitude, duration and latency of such AEPs. The aim of the present study was to compare the density of cells in the temporal cerebral cortex and the N40-AEP of adult NVHL rats versus adult sham rats. We found that rats with NVHL exhibit significant lower amplitude of the N40-AEP and a significant lower number of cells in bilateral regions of the temporal cerebral cortex compared to sham rats. Because the AEP recordings were obtained from anesthetized rats, we suggest that NVHL leads to inappropriate innervation in thalamic-cortical pathways in the adult rat, leading to altered function of cortical networks involved in processing of primary auditory information.

  5. Effects of antiarrhythmic drugs on ventricular fibrillation thresholds of normal and ischaemic myocardium in the anaesthetized rat.

    PubMed Central

    Marshall, R. J.; Muir, A. W.; Winslow, E.

    1983-01-01

    1 The effects of agents which produce membrane stabilization (class I), beta 1-adrenoceptor blockade (class II), prolongation of the cardiac action potential (class III) or inhibition of the slow inward current (class IV) were investigated for their ability to increase the ventricular fibrillation threshold (VFT) or to modify the fall in VFT consequent upon coronary artery ligation in the anaesthetized rat. 2 The class I agent, Org6001, increased VFT of normal myocardium and in lower doses reduced the postligation fall in VFT. 3 The class II agent, metoprolol, failed to increase VFT of normal myocardium but reduced the postligation fall. 4 The class III agent, melperone, increased VFT of both normal and ischaemic myocardium whereas the class IV agent, nifedipine failed to influence VFT in either region. 5 Bepridil (class I and IV) was similar to Org6001 and sotalol (class II and III) in that it increased VFT of normal myocardium and in lower doses reduced the postligation fall in VFT. 6 Measurement of VFT before and after coronary artery ligation in the rat constitutes a rapid and reproducible screen to detect antifibrillatory activity. 7 The results also suggest that in the rat, the low currents used (approximately 400 microA) do not release substantial quantities of catecholamines whereas these may be released by coronary artery ligation. PMID:6824812

  6. Non-targeted metabolomics identified a common metabolic signature of lethal ventricular tachyarrhythmia (LVTA) in two rat models.

    PubMed

    Wang, Xingxing; Wang, Dian; Yu, Xiaojun; Zhang, Guohong; Wu, Jiayan; Zhu, Guanghui; Su, Ruibing; Lv, Junyao

    2016-06-21

    Lethal ventricular tachyarrhythmia (LVTA) is the predominant underlying mechanism of sudden cardiac death (SCD). The aim of this study is to characterize the metabolic features of myocardia following LVTA, and identify potential biomarkers to diagnose LVTA. We developed two LVTA rat models induced by aconitine injection or coronary artery ligation, which represent cardiac ion channel disease-related and cardiac ischemia-related SCD, respectively. The myocardial metabolic profile was investigated by gas chromatography-mass spectrometry and proton nuclear magnetic resonance-based metabolomics. Twenty-three aconitine-injected and 14 coronary artery ligation-treated rats developed LVTA SCD. A total of 38 differential metabolites of myocardia were identified in aconitine-induced LVTA rats, of which 31 metabolites showed a similar change in coronary artery ligation-related LVTA rats. Fatty acids (stearic, palmitic, linoleic, elaidic, and myristic) and branched-chain amino acids (valine, leucine, and isoleucine) were the most down-regulated metabolites. Furthermore, elevated ADP, phosphate, lactate, glutamate, aspartate, threonine, choline and arginine were also observed. Major pathways regarding these dysregulated metabolites post LVTA are energy excessive consumption and deficit, ionic imbalance, oxidative stress, cardiac cytotoxicity and membrane injury. Valine, stearic acid and leucine collectively enable a precision of 92.9% to distinguish LVTA from its control, and are correlated with several arrhythmia indices. Our results uncovered a common metabolic feature of LVTA in myocardia in two rat models, which represent cardiac ion channel disease and cardiac ischemia, respectively. l-Valine, l-leucine and stearic acid jointly confer good potential for distinguishing LVTA, which might be potential biomarkers of LVTA-related SCD. PMID:27138062

  7. Lobeline attenuates neonatal ethanol-mediated changes in hyperactivity and dopamine transporter function in the prefrontal cortex in rats.

    PubMed

    Smith, A M; Wellmann, K A; Lundblad, T M; Carter, M L; Barron, S; Dwoskin, L P

    2012-03-29

    Current therapies for attention deficit hyperactivity disorder (ADHD) have varying efficacy in individuals with fetal alcohol spectrum disorders (FASD), suggesting that alternative therapeutics are needed. Developmental exposure to ethanol produces changes in dopamine (DA) systems, and DA has also been implicated in ADHD pathology. In the current study, lobeline, which interacts with proteins in dopaminergic presynaptic terminals, was evaluated for its ability to attenuate neonatal ethanol-induced locomotor hyperactivity and alterations in dopamine transporter (DAT) function in striatum and prefrontal cortex (PFC). From postnatal days (PND) 1-7, male and female rat pups were intubated twice daily with either 3 g/kg ethanol or milk, or were not intubated (non-intubated control) as a model for "third trimester" ethanol exposure. On PND 21 and 22, pups received acute lobeline (0, 0.3, 1, or 3 mg/kg), and locomotor activity was assessed. On PND 23-25, pups again received an acute injection of lobeline (1 or 3 mg/kg), and DAT kinetic parameters (Km and V(max)) were determined. Results demonstrated that neonatal ethanol produced locomotor hyperactivity on PND 21 that was reversed by lobeline (1 and 3 mg/kg). Although striatal DAT function was not altered by neonatal ethanol or acute lobeline, neonatal ethanol exposure increased the V(max) for DAT in the PFC, suggesting an increase in DAT function in PFC. Lobeline ameliorated this effect on PFC V(max) at the same doses that decreased hyperactivity. Methylphenidate, the gold standard therapeutic for ADHD, was also evaluated for comparison with lobeline. Methylphenidate decreased DAT V(max) and Km in PFC from ethanol-treated pups. Thus, lobeline and methylphenidate differentially altered DAT function following neonatal ethanol exposure. Collectively, these findings provide support that lobeline may be a useful pharmacotherapy for some of the deficits associated with neonatal ethanol exposure.

  8. Calcium influx inhibition: possible mechanism of the negative effect of tetrahydropalmatine on left ventricular pressure in isolated rat heart.

    PubMed

    Chan, P; Chiu, W T; Chen, Y J; Wu, P J; Cheng, J T

    1999-05-01

    The active ingredient dl-tetrahydropalmatine (THP) isolated from the traditional Chinese herb Corydalis racemosa has been found to have antihypertensive effects. However, severe cardiac and neurological toxic effects were reported from using this herb for the treatment of pain. In an isolated perfused rat heart model, THP at the concentration of 100 microM was found to have a negative effect (-45%) on left ventricular pressure and this effect was produced concentration-dependently from concentrations lower than 50 microM. In isolated cardiomyocytes, radioactive calcium influx was also inhibited significantly by THP at the concentration of 100 microM and this effect was also in a concentration-dependent manner (-39%). In a patient with latent heart disease, the use of Corydalis should probably be detrimental, the toxic effect was probably due to calcium influx inhibition.

  9. Intranasal delivery of bone marrow mesenchymal stem cells improved neurovascular regeneration and rescued neuropsychiatric deficits after neonatal stroke in rats.

    PubMed

    Wei, Zheng Zachory; Gu, Xiaohuan; Ferdinand, Anwar; Lee, Jin Hwan; Ji, Xiaoya; Ji, Xun Ming; Yu, Shan Ping; Wei, Ling

    2015-01-01

    Neonatal stroke is a major cause of mortality and long-term morbidity in infants and children. Currently, very limited therapeutic strategies are available to protect the developing brain against ischemic damage and promote brain repairs for pediatric patients. Moreover, children who experienced neonatal stroke often have developmental social behavior problems. Cellular therapy using bone marrow mesenchymal stem cells (BMSCs) has emerged as a regenerative therapy after stroke. In the present investigation, neonatal stroke of postnatal day 7 (P7) rat pups was treated with noninvasive and brain-specific intranasal delivery of BMSCs at 6 h and 3 days after stroke (1 × 10(6)cells/animal). Prior to transplantation, BMSCs were subjected to hypoxic preconditioning to enhance their tolerance and regenerative properties. The effects on regenerative activities and stroke-induced sensorimotor and social behavioral deficits were specifically examined at P24 of juvenile age. The BMSC treatment significantly reduced infarct size and blood-brain barrier disruption, promoted angiogenesis, neurogenesis, neurovascular repair, and improved local cerebral blood flow in the ischemic cortex. BMSC-treated rats showed better sensorimotor and olfactory functional recovery than saline-treated animals, measured by the adhesive removal test and buried food finding test. In social behavioral tests, we observed functional and social behavioral deficits in P24 rats subjected to stroke at P7, while the BMSC treatment significantly improved the performance of stroke animals. Overall, intranasal BMSC transplantation after neonatal stroke shows neuroprotection and great potential as a regenerative therapy to enhance neurovascular regeneration and improve functional recovery observed at the juvenile stage of development. PMID:25647744

  10. Neonatal androgenization increases vasoactive intestinal peptide levels in rat anterior pituitary: possible involvement of vasoactive intestinal peptide in the neonatal androgenization-induced hyperprolactinemia.

    PubMed

    Watanobe, H; Sasaki, S; Takebe, K

    1991-11-01

    Accumulating evidence suggests that vasoactive intestinal peptide (VIP) may be a physiological PRL-releasing factor. In the present study, we examined a possible involvement of VIP in the neonatal androgenization (NA)-induced hyperprolactinemia. Twenty-four hours after birth, newborn female rats were injected sc with 1,000 micrograms of testosterone (NA) or with oil vehicle only (control). Both groups were sacrificed at 8 weeks of age. Compared to controls, NA rats showed significantly higher plasma PRL levels (7.3 fold), anterior pituitary (AP) PRL content (2.1 fold) and plasma estradiol levels (2.1 fold). AP VIP content was extremely higher (61 fold) in NA rats than in controls. However, NA did not affect VIP content in the suprachiasmatic nucleus, paraventricular nucleus or median eminence. These results suggest that the NA-induced hyperprolactinemia may be mediated, at least in part, by paracrine and/or autocrine effects of the increased AP VIP on PRL secretion. However, since the potentiation by NA of the AP VIP content was extremely marked compared to those of the other parameters, the possibility was also raised that the increased AP VIP may be involved in other endocrine and/or nonendocrine events occurring in the AP. PMID:1802925

  11. Interactive toxicity of chlorpyrifos and parathion in neonatal rats: Role of esterases in exposure sequence-dependent toxicity

    SciTech Connect

    Kacham, R.; Karanth, S.; Baireddy, P.; Liu, J.; Pope, C. . E-mail: carey.pope@okstate.edu

    2006-01-15

    We previously reported that sequence of exposure to chlorpyrifos and parathion in adult rats can markedly influence toxic outcome. In the present study, we evaluated the interactive toxicity of chlorpyrifos (8 mg/kg, po) and parathion (0.5 mg/kg, po) in neonatal (7 days old) rats. Rats were exposed to the insecticides either concurrently or sequentially (separated by 4 h) and sacrificed at 4, 8, and 24 h after the first exposure for biochemical measurements (cholinesterase activity in brain, plasma, and diaphragm and carboxylesterase activity in plasma and liver). The concurrently-exposed group showed more cumulative lethality (15/24) than either of the sequential dosing groups. With sequential dosing, rats treated initially with chlorpyrifos prior to parathion (C/P) exhibited higher lethality (7/23) compared to those treated with parathion before chlorpyrifos (P/C; 1/24). At 8 h after initial dosing, brain cholinesterase inhibition was significantly greater in the C/P group (59%) compared to the P/C group (28%). Diaphragm and plasma cholinesterase activity also followed a relatively similar pattern of inhibition. Carboxylesterase inhibition in plasma and liver was relatively similar among the treatment groups across time-points. Similar sequence-dependent differences in brain cholinesterase inhibition were also noted with lower binary exposures to chlorpyrifos (2 mg/kg) and parathion (0.35 mg/kg). In vitro and ex vivo studies compared relative oxon detoxification of carboxylesterases (calcium-insensitive) and A-esterases (calcium-sensitive) in liver homogenates from untreated and insecticide pretreated rats. Using tissues from untreated rats, carboxylesterases detoxified both chlorpyrifos oxon and paraoxon, while A-esterases only detoxified chlorpyrifos oxon. With parathion pretreatment, A-esterases still detoxified chlorpyrifos oxon while liver from chlorpyrifos pretreated rats had little apparent effect on paraoxon. We conclude that while neonatal rats are less

  12. Inhibitory Effect of Cinobufagin on L-Type Ca2+ Currents, Contractility, and Ca2+ Homeostasis of Isolated Adult Rat Ventricular Myocytes

    PubMed Central

    Li, Pinya; Song, Qiongtao; Liu, Tao; Wu, Zhonglin; Chu, Xi; Zhang, Xuan; Zhang, Ying; Gao, Yonggang; Zhang, Jianping; Chu, Li

    2014-01-01

    Cinobufagin (CBG), a major bioactive ingredient of the bufanolide steroid compounds of Chan Su, has been widely used to treat coronary heart disease. At present, the effect of CBG on the L-type Ca2+ current (ICa-L) of ventricular myocytes remains undefined. The aim of the present study was to characterize the effect of CBG on intracellular Ca2+ ([Ca2+]i) handling and cell contractility in rat ventricular myocytes. CBG was investigated by determining its influence on ICa-L, Ca2+ transient, and contractility in rat ventricular myocytes using the whole-cell patch-clamp technique and video-based edge-detection and dual-excitation fluorescence photomultiplier systems. The dose of CBG (10−8 M) decreased the maximal inhibition of CBG by 47.93%. CBG reduced ICa-L in a concentration-dependent manner with an IC50 of 4 × 10−10 M, upshifted the current-voltage curve of ICa-L, and shifted the activation and inactivation curves of ICa-L leftward. Moreover, CBG diminished the amplitude of the cell shortening and Ca2+ transients with a decrease in the time to peak (Tp) and the time to 50% of the baseline (Tr). CBG inhibited L-type Ca2+ channels, and reduced [Ca2+]i and contractility in adult rat ventricular myocytes. These findings contribute to the understanding of the cardioprotective efficacy of CBG. PMID:24977199

  13. Evaluation of neonatally-induced mild diabetes in rats: Maternal and fetal repercussions

    PubMed Central

    2010-01-01

    Many experimental studies have been performed to evaluate mild diabetes effects. However, results are divergent regarding glycemia and insulin measurement, fetal macrossomia, and placental weights. The aim was to investigate repercussions of neonatally-induced mild diabetes on the maternal organism and presence of congenital defects in their offspring in other mild diabetes model. On the day of birth, female offspring were distributed into two groups: Group streptozotocin (STZ): received 100 mg STZ/kg body weight, and Control Group: received vehicle in a similar time period. Maternal weights and glycemias were determined at days 0, 7, 14 and 21 of pregnancy. At day 21 of pregnancy, the rats were anesthetized and a laparotomy was performed to weigh and analyze living fetuses and placentas. The fetuses were classified as small (SPA), appropriate (APA) and large (LPA) for pregnancy age. Fetuses were also analyzed for the presence of external anomalies and processed for skeletal anomaly and ossification sites analysis. Statistical significance was considered as p < 0.05. In STZ group, there was increased glycemia at 0 and 14 days of pregnancy, lower weights throughout pregnancy, higher placental weight and index, an increased proportion of fetuses classified as SPA and LPA, and their fetuses presented with an increased frequency of abnormal sternebra, and absent cervical nuclei, which were not enough to cause the emergence of skeletal anomalies. Thus, this study shows that mild diabetes altered fetal development, characterized by intrauterine growth restriction. Further, the reached glycemia does not lead to any major congenital defects in the fetuses of streptozotocin-induced mild diabetic rats. PMID:20529353

  14. Endocrine and neurobehavioral abnormalities induced by propofol administered to neonatal rats

    PubMed Central

    Tan, Sijie; Xu, Changqing; Zhu, Wanting; Willis, Jesse; Seubert, Christoph N.; Gravenstein, Nikolaus; Sumners, Colin; Martynyuk, Anatoly E.

    2014-01-01

    Background We studied whether neonatal propofol anesthesia affects development of the endocrine and neural systems. Methods Sprague-Dawley rats were anesthetized using intraperitoneal propofol for 5 h on postnatal days (P) 4, 5, or 6. Pups that received either saline or intralipid, but not those in the negative control groups, were also maternally separated for 5 h. Serum levels of corticosterone were measured immediately after anesthesia and in adulthood after prepulse inhibition (PPI) of acoustic startle testing (≥P80), followed by measurement of hippocampal neuronal activity. Results Propofol acutely increased corticosterone levels to 146.6 ± 23.5 ng/ml (n=6) vs 16.4 ± 3.5 ng/ml (n=6) and 18.4 ± 3.2 ng/ml (n=6) in saline- and intralipd-treated pups, respectively. In adulthood, the propofol group exhibited exacerbated endocrine responses to stress in a form of increased corticosterone levels (1171.58 ± 149.17 ng/ml (n=15) vs 370.02 ± 36.01 ng/ml (n=10) in the saline group). The propofol group had increased the frequency of miniature inhibitory postsynaptic currents in CA1 neurons of male and female rats, but reduced PPI of startle was detected only in males. The Na+–K+–2Cl− co-transporter inhibitor bumetanide, administered to pups prior to propofol, alleviated long-term endocrine and PPI abnormalities. Exogenous corticosterone, administered to naïve pups, induced synaptic and endocrine, but not PPI effects, similar to those of propofol. Conclusions Propofol-caused acute increases in corticosterone levels and gamma-aminobutyric acid type A receptor-mediated excitation at the time of anesthesia may play mechanistic roles in development of exacerbated endocrine responses to stress and neurobehavioral abnormalities. PMID:24992523

  15. Regulation of alkaline phosphatase expression in a neonatal rat clonal calvarial cell strain by retinoic acid.

    PubMed

    Ng, K W; Gummer, P R; Michelangeli, V P; Bateman, J F; Mascara, T; Cole, W G; Martin, T J

    1988-02-01

    A clonal cell strain, UMR 201, was established from a culture of rat calvarial cells by the process of limiting dilution on a collagen substratum. One-day-old neonatal rat calvaria stripped of periosteum were placed on collagen in alpha-MEM with 10% fetal bovine serum (FBS). Cells that grew out from the calvaria were passaged eight times to select cells with the ability to proliferate in culture before cloning was attempted. Cells from the clonal strain were homogeneous in appearance with a doubling time in culture of about 24 hours. The UMR 201 cells formed predominantly type 1 collagen. When treated with retinoic acid (RA), all cells showed an intense staining for alkaline phosphatase (ALP). This effect of RA on the expression of ALP activity was reversible and was time and dose dependent. The earliest change was observed within 6 hours. In contrast, single and isolated clumps of untreated cells stained positively for ALP only when they were confluent. Coincubation with dactinomycin up to 3 hours after the addition of RA completely prevented the expression of ALP, whereas dactinomycin became progressively less effective when added at later times. This is interpreted as indicating a regulatory role of RA on the gene expression of ALP. Other hormones acting on bone, such as 1,25(OH)2 vitamin D3 and dexamethasone, also modulate ALP activity. The cells showed morphologic evidence of senescence after passage 12. Our preliminary studies showed that the UMR 201 cells had the characteristics of relatively undifferentiated mesenchymal cells.(ABSTRACT TRUNCATED AT 250 WORDS)

  16. Photocontrol of Voltage-Gated Ion Channel Activity by Azobenzene Trimethylammonium Bromide in Neonatal Rat Cardiomyocytes

    PubMed Central

    Frolova, Sheyda R.; Gaiko, Olga; Tsvelaya, Valeriya A.; Pimenov, Oleg Y.; Agladze, Konstantin I.

    2016-01-01

    The ability of azobenzene trimethylammonium bromide (azoTAB) to sensitize cardiac tissue excitability to light was recently reported. The dark, thermally relaxed trans- isomer of azoTAB suppressed spontaneous activity and excitation propagation speed, whereas the cis- isomer had no detectable effect on the electrical properties of cardiomyocyte monolayers. As the membrane potential of cardiac cells is mainly controlled by activity of voltage-gated ion channels, this study examined whether the sensitization effect of azoTAB was exerted primarily via the modulation of voltage-gated ion channel activity. The effects of trans- and cis- isomers of azoTAB on voltage-dependent sodium (INav), calcium (ICav), and potassium (IKv) currents in isolated neonatal rat cardiomyocytes were investigated using the whole-cell patch-clamp technique. The experiments showed that azoTAB modulated ion currents, causing suppression of sodium (Na+) and calcium (Ca2+) currents and potentiation of net potassium (K+) currents. This finding confirms that azoTAB-effect on cardiac tissue excitability do indeed result from modulation of voltage-gated ion channels responsible for action potential. PMID:27015602

  17. Orexin induces excitation of respiratory neuronal network in isolated brainstem spinal cord of neonatal rat.

    PubMed

    Sugita, Takeo; Sakuraba, Shigeki; Kaku, Yuki; Yoshida, Kazu-ichi; Arisaka, Hirofumi; Kuwana, Shun-ichi

    2014-08-15

    Endogenous neuropeptides known as orexins (hypocretins) play important roles in the regulation of feeding, drinking, endocrine function, and sleep/wakefulness. Orexin neuron projection sites include the rostral ventrolateral medulla of brainstem, which is related to the control of breathing. Previous studies suggest that orexins modulate the central CO2 ventilatory response during wakefulness in rodent. In the present study, we examined the effects of the orexinergic system on central respiratory control by adding orexin into a superfusion medium in the isolated brainstem-spinal cord of neonatal rat. Exposure to orexin B resulted in dose-dependent increases in C4 burst rate via brainstem, but not spinal cord. These increases in C4 burst rate induced concomitant increases in the depolarizing cycle rate of pre-inspiratory (Pre-I) and inspiratory (Insp) neurons. Tonic discharge was induced on C4 recording, although the rhythmic bursts of Pre-I and Insp neurons were maintained. Expiratory (Exp) neurons were also depolarized on administration of orexin B. Our findings indicate that orexin B activates central respiratory activity, mainly through depolarization and decreases in membrane resistance in Pre-I and Insp neurons, and possibly through early initiation of the expiratory phase induced by depolarization of Exp neurons.

  18. Lactational Vitamin E Protects Against the Histotoxic Effects of Systemically Administered Vanadium in Neonatal Rats.

    PubMed

    Olaolorun, F A; Obasa, A A; Balogun, H A; Aina, O O; Olopade, J O

    2014-12-29

    The work investigated the protective role of lactational vitamin E administration on vanadium-induced histotoxicity. Three groups of Wistar rats, with each group comprising of two dams and their pups, were used in this study. Group I pups were administered intraperitoneal injection of sterile water at volumes corresponding to the dose rate of the vanadium (sodium metavanadate) treated group from postnatal day (PND) 1-14 while those in Group II were administered intraperitoneal injection of 3mg/kg vanadium from PND 1-14. Group III pups were administered intraperitoneal injection of 3mg/kg vanadium while the dam received oral vitamin E (500 mg) concurrently every 72 hours. The results showed that group II pups exhibited histopathological changes which included seminiferous tubule disruption of the testes characterised by vacuolar degeneration and coagulative necrosis of spermatogonia and Sertoli cells with reduction in mitosis, and areas of interstitial thickening with fibroblast proliferation. In addition, the lungs showed disruption of the bronchiolar wall and denudation of the bronchiolar respiratory epithelium while the liver showed hydropic degeneration and coagulative necrosis of the centrilobular hepatocytes. These histotoxic changes were ameliorated in the vanadium + vitamin E group. We conclude that lactational vitamin E protects against the histotoxic effects of vanadium and could be a consideration for supplementation in the occupationally and environmentally exposed neonates. However, caution should be taken in vitamin E supplementation because there is still equivocal evidence surrounding its benefits as a supplement at the moment.

  19. Anthraquinones and flavonoids of Cassia tora leaves ameliorate sodium selenite induced cataractogenesis in neonatal rats.

    PubMed

    Sreelakshmi, V; Abraham, Annie

    2016-02-01

    The present study was undertaken to evaluate the efficacy of Cassia tora leaves, an edible plant traditionally used for eye ailments, in preventing experimental cataractogenesis. Cataract is the leading cause of irreversible visual impairment worldwide characterized by the cloudiness or opacification of the lens due to the disturbance of even distribution of lens proteins and lipids. A significant number of epidemiological studies have suggested the potential role of herbal medicine in the prevention of cataract by maintaining lens architecture. The study was conducted in neonatal rat pups of 8-10 days old with an ethyl acetate fraction of Cassia tora leaves (ECT) administered by gastric intubation. After 30 days, the animals were sacrificed and various parameters such as redox status and gene expressions were evaluated in lenses. ECT administration caused a significant decrease in the onset and maturation of cataract, potentiated antioxidant defense and normalized lens crystallin expression against cataract induced animals. HPLC and ESI-MS analysis of ECT revealed the presence of flavonoids and anthraquinones. Thus, the present study indicates the therapeutic potential of Cassia tora leaves in preventing cataract and the effect is endorsed by the presence of antioxidants in Cassia tora leaves. PMID:26786764

  20. Neonicotinoid Insecticides Alter the Gene Expression Profile of Neuron-Enriched Cultures from Neonatal Rat Cerebellum

    PubMed Central

    Kimura-Kuroda, Junko; Nishito, Yasumasa; Yanagisawa, Hiroko; Kuroda, Yoichiro; Komuta, Yukari; Kawano, Hitoshi; Hayashi, Masaharu

    2016-01-01

    Neonicotinoids are considered safe because of their low affinities to mammalian nicotinic acetylcholine receptors (nAChRs) relative to insect nAChRs. However, because of importance of nAChRs in mammalian brain development, there remains a need to establish the safety of chronic neonicotinoid exposures with regards to children’s health. Here we examined the effects of long-term (14 days) and low dose (1 μM) exposure of neuron-enriched cultures from neonatal rat cerebellum to nicotine and two neonicotinoids: acetamiprid and imidacloprid. Immunocytochemistry revealed no differences in the number or morphology of immature neurons or glial cells in any group versus untreated control cultures. However, a slight disturbance in Purkinje cell dendritic arborization was observed in the exposed cultures. Next we performed transcriptome analysis on total RNAs using microarrays, and identified significant differential expression (p < 0.05, q < 0.05, ≥1.5 fold) between control cultures versus nicotine-, acetamiprid-, or imidacloprid-exposed cultures in 34, 48, and 67 genes, respectively. Common to all exposed groups were nine genes essential for neurodevelopment, suggesting that chronic neonicotinoid exposure alters the transcriptome of the developing mammalian brain in a similar way to nicotine exposure. Our results highlight the need for further careful investigations into the effects of neonicotinoids in the developing mammalian brain. PMID:27782041

  1. The length-dependent activation of contraction is equally impaired in impuberal male and female rats in monocrotaline-induced right ventricular failure.

    PubMed

    Lookin, Oleg; Balakin, Alexander; Kuznetsov, Daniil; Protsenko, Yuri

    2015-11-01

    The length-dependent activation of contraction is attenuated in the failing myocardium of adult male rats. This pathological change is not seen in adult female rats, possibly because of a protective effect of sex hormones. The present study evaluated length-dependent changes in isometric twitch, Ca(2+) transient (CaT) and action potential (AP) in the right ventricular myocardium of impuberal healthy male and female rats (control) and in rats treated with a single injection of 50 mg/kg monocrotaline (MCT). Compared with sex-matched control rats, MCT-treated male and female rats exhibited increased right ventricular weight (134% and 142% of control, respectively), decreased left ventricular weight (72% and 79%), twitch attenuation (48.8 ± 2.7% and 57.5 ± 1.2%) and prolongation (125 ± 3% and 127 ± 2%), CaT attenuation (37.8 ± 0.4% and 39.1 ± 1.1%) and prolongation (114 ± 1% and 116 ± 1%) and AP prolongation at 90% repolarization (195 ± 2% and 203 ± 1%). The MCT-treated male rats exhibited a 50% lower integral magnitude and an approximately 25% larger time-to-peak 'bump' compared with control male rats. These parameters in MCT-treated female rats tended to show similar changes to those seen in the control female rats, with no significant difference between the two groups. In all groups, integral magnitude and time-to-peak 'bump' increased with length. In conclusion, the length-dependent activation of contraction was equally blunted in the failing right ventricular myocardium of impuberal male and female rats. This was related to changes in CaT and AP, which were similar between male and female rats. Therefore, puberty is necessary for manifestation of the protective effects of sex hormones on this remodelling.

  2. Suppressive effect of neonatal treatment with a phytoestrogen, coumestrol, on lordosis and estrous cycle in female rats.

    PubMed

    Kouki, Tom; Okamoto, Miho; Wada, Shizuko; Kishitake, Miki; Yamanouchi, Korehito

    2005-01-15

    The neural control systems for the ovulatory cycle and lordosis behavior are sexually differentiated by estrogen during the perinatal period in rats. In the present study, the effects of a single neonatal injection with the phytoestrogen, coumestrol, on female reproductive functions were investigated. Female rats were injected subcutaneously with 1 or 3mg coumestrol (CM1, CM3), 1mg genistein (GS1), 1mg estradiol (E2), or oil at day 5 after birth (birth day=day 1) and an estrous cycle check and lordosis behavior test were performed. As a result, vaginal opening was advanced in CM1-, CM3- or E2-treated females. A vaginal smear check indicated that oil- or GS1-treated females showed a constant 4- or 5-day estrous cycle, whereas CM1-, CM3- or E2-treated rats showed a persistent or prolonged estrus. Ovariectomy was performed in all females at 60 days of age. The ovary weights in the CM1-, CM3- or E2-treated groups were lower than those in the oil- and GS1-treated groups and no corpora lutea were found in any rats of these three groups, except for two E2-treated rats. Behavioral tests were carried out after implantation of E2-tubes. All rats in the CM1-, GS1-treated groups showed a high lordosis quotient (LQ), being comparable to that in the oil-treated females. On the other hand, LQs in the CM3, E2 or male groups were lower than that in the control female group. These results suggest that a single neonatal injection of 3 mg coumestrol was effective in suppressing the functions of ovulation-inducing mechanisms and the induction of lordosis, but 1mg coumestrol was effective in only the estrous cycle of female rats.

  3. Functional diversity of electrogenic Na+–HCO3− cotransport in ventricular myocytes from rat, rabbit and guinea pig

    PubMed Central

    Yamamoto, Taku; Swietach, Pawel; Rossini, Alessandra; Loh, Shih-Hurng; Vaughan-Jones, Richard D; Spitzer, Kenneth W

    2005-01-01

    The Na+–HCO3− cotransporter (NBC) is an important sarcolemmal acid extruder in cardiac muscle. The characteristics of NBC expressed functionally in heart are controversial, with reports suggesting electroneutral (NBCn; 1HCO3− : 1Na+; coupling coefficient n = 1) or electrogenic forms of the transporter (NBCe; equivalent to 2HCO3− : 1Na+; n = 2). We have used voltage-clamp and epifluorescence techniques to compare NBC activity in isolated ventricular myocytes from rabbit, rat and guinea pig. Depolarization (by voltage clamp or hyperkalaemia) reversibly increased steady-state pHi while hyperpolarization decreased it, effects seen only in CO2/HCO3−-buffered solutions, and blocked by S0859 (cardiac NBC inhibitor). Species differences in amplitude of these pHi changes were rat > guinea pig ≈ rabbit. Tonic depolarization (−140 mV to −0 mV) accelerated NBC-mediated pHi recovery from an intracellular acid load. At 0 mV, NBC-mediated outward current at resting pHi was +0.52 ± 0.05 pA pF−1 (rat, n = 5), +0.26 ± 0.05 pA pF−1 (guinea pig, n = 5) and +0.10 ± 0.03 pA pF−1 (rabbit, n = 9), with reversal potentials near −100 mV, consistent with n = 2. The above results indicate a functionally active voltage-sensitive NBCe in these species. Voltage-clamp hyperpolarization negative to the reversal potential for NBCe failed, however, to terminate or reverse NBC-mediated pHi-recovery from an acid load although it was slowed significantly, suggesting electroneutral NBC may also be operational. NBC-mediated pHi recovery was associated with a rise of [Na+]i at a rate ∼25% of that mediated via NHE, and consistent with an apparent NBC stoichiometry between n = 1 and n = 2. In conclusion, NBCe in the ventricular myocyte displays considerable functional variation among the three species tested (greatest in rat, least in rabbit) and may coexist with some NBCn activity. PMID:15550467

  4. Mechanical effects of liriodenine on the left ventricular-arterial coupling in Wistar rats: pressure-stroke volume analysis.

    PubMed

    Chang, K C; Su, M J; Peng, Y I; Shao, C C; Wu, Y C; Tseng, Y Z

    2001-05-01

    1. In a recent in vivo study, liriodenine, an aporphine alkaloid, has been identified as a prominent anti-arrhythmic agent that can prevent rats' sudden deaths, even at the dose as low as 10(-7) g kg(-1). The aim of this study was to determine whether liriodenine at its effective anti-arrhythmic dose of 10(-7) g kg(-1) had effects on the left ventricular (LV)-arterial coupling in Wistar rats. 2. LV pressure and ascending aortic flow signals were recorded to construct the ventricular and arterial end-systolic pressure-stroke volume relationships to calculate LV end-systolic elastance (E(es)) and effective arterial volume elastance (E(a)), respectively. The optimal afterload (Q(load)) determined by the ratio of E(a) to E(es) was used to measure the optimality of energy transmission from the left ventricle to the arterial system. 3. Liriodenine at the dose of 10(-7) g kg(-1) showed no significant changes in basal heart rate (HR), cardiac output (CO), LV end-systolic pressure (P(es)), E(a), E(es), and Q(load). 4. By contrast, liriodenine at the dose of 10(-6) g kg(-1) produced a significant fall of 2.0% in HR and a significant rise of 5.8% in CO, but no significant change in P(es). Moreover, liriodenine administration of 10(-6) g kg(-1) to rats significantly decreased E(es) by 8.5% and E(a) by 10.6%, but did not change Q(load). 5. We conclude that liriodenine at the dose of 10(-7) g kg(-1) has no effects on the mechanical properties of the heart and the vasculature and the matching condition for the left ventricle coupled to its vasculature in rats. Even at 10 times the effective anti-arrhythmic dose, liriodenine shows no effects on the efficiency of energy transferred from the left ventricle to the arterial system. PMID:11325791

  5. The Effect of Iron Deficiency on Osmotic Sensitivity of Red Blood Cells from Neonatal Rats and Their Mothers.

    PubMed

    Al-Hashimi, L Mossa; Gambling, Lorraine; McArdle, H J

    2015-12-01

    Iron deficiency during pregnancy has many effects on both the mother and her developing foetus. These can be both short and long term. One effect is an alteration in fatty acid metabolism and we hypothesised that these changes may result in alterations in membrane function and structure. In order to test this hypothesis, we measured osmotic sensitivity in red blood cells isolated from neonates and their mothers at different times following birth. We fed female rats control or iron-deficient diets for 4 weeks prior to mating and kept them on the same diet until term. At that time, we returned one group of deficient dams to the control diet. The others were kept on the same diet. We showed that iron deficiency results in a decrease in osmotic sensitivity in the mothers but not in their neonates. Returning the dams to the control diet resulted in a return of their red cell osmotic sensitivity to control levels. In the neonates, there was no recovery in haematocrit or in any other parameter, though they did not get any worse, in contrast to the pups being suckled by deficient mothers. The data show two things. The first is that following birth, the mother restores her own iron stores at the expense of the pups, and secondly, there are differences in properties and sensitivities between red cells from mothers and their neonates. This latter observation cannot be explained by differences in the membrane fatty acid profiles, which were not significantly different.

  6. Increased rat cardiac angiotensin converting enzyme activity and mRNA expression in pressure overload left ventricular hypertrophy. Effects on coronary resistance, contractility, and relaxation.

    PubMed Central

    Schunkert, H; Dzau, V J; Tang, S S; Hirsch, A T; Apstein, C S; Lorell, B H

    1990-01-01

    We compared the activity and physiologic effects of cardiac angiotensin converting enzyme (ACE) using isovolumic hearts from male Wistar rats with left ventricular hypertrophy due to chronic experimental aortic stenosis and from control rats. In response to the infusion of 3.5 X 10(-8) M angiotensin I in the isolated buffer perfused beating hearts, the intracardiac fractional conversion to angiotensin II was higher in the hypertrophied hearts compared with the controls (17.3 +/- 4.1% vs 6.8 +/- 1.3%, P less than 0.01). ACE activity was also significantly increased in the free wall, septum, and apex of the hypertrophied left ventricle, whereas ACE activity from the nonhypertrophied right ventricle of the aortic stenosis rats was not different from that of the control rats. Northern blot analyses of poly(A)+ purified RNA demonstrated the expression of ACE mRNA, which was increased fourfold in left ventricular tissue obtained from the hearts with left ventricular hypertrophy compared with the controls. In both groups, the intracardiac conversion of angiotensin I to angiotensin II caused a comparable dose-dependent increase in coronary resistance. In the control hearts, angiotensin II activation had no significant effect on systolic or diastolic function; however, it was associated with a dose-dependent depression of left ventricular diastolic relaxation in the hypertrophied hearts. These novel observations suggest that cardiac ACE is induced in hearts with left ventricular hypertrophy, and that the resultant intracardiac activation of angiotensin II may have differential effects on myocardial relaxation in hypertrophied hearts relative to controls. Images PMID:2174912

  7. Arginase inhibition prevents bleomycin-induced pulmonary hypertension, vascular remodeling, and collagen deposition in neonatal rat lungs.

    PubMed

    Grasemann, Hartmut; Dhaliwal, Rupinder; Ivanovska, Julijana; Kantores, Crystal; McNamara, Patrick J; Scott, Jeremy A; Belik, Jaques; Jankov, Robert P

    2015-03-15

    Arginase is an enzyme that limits substrate L-arginine bioavailability for the production of nitric oxide by the nitric oxide synthases and produces L-ornithine, which is a precursor for collagen formation and tissue remodeling. We studied the pulmonary vascular effects of arginase inhibition in an established model of repeated systemic bleomycin sulfate administration in neonatal rats that results in pulmonary hypertension and lung injury mimicking the characteristics typical of bronchopulmonary dysplasia. We report that arginase expression is increased in the lungs of bleomycin-exposed neonatal rats and that treatment with the arginase inhibitor amino-2-borono-6-hexanoic acid prevented the bleomycin-induced development of pulmonary hypertension and deposition of collagen. Arginase inhibition resulted in increased L-arginine and L-arginine bioavailability and increased pulmonary nitric oxide production. Arginase inhibition also normalized the expression of inducible nitric oxide synthase, and reduced bleomycin-induced nitrative stress while having no effect on bleomycin-induced inflammation. Our data suggest that arginase is a promising target for therapeutic interventions in neonates aimed at preventing lung vascular remodeling and pulmonary hypertension.

  8. Gypenosides Protected the Neural Stem Cells in the Subventricular Zone of Neonatal Rats that Were Prenatally Exposed to Ethanol

    PubMed Central

    Dong, Lun; Yang, Kun-Qi; Fu, Wen-Yan; Shang, Zhen-Hua; Zhang, Qing-Yu; Jing, Fang-Miao; Li, Lin-Lin; Xin, Hua; Wang, Xiao-Jing

    2014-01-01

    Fetal alcohol spectrum disorder (FASD) can cause severe mental retardation in children who are prenatally exposed to ethanol. The effects of prenatal and early postnatal ethanol exposure on adult hippocampal neurogenesis have been investigated; however, the effects of prenatal ethanol exposure on the subventricular zone (SVZ) have not. Gypenosides (GPs) have been reported to have neuroprotective effects in addition to other bioactivities. The effects of GPs on neural stem cells (NSCs) in the FASD model are unknown. Here, we test the effect of prenatal ethanol exposure on the neonatal SVZ, and the protection potential of GPs on NSCs in FASD rats. Our results show that prenatal ethanol exposure can suppress the cell proliferation and differentiation of neural stem cells in the neonatal SVZ and that GPs (400 mg/kg/day) can significantly increase the cell proliferation and differentiation of neural stem cells inhibited by ethanol. Our data indicate that GPs have neuroprotective effects on the NSCs and can enhance the neurogenesis inhibited by ethanol within the SVZ of neonatal rats. These findings provide new evidence for a potential therapy involving GPs for the treatment of FASD. PMID:25464383

  9. Hormone replacement with 17β-estradiol plus dihydrotestosterone restores male sexual behavior in rats treated neonatally with clomipramine.

    PubMed

    Limón-Morales, Ofelia; Soria-Fregozo, Cesar; Arteaga-Silva, Marcela; González, Marisela Hernández; Vázquez-Palacios, Gonzalo; Bonilla-Jaime, Herlinda

    2014-11-01

    Male sexual behavior (MSB) in rodents, in both its consummatory and motivational components, is regulated by hormones such as testosterone, 17β-estradiol and 5-α-dihydrotestosterone. In experiments, neonatal treatment with clomipramine (CMI; a serotonin reuptake inhibitor) reproduces some of the signs of depression in adult age, including reduced sexual behavior manifested in a lower percentage of subjects that mount, intromit and ejaculate, although their testosterone levels were not altered. However, the effect of this treatment on estrogen levels and the consequences of hormone substitution using 17β-estradiol and 5-α-dihydrotestosterone on the expression of male sexual behavior are still unknown. Therefore, the objective of the present study was to analyze the effect of neonatal treatment with CMI on plasma testosterone and 17β-estradiol levels, and the role of testosterone, 17β-estradiol and 5-α-dihydrotestosterone in altering the consummatory and motivational components of sexual behavior in male rats. To this end, it analyzed the copulatory parameters and sexual incentive motivation (SIM) of rats treated with CMI under two conditions: basal and post-hormone replacements. Neonatal treatment with CMI did not affect plasma testosterone or 17β-estradiol concentrations, but did decrease both the consummatory component and sexual motivation according to the results of the SIM test. These aspects were recovered after administering 17β-estradiol +5-α-dihydrotestosterone, but not testosterone.

  10. Right ventricular assistance for experimental right ventricular dysfunction.

    PubMed

    Jett, G K; Applebaum, R E; Clark, R E

    1986-08-01

    Right ventricular dysfunction frequently occurs in patients undergoing correction of congenital cardiac defects, as well as in other clinical settings. The purpose of the present study was to surgically induce right ventricular dysfunction and then provide circulatory support with a right ventricular assist device. Right ventricular hypertrophy was created in 13 neonatal lambs by pulmonary artery banding. Right ventricular dysfunction was produced in all animals by performing a right ventriculotomy with the animal supported by cardiopulmonary bypass. In four unassisted animals the circulation failed after separation from bypass. Seven experimental animals underwent the insertion of a pneumatically activated ventricular assist device between the proximal pulmonary artery and the right ventricular apex. Periods with the right ventricular assist device on and off in each animal were compared. The right ventricular assist device increased cardiac output from 0.72 +/- 0.15 to 2.24 +/- 0.23 L/min (p less than 0.0002), increased left atrial pressure from 7 +/- 1 to 11 +/- 1 mm Hg (p less than 0.0005), and increased aortic systolic pressure from 53 +/- 9 to 85 +/- 9 mm Hg (p less than 0.0001). Right ventricular assistance significantly reduced the right ventricular end-diastolic pressure from 19 +/- 3 to 12 +/- 1 mm Hg (p less than 0.0001). Pulmonary artery peak pressure distal to the band increased from 27 +/- 3 to 52 +/- 5 mm Hg (p less than 0.0001). The results indicate that right ventricular dysfunction can be produced by a vertical cardiotomy in a hypertrophied right ventricle with persistent outflow tract obstruction. Right ventricular dysfunction can be effectively reversed by a right ventricular assist device, which may prove clinically useful in managing patients with refractory right ventricular failure.

  11. Aspirate from human stented saphenous vein grafts induces epicardial coronary vasoconstriction and impairs perfusion and left ventricular function in rat bioassay hearts with pharmacologically induced endothelial dysfunction.

    PubMed

    Lieder, Helmut R; Baars, Theodor; Kahlert, Philipp; Kleinbongard, Petra

    2016-08-01

    Stent implantation into aortocoronary saphenous vein grafts (SVG) releases particulate debris and soluble vasoactive mediators, for example, serotonin. We now analyzed effects of the soluble mediators released into the coronary arterial blood during stent implantation on vasomotion of isolated rat epicardial coronary artery segments and on coronary flow and left ventricular developed pressure in isolated perfused rat hearts. Coronary blood was retrieved during percutaneous SVG intervention using a distal occlusion/aspiration protection device in nine symptomatic patients with stable angina pectoris and a flow-limiting SVG stenosis. The blood was separated into particulate debris and plasma. Responses to coronary plasma were determined in isolated rat epicardial coronary arteries and in isolated, constant pressure-perfused rat hearts (±nitric oxide synthase [NOS] inhibition and ±serotonin receptor blockade, respectively). Coronary aspirate plasma taken after stent implantation induced a stronger vasoconstriction of rat epicardial coronary arteries (52 ± 8% of maximal potassium chloride induced vasoconstriction [% KClmax = 100%]) than plasma taken before stent implantation (12 ± 8% of KClmax); NOS inhibition augmented this vasoconstrictor response (to 110 ± 15% and 24 ± 9% of KClmax). Coronary aspirate plasma taken after stent implantation reduced in isolated perfused rat hearts only under NOS inhibition coronary flow by 17 ± 3% and left ventricular developed pressure by 25 ± 4%. Blockade of serotonin receptors abrogated these effects. Coronary aspirate plasma taken after stent implantation induces vasoconstriction in isolated rat epicardial coronary arteries and reduces coronary flow and left ventricular developed pressure in isolated perfused rat hearts with pharmacologically induced endothelial dysfunction. PMID:27482071

  12. Brief neonatal maternal separation alters extinction of conditioned fear and corticolimbic glucocorticoid and NMDA receptor expression in adult rats.

    PubMed

    Wilber, Aaron A; Southwood, Christopher J; Wellman, Cara L

    Neonatal maternal separation alters adult HPA axis responsiveness to stress, adult emotionality, and glucocorticoid receptor (GR) concentrations in forebrain regions such as hippocampus. To investigate effects of neonatal maternal separation on emotion regulation and its neural substrates, we assessed acquisition and extinction of conditioned fear in adult rats that underwent neonatal maternal separation. Corticolimbic structures including basolateral amygdala and medial prefrontal cortex are critical for acquisition and extinction of conditioned fear, and such learning is N-methyl-D-aspartic acid (NMDA) receptor-dependent. Thus, we used immunohistochemistry to assess expression of the GR and the NR1 subunit of the NMDA receptor in basolateral amygdala and medial prefrontal cortex. On postnatal days 2-14, pups underwent control rearing or maternal separation for 15 min per day. Fear conditioning and extinction in adulthood were then assessed in male rats. Rats received five tone-alone habituation trials, then seven tone/footshock pairings. After 1 h, rats received tone-alone extinction trials to criterion, and 15 recall of extinction trials the next day. Brains were processed for immunohistochemical labeling of GR and NR1, and staining was quantified. Brief maternal separation did not alter acquisition or initial extinction, but impaired extinction recall. Brief maternal separation did not alter GR or NR1 expression in basolateral amygdala. However, brief maternal separation increased GR and decreased NR1 expression specifically in the infralimbic region of medial prefrontal cortex, consistent with work implicating this area in extinction recall. Thus, brief maternal separation impaired extinction recall and altered GR and NR1 expression in its neural substrate in adults.

  13. Hypermethylation of Hippocampal Synaptic Plasticity-Related genes is Involved in Neonatal Sevoflurane Exposure-Induced Cognitive Impairments in Rats.

    PubMed

    Ju, Ling-sha; Jia, Min; Sun, Jie; Sun, Xiao-ru; Zhang, Hui; Ji, Mu-huo; Yang, Jian-jun; Wang, Zhong-yun

    2016-02-01

    General anesthetics given to immature rodents cause delayed neurobehavioral abnormalities via incompletely understood mechanisms. DNA methylation, one of the epigenetic modifications, is essential for the modulation of hippocampal synaptic plasticity through regulating the related genes. Therefore, we investigated whether abnormalities in the hippocampal DNA methylation of synaptic plasticity-related genes are involved in neonatal sevoflurane exposure-induced cognitive impairments in rats. Male Sprague-Dawley rats were exposed to 3 % sevoflurane or 30 % oxygen/air for 2 h daily from postnatal day 7 (P7) to P9 and were treated with DNA methyltransferases (DNMTs) inhibitor 5-aza-2-deoxycytidine (5-AZA) or vehicle 1 h before the first sevoflurane exposure on P7. The rats were euthanized 1, 6, 24 h, and 30 days after the last sevoflurane exposure, and the brain tissues were harvested for biochemical analysis. Cognitive functions were evaluated by the open field, fear conditioning, and Morris water maze (MWM) tests on P39, P41-43, and P50-57, respectively. In the present study, repeated neonatal sevoflurane exposure resulted in hippocampus-dependent cognitive impairments as assessed by fear conditioning and MWM tests. The cognitive impairments were associated with the increased DNMTs and hypermethylation of brain-derived neurotrophic factor (BDNF) and Reelin genes, and subsequent down-regulation of BDNF and Reelin genes, which finally led to the decrease of dendritic spines in the hippocampal pyramidal neurons in adolescent rats. Notably, pretreatment with 5-AZA reversed these sevoflurane-induced abnormalities. In conclusion, our results suggest that hypermethylation of hippocampal BDNF and Reelin is involved in neonatal sevoflurane exposure-induced cognitive impairments.

  14. Effects of aged garlic extract on left ventricular diastolic function and fibrosis in a rat hypertension model.

    PubMed

    Hara, Yuki; Noda, Akiko; Miyata, Seiko; Minoshima, Makoto; Sugiura, Mari; Kojima, Jun; Otake, Masafumi; Furukawa, Mayuko; Cheng, Xian Wu; Nagata, Kohzo; Murohara, Toyoaki

    2013-01-01

    Daily consumption of garlic is known to lower the risk of hypertension and ischemic heart disease. In this study, we examined whether aged garlic extract (AGE) prevents hypertension and the progression of compensated left ventricular (LV) hypertrophy in Dahl salt-sensitive (DS) rats. DS rats were randomly divided into three groups: those fed an 8% NaCl diet until 18 weeks of age (8% NaCl group), those additionally treated with AGE (8% NaCl + AGE group), and control rats maintained on a diet containing 0.3% NaCl until 18 weeks of age (0.3% NaCl group). AGE was administered orally by gastric gavage once a day until 18 weeks of age. LV mass was significantly higher in the 8% NaCl + AGE group than in the 0.3% NaCl group at 18 weeks of age, but significantly lower in the 8% NaCl + AGE group than in the 8% NaCl group. No significant differences were observed in systolic blood pressure (SBP) between the 8% NaCl and 8% NaCl + AGE groups at 12 and 18 weeks of age. LV end-diastolic pressure and pressure half-time at 12 and 18 weeks of age were significantly lower in the 8% NaCl + AGE group compared with the 8% NaCl group. AGE significantly reduced LV interstitial fibrosis at 12 and 18 weeks of age. Chronic AGE intake attenuated LV diastolic dysfunction and fibrosis without significantly decreasing SBP in hypertensive DS rats.

  15. Reduced subcommissural organ glycoprotein immunoreactivity precedes aqueduct closure and ventricular dilatation in H-Tx rat hydrocephalus.

    PubMed

    Somera, K C; Jones, H C

    2004-03-01

    The H-Tx rat has fetal-onset hydrocephalus associated with closure of the cerebral aqueduct and a reduction in the secretory cells of the subcommissural organ (SCO), a circumventricular organ situated in the dorsal wall of the cerebral aqueduct. The objective of this study was to determine the role of the SCO in hydrocephalus pathogenesis. Serial brain sections through aqueduct regions containing the SCO from H-Tx rats, together with non-hydrocephalic Fischer F344 rats, were studied at E16, before hydrocephalus onset, at E17, the beginning of onset, and at P0 when the hydrocephalus was overt. Tissues were immunostained by AFRU, an antibody against the SCO glycoprotein, and for the intermediate filament nestin. The area of SCO cells with AFRU immunostaining and the severity of lateral ventricle dilatation were quantified by image analysis. At E16 all fetuses had distinct SCO ependymal cells, open aqueducts and normal lateral ventricles. The H-Tx fetuses fell into two groups with large areas and small areas of AFRU immunoreactivity, all with a full complement of SCO cells. By E17, fetuses with small areas of immunoreactivity had reduced numbers of tall SCO secretory cells, and most had aqueducts closed posteriorly and dilated ventricles. Three additional fetuses with small areas of immunoreactivity had narrow but patent aqueducts and normal ventricles, and another had an open aqueduct and dilated ventricles. At P0, pups previously identified as hydrocephalic had small areas of AFRU immunoreactivity, an aqueduct that was closed anteriorly but open posteriorly, ventricular dilatation, and an absence of SCO secretory cells. The aqueduct even when closed was lined by typical ependymal cells throughout. Decreased nestin immunostaining accompanied the SCO changes. It is concluded that reduced SCO glycoprotein immunoreactivity precedes both aqueduct closure and expansion of the lateral ventricles in the H-Tx rat.

  16. Estradiol improves right ventricular function in rats with severe angioproliferative pulmonary hypertension: effects of endogenous and exogenous sex hormones

    PubMed Central

    Frump, Andrea L.; Goss, Kara N.; Vayl, Alexandra; Albrecht, Marjorie; Fisher, Amanda; Tursunova, Roziya; Fierst, John; Whitson, Jordan; Cucci, Anthony R.; Brown, M. Beth

    2015-01-01

    Estrogens are disease modifiers in PAH. Even though female patients exhibit better right ventricular (RV) function than men, estrogen effects on RV function (a major determinant of survival in PAH) are incompletely characterized. We sought to determine whether sex differences exist in RV function in the SuHx model of PAH, whether hormone depletion in females worsens RV function, and whether E2 repletion improves RV adaptation. Furthermore, we studied the contribution of ERs in mediating E2’s RV effects. SuHx-induced pulmonary hypertension (SuHx-PH) was induced in male and female Sprague-Dawley rats as well as OVX females with or without concomitant E2 repletion (75 μg·kg−1·day−1). Female SuHx rats exhibited superior CI than SuHx males. OVX worsened SuHx-induced decreases in CI and SuHx-induced increases in RVH and inflammation (MCP-1 and IL-6). E2 repletion in OVX rats attenuated SuHx-induced increases in RV systolic pressure (RVSP), RVH, and pulmonary artery remodeling and improved CI and exercise capacity (V̇o2max). Furthermore, E2 repletion ameliorated SuHx-induced alterations in RV glutathione activation, proapoptotic signaling, cytoplasmic glycolysis, and proinflammatory cytokine expression. Expression of ERα in RV was decreased in SuHx-OVX but was restored upon E2 repletion. RV ERα expression was inversely correlated with RVSP and RVH and positively correlated with CO and apelin RNA levels. RV-protective E2 effects observed in females were recapitulated in male SuHx rats treated with E2 or with pharmacological ERα or ERβ agonists. Our data suggest significant RV-protective ER-mediated effects of E2 in a model of severe PH. PMID:25713318

  17. Effects of aged garlic extract on left ventricular diastolic function and fibrosis in a rat hypertension model.

    PubMed

    Hara, Yuki; Noda, Akiko; Miyata, Seiko; Minoshima, Makoto; Sugiura, Mari; Kojima, Jun; Otake, Masafumi; Furukawa, Mayuko; Cheng, Xian Wu; Nagata, Kohzo; Murohara, Toyoaki

    2013-01-01

    Daily consumption of garlic is known to lower the risk of hypertension and ischemic heart disease. In this study, we examined whether aged garlic extract (AGE) prevents hypertension and the progression of compensated left ventricular (LV) hypertrophy in Dahl salt-sensitive (DS) rats. DS rats were randomly divided into three groups: those fed an 8% NaCl diet until 18 weeks of age (8% NaCl group), those additionally treated with AGE (8% NaCl + AGE group), and control rats maintained on a diet containing 0.3% NaCl until 18 weeks of age (0.3% NaCl group). AGE was administered orally by gastric gavage once a day until 18 weeks of age. LV mass was significantly higher in the 8% NaCl + AGE group than in the 0.3% NaCl group at 18 weeks of age, but significantly lower in the 8% NaCl + AGE group than in the 8% NaCl group. No significant differences were observed in systolic blood pressure (SBP) between the 8% NaCl and 8% NaCl + AGE groups at 12 and 18 weeks of age. LV end-diastolic pressure and pressure half-time at 12 and 18 weeks of age were significantly lower in the 8% NaCl + AGE group compared with the 8% NaCl group. AGE significantly reduced LV interstitial fibrosis at 12 and 18 weeks of age. Chronic AGE intake attenuated LV diastolic dysfunction and fibrosis without significantly decreasing SBP in hypertensive DS rats. PMID:24172194

  18. The Preventive Effects of Neural Stem Cells and Mesenchymal Stem Cells Intra-ventricular Injection on Brain Stroke in Rats

    PubMed Central

    Hosseini, Seyed Mojtaba; Samimi, Nastaran; Farahmandnia, Mohammad; Shakibajahromi, Benafshe; Sarvestani, Fatemeh Sabet; Sani, Mahsa; Mohamadpour, Masoomeh

    2015-01-01

    Introduction: Stroke is one of the most important causes of disability in developed countries and, unfortunately, there is no effective treatment for this major problem of central nervous system (CNS); cell therapy may be helpful to recover this disease. In some conditions such as cardiac surgeries and neurosurgeries, there are some possibilities of happening brain stroke. Inflammation of CNS plays an important role in stroke pathogenesis, in addition, apoptosis and neural death could be the other reasons of poor neurological out come after stroke. In this study, we examined the preventive effects of the neural stem cells (NSCs) and mesenchymal stem cells (MSCs) intra-ventricular injected on stroke in rats. Aim: The aim of this study was to investigate the preventive effects of neural and MSCs for stroke in rats. Materials and Methods: The MSCs were isolated by flashing the femurs and tibias of the male rats with appropriate media. The NSCs were isolated from rat embryo ganglion eminence and they cultured NSCs media till the neurospheres formed. Both NSCs and MSCs were labeled with PKH26-GL. One day before stroke, the cells were injected into lateral ventricle stereotactically. Results: During following for 28 days, the neurological scores indicated that there are better recoveries in the groups received stem cells and they had less lesion volume in their brain measured by hematoxylin and eosin staining. Furthermore, the activities of caspase-3 were lower in the stem cell received groups than control group and the florescent microscopy images showed that the stem cells migrated to various zones of the brains. Conclusion: Both NSCs and MSCs are capable of protecting the CNS against ischemia and they may be good ways to prevent brain stroke consequences situations. PMID:26605202

  19. The Actions of Lyophilized Apple Peel on the Electrical Activity and Organization of the Ventricular Syncytium of the Hearts of Diabetic Rats

    PubMed Central

    Martínez-Ladrón de Guevara, Elideth; Pérez-Hernández, Nury; Villalobos-López, Miguel Ángel; Pérez-Ishiwara, David Guillermo; Salas-Benito, Juan Santiago; Martínez Martínez, Alejandro; Hernández-García, Vicente

    2016-01-01

    This study was designed to examine the effects of lyophilized red delicious apple peel (RDP) on the action potentials (APs) and the input resistance-threshold current relationship. The experiments were performed on isolated papillary heart muscles from healthy male rats, healthy male rats treated with RDP, diabetic male rats, and diabetic male rats treated with RDP. The preparation was superfused with oxygenated Tyrode's solution at 37°C. The stimulation and the recording of the APs, the input resistance, and the threshold current were made using conventional electrophysiological methods. The RDP presented no significant effect in normal rats. Equivalent doses in diabetic rats reduced the APD and ARP. The relationship between input resistance and threshold current established an inverse correlation. The results indicate the following: (1) The functional structure of the cardiac ventricular syncytium in healthy rats is heterogeneous, in terms of input resistance and threshold current. Diabetes further accentuates the heterogeneity. (2) As a consequence, conduction block occurs and increases the possibility of reentrant arrhythmias. (3) These modifications in the ventricular syncytium, coupled with the increase in the ARP, are the adequate substrate so that, with diabetes, the heart becomes more arrhythmogenic. (4) RDP decreases the APD, the ARP, and most syncytium irregularity caused by diabetes. PMID:26839897

  20. Anesthesia with sevoflurane in neonatal rats: developmental neuroendocrine abnormalities and alleviating effects of the corticosteroid and Cl− importer antagonists

    PubMed Central

    Xu, Changqing; Tan, Sijie; Zhang, Jiaqiang; Seubert, Christoph N.; Gravenstein, Nikolaus; Sumners, Colin; Vasilopoulos, Terrie; Martynyuk, Anatoly E.

    2015-01-01

    Background 1.5 million children under 12 months of age are exposed to general anesthesia annually in the United States alone. Human and especially animal studies provide evidence that exposure to general anesthesia during the early postnatal period may lead to long-term neurocognitive abnormalities via poorly understood mechanisms. We investigated whether an immature stress response system and γ-aminobutyric acid (GABA) type A receptor activities are involved in mediating these abnormalities. Methods Sprague-Dawley rats at postnatal days 4, 5 or 6 were anesthetized with 2.1% sevoflurane for 6 hrs; maternally separated and house reared rats served as controls. Results Sevoflurane anesthesia markedly increased corticosterone levels in rat pups of both genders. In adulthood, these rats responded to stress with heightened secretion of corticosterone and a greater increase in corticosterone levels in males versus females. Only male rats, previously exposed to neonatal sevoflurane, had a higher frequency of miniature inhibitory postsynaptic currents in CA1 neurons, spent a shorter time in open arms of the elevated plus maze (EPM) and exhibited impaired prepulse inhibition (PPI) of startle. Pretreatment of male rats prior to sevoflurane with the Na+-K+-2Cl− cotransporter inhibitor, bumetanide, or the mineralocorticoid receptor antagonist, RU28318, normalized endocrine responses to stress and the EPM behavior in adulthood, while only those pretreated with bumetanide exhibited normalized PPI of startle responses. Neither bumetanide nor RU28318 altered the effect of sevoflurane on synaptic activity. Conclusions Sevoflurane-enhanced neuronal excitation and elevated corticosteroid levels at the time of anesthesia contribute to the mechanisms initiating neonatal sevoflurane-induced long-term endocrine and neurobehavioral abnormalities. PMID:26150359

  1. Erythropoietin Ameliorates Neonatal Hypoxia-Ischemia-Induced Neurobehavioral Deficits, Neuroinflammation, and Hippocampal Injury in the Juvenile Rat

    PubMed Central

    Lan, Kuo-Mao; Tien, Lu-Tai; Cai, Zhengwei; Lin, Shuying; Pang, Yi; Tanaka, Sachiko; Rhodes, Philip G.; Bhatt, Abhay J.; Savich, Renate D.; Fan, Lir-Wan

    2016-01-01

    The hematopoietic growth factor erythropoietin (EPO) has been shown to be neuroprotective against hypoxia-ischemia (HI) in Postnatal Day 7 (P7)–P10 or adult animal models. The current study was aimed to determine whether EPO also provides long-lasting neuroprotection against HI in P5 rats, which is relevant to immature human infants. Sprague-Dawley rats at P5 were subjected to right common carotid artery ligation followed by an exposure to 6% oxygen with balanced nitrogen for 1.5 h. Human recombinant EPO (rEPO, at a dose of 5 units/g) was administered intraperitoneally one hour before or immediately after insult, followed by additional injections at 24 and 48 h post-insult. The control rats were injected with normal saline following HI. Neurobehavioral tests were performed on P8 and P20, and brain injury was examined on P21. HI insult significantly impaired neurobehavioral performance including sensorimotor, locomotor activity and cognitive ability on the P8 and P20 rats. HI insult also resulted in brain inflammation (as indicated by microglia activation) and neuronal death (as indicated by Jade B positive staining) in the white matter, striatum, cortex, and hippocampal areas of the P21 rat. Both pre- and post-treatment with rEPO significantly improved neurobehavioral performance and protected against the HI-induced neuronal death, microglia activation (OX42+) as well as loss of mature oligodendrocytes (APC-CC1+) and hippocampal neurons (Nissl+). The long-lasting protective effects of rEPO in the neonatal rat HI model suggest that to exert neurotrophic activity in the brain might be an effective approach for therapeutic treatment of neonatal brain injury induced by hypoxia-ischemia. PMID:26927081

  2. Erythropoietin Ameliorates Neonatal Hypoxia-Ischemia-Induced Neurobehavioral Deficits, Neuroinflammation, and Hippocampal Injury in the Juvenile Rat.

    PubMed

    Lan, Kuo-Mao; Tien, Lu-Tai; Cai, Zhengwei; Lin, Shuying; Pang, Yi; Tanaka, Sachiko; Rhodes, Philip G; Bhatt, Abhay J; Savich, Renate D; Fan, Lir-Wan

    2016-01-01

    The hematopoietic growth factor erythropoietin (EPO) has been shown to be neuroprotective against hypoxia-ischemia (HI) in Postnatal Day 7 (P7)-P10 or adult animal models. The current study was aimed to determine whether EPO also provides long-lasting neuroprotection against HI in P5 rats, which is relevant to immature human infants. Sprague-Dawley rats at P5 were subjected to right common carotid artery ligation followed by an exposure to 6% oxygen with balanced nitrogen for 1.5 h. Human recombinant EPO (rEPO, at a dose of 5 units/g) was administered intraperitoneally one hour before or immediately after insult, followed by additional injections at 24 and 48 h post-insult. The control rats were injected with normal saline following HI. Neurobehavioral tests were performed on P8 and P20, and brain injury was examined on P21. HI insult significantly impaired neurobehavioral performance including sensorimotor, locomotor activity and cognitive ability on the P8 and P20 rats. HI insult also resulted in brain inflammation (as indicated by microglia activation) and neuronal death (as indicated by Jade B positive staining) in the white matter, striatum, cortex, and hippocampal areas of the P21 rat. Both pre- and post-treatment with rEPO significantly improved neurobehavioral performance and protected against the HI-induced neuronal death, microglia activation (OX42+) as well as loss of mature oligodendrocytes (APC-CC1+) and hippocampal neurons (Nissl+). The long-lasting protective effects of rEPO in the neonatal rat HI model suggest that to exert neurotrophic activity in the brain might be an effective approach for therapeutic treatment of neonatal brain injury induced by hypoxia-ischemia. PMID:26927081

  3. Altered Left Ventricular Ion Channel Transcriptome in a High-Fat-Fed Rat Model of Obesity: Insight into Obesity-Induced Arrhythmogenesis

    PubMed Central

    Yon, Marianne; Pickavance, Lucy; Yanni Gerges, Joseph; Davis, Gershan; Wilding, John; Jian, Kun; Hart, George; Boyett, Mark

    2016-01-01

    Introduction. Obesity is increasingly common and is associated with an increased prevalence of cardiac arrhythmias. The aim of this study was to see whether in obesity there is proarrhythmic gene expression of ventricular ion channels and related molecules. Methods and Results. Rats were fed on a high-fat diet and compared to control rats on a normal diet (n = 8). After 8 weeks, rats on the high-fat diet showed significantly greater weight gain and higher adiposity. Left ventricle samples were removed at 8 weeks and mRNA expression of ion channels and other molecules was measured using qPCR. Obese rats had significant upregulation of Cav1.2, HCN4, Kir2.1, RYR2, NCX1, SERCA2a, and RYR2 mRNA and downregulation of ERG mRNA. In the case of HCN4, it was confirmed that there was a significant increase in protein expression. The potential effects of the mRNA changes on the ventricular action potential and intracellular Ca2+ transient were predicted using computer modelling. Modelling predicted prolongation of the ventricular action potential and an increase in the intracellular Ca2+ transient, both of which would be expected to be arrhythmogenic. Conclusion. High-fat diet causing obesity results in arrhythmogenic cardiac gene expression of ion channels and related molecules. PMID:27747100

  4. Inhibition of anandamide hydrolysis dampens the neuroendocrine response to stress in neonatal rats subjected to suboptimal rearing conditions.

    PubMed

    McLaughlin, Ryan Joseph; Verlezza, Silvanna; Gray, Jennifer Megan; Hill, Matthew Nicholas; Walker, Claire-Dominique

    2016-01-01

    Exposure to stress during early development can exert profound effects on the maturation of the neuroendocrine stress axis. The endocannabinoid (ECB) system has recently surfaced as a fundamental component of the neuroendocrine stress response; however, the effect of early-life stress on neonatal ECB signaling and the capacity to which ECB enhancement may modulate neonatal stress responses is relatively unknown. The present study assessed whether exposure to early-life stress in the form of limited access to nesting/bedding material (LB) from postnatal (PND) day 2 to 9 alters neuroendocrine activity and hypothalamic ECB content in neonatal rats challenged with a novel immobilization stressor. Furthermore, we examined whether inhibition of fatty acid amide hydrolase (FAAH), the enzyme responsible for the degradation of anandamide (AEA) affects neuroendocrine responses in PND10 pups as a function of rearing conditions. Neonatal rats showed a robust increase in corticosterone (CORT) and adrenocorticotropin hormone (ACTH) secretion in response to immobilization stress, which was significantly blunted in pups reared in LB conditions. Accordingly, LB pups exhibited reduced stress-induced Fos immunoreactivity in the paraventricular nucleus of the hypothalamus, with no significant differences in hypothalamic ECB content. Administration of the FAAH inhibitor URB597 (0.3 mg/kg, ip) 90 min prior to immobilization stress significantly dampened stress-induced CORT release, but only in pups reared in LB conditions. These results suggest that rearing in restricted bedding conditions dampens the neuroendocrine response to stress, while augmenting AEA mitigates stress-induced alterations in glucocorticoid secretion preferentially in pups subjected to early-life stress.

  5. (/sup 3/H)-8-cyclopentyl-1,3-dipropylxanthine binding to A1 adenosine receptors of intact rat ventricular myocytes

    SciTech Connect

    Martens, D.; Lohse, M.J.; Schwabe, U.

    1988-09-01

    The purpose of the present study was the identification of A1 adenosine receptors in intact rat ventricular myocytes, which are thought to mediate the negative inotropic effects of adenosine. The adenosine receptor antagonist (/sup 3/H)-8-cyclopentyl-1,3-dipropylxanthine was used as radioligand. Binding of the radioligand to intact myocytes was rapid, reversible, and saturable with a binding capacity of 40,000 binding sites per cell. The dissociation constant of the radioligand was 0.48 nM. The adenosine receptor antagonists 8-cyclopentyl-1,3-dipropylxanthine, xanthine amine congener, and theophylline were competitive inhibitors with affinities in agreement with results obtained for A1 receptors in other tissues. Competition experiments using the adenosine receptor agonists R-N(6)-phenylisopropyladenosine, 5'-N-ethylcarboxamidoadenosine, and S-N(6)-phenylisopropyladenosine gave monophasic displacement curves with Ki values of 50 nM, 440 nM, and 4,300 nM, which agreed well with the GTP-inducible low affinity state in cardiac membranes. The low affinity for agonists was not due to agonist-induced desensitization, and correlated well with the corresponding IC50 values for the inhibition of cyclic AMP accumulation by isoprenaline. It is suggested that only a low affinity state of A1 receptors can be detected in intact rat myocytes due to the presence of high concentrations of guanine nucleotides in intact cells.

  6. Effects of Dantrolene Treatment on Ventricular Electrophysiology and Arrhythmogenesis in Rats With Chronic β-Adrenergic Receptor Activation.

    PubMed

    Liu, Tao; Shi, Shao-bo; Qin, Mu; Huang, Cong-xin

    2015-07-01

    Dantrolene, which is primarily used to treat malignant hyperthermia, has recently been suggested for the prevention of arrhythmogenesis in various animal models. In this study, the effects of dantrolene treatment on electrophysiological properties and ventricular arrhythmias (VAs) in rats with chronic β-adrenergic receptor (β-AR) activation were investigated. Rats were randomized to treatment with saline (control group), isoproterenol (ISO; ISO group), or ISO + dantrolene (ID group) for 2 weeks. An electrophysiological study was performed to assess action potential duration restitution (APDR) and induce action potential duration (APD) alternans or VA in vitro. The protein levels of Cav1.2, sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a), and ryanodine receptor 2 (RyR2) were detected by Western blot. Compared with the control group, chronic administration of ISO significantly increased APD, the maximum slope (Smax) of APDR curve, and the spatial dispersions of Smax and APD (all P < .01), and all effects were attenuated by dantrolene treatment (all P < .05). Additionally, chronic ISO administration significantly reduced the protein levels of SERCA2 and RyR2, but increased the Cav1.2 protein expression (all P < .05). However, compared with the ISO group, dantrolene treatment preserved SERCA2a and RyR2 protein levels and decreased Cav1.2 protein levels in the ID group (all P < .05). The intracellular Ca(2+) ([Ca(2+)]i) levels measured by incubating isolated cardiomyocytes with Fluo-3/alveolar macrophages were significantly increased in the ISO group compared with the control group (P < .01). Dantrolene treatment markedly reduced the rise of [Ca(2+)]i levels caused by chronic administration of ISO (P < .05). Dantrolene treatment also prevented the reductions in the APD alternans and VA thresholds induced by chronic ISO stimulation (all P < .05). These data suggest that dantrolene stabilizes ventricular electrophysiological characteristics and increases the expression

  7. Neonatal Nicotine Exposure Increases Excitatory Synaptic Transmission and Attenuates Nicotine-stimulated GABA release in the Adult Rat Hippocampus

    PubMed Central

    Damborsky, Joanne C.; Griffith, William H.; Winzer-Serhan, Ursula H.

    2014-01-01

    Developmental exposure to nicotine has been linked to long-lasting changes in synaptic transmission which may contribute to behavioral abnormalities seen in offspring of women who smoke during pregnancy. Here, we examined the long-lasting effects of developmental nicotine exposure on glutamatergic and GABAergic neurotransmission, and on acute nicotine-induced glutamate and GABA release in the adult hippocampus, a structure important in cognitive and emotional behaviors. We utilized a chronic neonatal nicotine treatment model to administer nicotine (6 mg/kg/day) to rat pups from postnatal day (P) 1–7, a period that falls developmentally into the third human trimester. Using whole-cell voltage clamp recordings from CA1 pyramidal neurons in hippocampal slices, we measured excitatory and inhibitory postsynaptic currents in neonatally control- and nicotine-treated young adult males. Neonatal nicotine exposure significantly increased AMPA receptor-mediated spontaneous and evoked excitatory signaling, with no change in glutamate release probability in adults. Conversely, there was no increase in spontaneous GABAergic neurotransmission in nicotine-males. Chronic neonatal nicotine treatment had no effect on acute nicotine-stimulated glutamate release in adults, but acute nicotine-stimulated GABA release was significantly attenuated. Thus, neonatal nicotine exposure results in a persistent net increase in excitation and a concurrent loss of nicotinic acetylcholine receptor (nAChR)-mediated regulation of presynaptic GABA but not glutamate release, which would exacerbate excitation following endogenous or exogenous nAChR activation. Our data underscore an important role for nAChRs in hippocampal excitatory synapse development, and suggest selective long-term changes at specific presynaptic nAChRs which together could explain some of the behavioral abnormalities associated with maternal smoking. PMID:24950455

  8. Myocardial impulse propagation is impaired in right ventricular tissue of Zucker Diabetic Fatty (ZDF) rats

    PubMed Central

    2013-01-01

    Background Diabetes increases the risk of cardiovascular complications including arrhythmias, but the underlying mechanisms remain to be established. Decreased conduction velocity (CV), which is an independent risk factor for re-entry arrhythmias, is present in models with streptozotocin (STZ) induced type 1 diabetes. Whether CV is also disturbed in models of type 2 diabetes is currently unknown. Methods We used Zucker Diabetic Fatty (ZDF) rats, as a model of type 2 diabetes, and their lean controls Zucker Diabetic Lean (ZDL) rats to investigate CV and its response to the anti-arrhythmic peptide analogue AAP10. Gap junction remodeling was examined by immunofluorescence and western blotting. Cardiac histomorphometry was examined by Masson`s Trichrome staining and intracellular lipid accumulation was analyzed by Bodipy staining. Results CV was significantly slower in ZDF rats (56±1.9 cm/s) compared to non-diabetic controls (ZDL, 66±1.6 cm/s), but AAP10 did not affect CV in either group. The total amount of Connexin43 (C×43) was identical between ZDF and ZDL rats, but the amount of lateralized C×43 was significantly increased in ZDF rats (42±12 %) compared to ZDL rats (30±8%), p<0.04. Judged by electrophoretic mobility, C×43 phosphorylation was unchanged between ZDF and ZDL rats. Also, no differences in cardiomyocyte size or histomorphometry including fibrosis were observed between groups, but the volume of intracellular lipid droplets was 4.2 times higher in ZDF compared to ZDL rats (p<0.01). Conclusion CV is reduced in type 2 diabetic ZDF rats. The CV disturbance may be partly explained by increased lateralization of C×43, but other factors are likely also involved. Our data indicates that lipotoxicity potentially may play a role in development of conduction disturbances and arrhythmias in type 2 diabetes. PMID:23327647

  9. Functional responses to the cannabinoid agonist WIN 55,212-2 in neonatal rats of both genders: influence of weaning.

    PubMed

    Borcel, Erika; Pérez-Alvarez, Laura; de Ceballos, María L; Ramirez, Belén G; Marco, Eva Maria; Fernández, Beatriz; Rubio, Marina; Guaza, Carmen; Viveros, Ma-Paz

    2004-07-01

    We have studied behavioural, biochemical and endocrine responses to the cannabinoid agonist WIN 55,212-2 (WIN) in neonatal rats, as well as the effects of weaning on such responses. We used preweanling rats (20 days of age), 25-day-old weaned rats (weaning at Day 22) and 25-day-old nonweaned rats of both sexes. The behavioural effects of WIN were assessed in the nociceptive tail immersion test and in the open field. We also analysed the effect of weaning on corticosterone responses to WIN (radioimmunoassay) as well as on WIN-stimulated [35S] GTPgammaS binding in periaqueductal grey (PAG) and striatum. The cannabinoid agonist induced a modest increase in pain thresholds, whereas the effect of the drug on open-field activity, particularly on vertical activity, was much more marked. The weaning process appeared to reduce the baseline nociceptive latencies of the female rats. No significant effect of weaning on the behavioural responses to WIN was found. However, the group of weaned females (but not males) showed a significantly reduced WIN-stimulated [35S] GTPgammaS binding in the striatum. The cannabinoid agonist significantly increased the corticosterone levels of 25-day-old rats with the effect being more marked in weaned than in nonweaned animals. The results suggest that the weaning process might produce some sexually dimorphic developmental changes in CB1 receptor function.

  10. REDUCED INFARCT SIZE AND ACCUMULATION OF MICROGLIA IN RATS TREATED WITH WIN 55,212-2 AFTER NEONATAL STROKE

    PubMed Central

    Fernández-López, David; Faustino, Joel; Derugin, Nikita; Wendland, Michael; Lizasoain, Ignacio; Moro, Maria A.; Vexler, Zinaida S.

    2012-01-01

    Cannabinoids have emerged as brain protective agents under neurodegenerative conditions. Many neuroprotective actions of cannabinoids depend on the activation of specific receptors, cannabinoid receptor type 1 (CB1R) and type 2 (CB2R). The aim of the present study was to determine whether the CB2R and CB1R agonist WIN 55,212-2 (WIN) protects neonatal brain against focal cerebral ischemia-reperfusion and whether anti-inflammatory mechanisms play a role in protection. 7-day-old rats were subjected to 90 minutes middle cerebral artery occlusion (MCAO) and injured rats identified by diffusion-weighted MRI during the occlusion. After reperfusion rats were subcutaneously administered 1mg/kg of WIN or vehicle twice daily until sacrifice. MCAO led to increased mRNA expression of CB2R (but not CB1R), chemokine receptors (CCR2 and CX3CR1) and cytokines (IL-1β and TNFα), as well as increased protein expression of chemokines MCP-1 and MIP-1α and microglial activation 24 hours after MCAO. WIN administration significantly reduced microglial activation at this point and attenuated infarct volume and microglial accumulation and proliferation in the injured cortex 72 hours after MCAO. Cumulatively, our results show that the cannabinoid agonist WIN protects against neonatal focal stroke in part due to inhibitory effects on microglia. PMID:22285309

  11. Endothelin receptor-A (ETa) inhibition fails to improve neonatal hypoxic-ischemic brain injury in rats.

    PubMed

    Khatibi, Nikan H; Lee, Lillian K; Zhou, Yilin; Chen, Wanqiu; Rolland, William; Fathali, Nancy; Martin, Robert; Applegate, Richard; Stier, Gary; Zhang, John H

    2011-01-01

    Cerebral hypoxia-ischemia (HI) is an important cause of mortality and disability in newborns. It is a result of insufficient oxygen and glucose circulation to the brain, initiating long-term cerebral damage and cell death. Emerging evidence suggests that endothelin receptor-A (ETA) activation can play an important role in mediating brain damage. In this study, we investigated the role of ETA receptor inhibition using ABT-627 in neonatal HI injured rats. Postnatal day 10 Sprague-Dawley rat pups (n=91) were assigned to the following groups: sham (n=28), HI (vehicle, n=32), and HI with ABT-627 at 3 mg/kg (n=31). The Rice-Vannucci model was used to induce ischemia by ligating the right common carotid artery, followed by a 2 h hypoxic episode using 8% oxygen in a 37°C chamber. Postoperative assessment was conducted at 48 h after injury and again at 4 weeks. At the acute time point, investigative markers included cerebral edema, infarction volume, and body weight change. Neurobehavioral testing was measured at 4 weeks post-injury. Our findings indicated that ABT-627 had no effect on the measured parameters. This study suggests that ETA receptor blockade using ABT-627 post-treatment fails to improve neurological outcomes in neonatal HI injured rats. PMID:21725757

  12. Culturing Schwann Cells from Neonatal Rats by Improved Enzyme Digestion Combined with Explants-culture Method.

    PubMed

    Liu, Di; Liang, Xiao-Chun; Zhang, Hong

    2016-08-01

    Objective To develop an improved method for culturing Schwann cells(SCs) by using both enzyme digestion and explants-culture approaches and compared with traditional explants-culture method and general hemi-explants-culture method. Methods Bilaterally sciatic nerves and brachial plexus nerves were dissected from 3 to 5-day-old neonatal SD rats and explants-culture method,general hemi-explants-culture method,and improved enzyme digestion combined with explants-culture method were adopted to culture SCs,respectively. SCs were digested and passaged after 7 days in culture and counted under the microscope. The purity of SCs was identified by S-100 immunofluorescence staining. Results The SCs of improved method group grew fastest and the total number of cells obtained was(1.85±0.13)×10(6);the SCs of the hemi-explants-culture method group grew slower than the improved method group and the total number of cells obtained was (1.10±0.10)×10(6);the SCs of the explants-culture method group grew slowest and the total number of cells obtained was (0.77±0.03)×10(6).The total number of cells obtained showed significant difference among the three groups(P<0.01). Immunofluorescence staining showed that the SCs purity was (95.73±1.51)% in the improved method group,(84.66±2.68)% in the hemi-explants-culture method group,and (74.50±4.23)% in the explants-culture method group(P<0.01). Conclusion The improved enzyme digestion combined with explants-culture method can obtain sufficient amount of high-purity SCs in a short time and thus may be applied in further research on peripheral nerve regeneration.

  13. Isolation and partial characterisation of neuronal growth cones from neonatal rat forebrain.

    PubMed

    Gordon-Weeks, P R; Lockerbie, R O

    1984-09-01

    We have devised a method for the isolation of viable neuronal growth cones from neonatal rat forebrain. The method involves differential and density gradient centrifugation and exploits the relatively low buoyant density (approximately 1.018 g/cm3) of growth cones. There are no known biochemical markers for growth cones and it was necessary therefore to monitor for their presence during the isolation using transmission electron microscopy. Several criteria were used to identify isolated growth cones including the presence of filopodia, an extensive system of branching, tubular smooth endoplasmic reticulum and a region rich in microfilaments subjacent to the plasma membrane. These morphological features are similar to those of growth cones identified unequivocally in intact developing brain and in tissue culture. Electron microscopical analysis showed that greater than 90% of membrane-bound, identifiable objects in one fraction were growth cones by these criteria. The major contaminant consisted of membrane sacs and vesicles of unidentified origin. There were only small amounts of isolated rough endoplasmic reticulum and mitochondria. Isolated growth cones were roughly spherical in shape with a diameter of 1.9 +/- 0.5 micron (mean +/- 1 SD). They usually contained mitochondria, large granular vesicles and small vesicles, and occasionally contained coated vesicles, lysosomes, lamellar bodies and multivesicular bodies, and only very rarely, intermediate filaments. Occasionally, growth cones had rudimentary synapses on them. The viability of isolated growth cones was investigated by observing their behaviour in short-term culture. After a few hours in culture on poly-D-lysine-coated coverslips, growth cones flattened down and extended filopodia-like processes. This behaviour was inhibited by cytochalasin B and reversibly by cold (4 degrees C). We conclude that physiologically active growth cones can be isolated rapidly and in large numbers by the method described here.

  14. Culturing Schwann Cells from Neonatal Rats by Improved Enzyme Digestion Combined with Explants-culture Method.

    PubMed

    Liu, Di; Liang, Xiao-Chun; Zhang, Hong

    2016-08-01

    Objective To develop an improved method for culturing Schwann cells(SCs) by using both enzyme digestion and explants-culture approaches and compared with traditional explants-culture method and general hemi-explants-culture method. Methods Bilaterally sciatic nerves and brachial plexus nerves were dissected from 3 to 5-day-old neonatal SD rats and explants-culture method,general hemi-explants-culture method,and improved enzyme digestion combined with explants-culture method were adopted to culture SCs,respectively. SCs were digested and passaged after 7 days in culture and counted under the microscope. The purity of SCs was identified by S-100 immunofluorescence staining. Results The SCs of improved method group grew fastest and the total number of cells obtained was(1.85±0.13)×10(6);the SCs of the hemi-explants-culture method group grew slower than the improved method group and the total number of cells obtained was (1.10±0.10)×10(6);the SCs of the explants-culture method group grew slowest and the total number of cells obtained was (0.77±0.03)×10(6).The total number of cells obtained showed significant difference among the three groups(P<0.01). Immunofluorescence staining showed that the SCs purity was (95.73±1.51)% in the improved method group,(84.66±2.68)% in the hemi-explants-culture method group,and (74.50±4.23)% in the explants-culture method group(P<0.01). Conclusion The improved enzyme digestion combined with explants-culture method can obtain sufficient amount of high-purity SCs in a short time and thus may be applied in further research on peripheral nerve regeneration. PMID:27594149

  15. Histamine excites neonatal rat sympathetic preganglionic neurons in vitro via activation of H1 receptors.

    PubMed

    Whyment, Andrew D; Blanks, Andrew M; Lee, Kevin; Renaud, Leo P; Spanswick, David

    2006-04-01

    The role of histamine in regulating excitability of sympathetic preganglionic neurons (SPNs) and the expression of histamine receptor mRNA in SPNs was investigated using whole-cell patch-clamp electrophysiological recording techniques combined with single-cell reverse transcriptase polymerase chain reaction (RT-PCR) in transverse neonatal rat spinal cord slices. Bath application of histamine (100 microM) or the H1 receptor agonist histamine trifluoromethyl toluidide dimaleate (HTMT; 10 microM) induced membrane depolarization associated with a decrease in membrane conductance in the majority (70%) of SPNs tested, via activation of postsynaptic H1 receptors negatively coupled to one or more unidentified K+ conductances. Histamine and HTMT application also induced or increased the amplitude and/or frequency of membrane potential oscillations in electrotonically coupled SPNs. The H2 receptor agonist dimaprit (10 microM) or the H3 receptor agonist imetit (100 nM) were without significant effect on the membrane properties of SPNs. Histamine responses were sensitive to the H1 receptor antagonist triprolidine (10 microM) and the nonselective potassium channel blocker barium (1 mM) but were unaffected by the H2 receptor antagonist tiotidine (10 microM) and the H3 receptor antagonist, clobenpropit (5 microM). Single cell RT-PCR revealed mRNA expression for H1 receptors in 75% of SPNs tested, with no expression of mRNA for H2, H3, or H4 receptors. These data represent the first demonstration of H1 receptor expression in SPNs and suggest that histamine acts to regulate excitability of these neurons via a direct postsynaptic effect on H1 receptors.

  16. Hypothermia modulates cytokine responses after neonatal rat hypoxic-ischemic injury and reduces brain damage.

    PubMed

    Yuan, Xiangpeng; Ghosh, Nirmalya; McFadden, Brian; Tone, Beatriz; Bellinger, Denise L; Obenaus, Andre; Ashwal, Stephen

    2014-01-01

    While hypothermia (HT) is the standard-of-care for neonates with hypoxic ischemic injury (HII), the mechanisms underlying its neuroprotective effect are poorly understood. We examined ischemic core/penumbra and cytokine/chemokine evolution in a 10-day-old rat pup model of HII. Pups were treated for 24 hr after HII with HT (32℃; n = 18) or normothermia (NT, 35℃; n = 15). Outcomes included magnetic resonance imaging (MRI), neurobehavioral testing, and brain cytokine/chemokine profiling (0, 24, 48, and 72 hr post-HII). Lesion volumes (24 hr) were reduced in HT pups (total 74%, p < .05; penumbra 68%, p < .05; core 85%, p = .19). Lesion volumes rebounded at 72 hr (48 hr post-HT) with no significant differences between NT and HT pups. HT reduced interleukin-1β (IL-1β) at all time points (p < .05); monocyte chemoattractant protein-1 (MCP-1) trended toward being decreased in HT pups (p = .09). The stem cell signaling molecule, stromal cell-derived factor-1 (SDF-1) was not altered by HT. Our data demonstrate that HT reduces total and penumbral lesion volumes (at 24 and 48 hr), potentially by decreasing IL-1β without affecting SDF-1. Disassociation between the increasing trend in HII volumes from 48 to 72 hr post-HII when IL-1β levels remained low suggests that after rewarming, mechanisms unrelated to IL-1β expression are likely to contribute to this delayed increase in injury. Additional studies should be considered to determine what these mechanisms might be and also to explore whether extending the duration or degree of HT might ameliorate this delayed increase in injury.

  17. Hypothermia modulates cytokine responses after neonatal rat hypoxic-ischemic injury and reduces brain damage.

    PubMed

    Yuan, Xiangpeng; Ghosh, Nirmalya; McFadden, Brian; Tone, Beatriz; Bellinger, Denise L; Obenaus, Andre; Ashwal, Stephen

    2014-01-01

    While hypothermia (HT) is the standard-of-care for neonates with hypoxic ischemic injury (HII), the mechanisms underlying its neuroprotective effect are poorly understood. We examined ischemic core/penumbra and cytokine/chemokine evolution in a 10-day-old rat pup model of HII. Pups were treated for 24 hr after HII with HT (32℃; n = 18) or normothermia (NT, 35℃; n = 15). Outcomes included magnetic resonance imaging (MRI), neurobehavioral testing, and brain cytokine/chemokine profiling (0, 24, 48, and 72 hr post-HII). Lesion volumes (24 hr) were reduced in HT pups (total 74%, p < .05; penumbra 68%, p < .05; core 85%, p = .19). Lesion volumes rebounded at 72 hr (48 hr post-HT) with no significant differences between NT and HT pups. HT reduced interleukin-1β (IL-1β) at all time points (p < .05); monocyte chemoattractant protein-1 (MCP-1) trended toward being decreased in HT pups (p = .09). The stem cell signaling molecule, stromal cell-derived factor-1 (SDF-1) was not altered by HT. Our data demonstrate that HT reduces total and penumbral lesion volumes (at 24 and 48 hr), potentially by decreasing IL-1β without affecting SDF-1. Disassociation between the increasing trend in HII volumes from 48 to 72 hr post-HII when IL-1β levels remained low suggests that after rewarming, mechanisms unrelated to IL-1β expression are likely to contribute to this delayed increase in injury. Additional studies should be considered to determine what these mechanisms might be and also to explore whether extending the duration or degree of HT might ameliorate this delayed increase in injury. PMID:25424430

  18. Brain stem serotonin protects blood pressure in neonatal rats exposed to episodic anoxia.

    PubMed

    Yang, Hsiao T; Cummings, Kevin J

    2013-12-01

    In neonatal rodents, a loss of brain stem serotonin [5-hydroxytryptamine (5-HT)] in utero or at birth compromises anoxia-induced gasping and the recovery of heart rate (HR) and breathing with reoxygenation (i.e., autoresuscitation). How mean arterial pressure (MAP) is influenced after an acute loss of brain stem 5-HT content is unknown. We hypothesized that a loss of 5-HT for ∼1 day would compromise MAP during episodic anoxia. We injected 6-fluorotryptophan (20 mg/kg ip) into rat pups (postnatal days 9-10 or 11-13, n = 22 treated, 24 control), causing a ∼70% loss of brain stem 5-HT. Pups were exposed to a maximum of 15 anoxic episodes, separated by 5 min of room air to allow autoresuscitation. In younger pups, we measured breathing frequency and tidal volume using "head-out" plethysmography and HR from the electrocardiogram. In older pups, we used whole body plethysmography to detect gasping, while monitoring MAP. Gasp latency and the time required for respiratory, HR, and MAP recovery following each episode were determined. Despite normal gasp latency, breathing frequency and a larger tidal volume (P < 0.001), 5-HT-deficient pups survived one-half the number of episodes as controls (P < 0.001). The anoxia-induced decrease in MAP experienced by 5-HT-deficient pups was double that of controls (P = 0.017), despite the same drop in HR (P = 0.48). MAP recovery was delayed ∼10 s by 5-HT deficiency (P = 0.001). Our data suggest a loss of brain stem 5-HT leads to a pronounced, premature loss of MAP in response to episodic anoxia. These data may help explain why some sudden infant death syndrome cases die from what appears to be cardiovascular collapse during apparent severe hypoxia. PMID:24136109

  19. Responses of neonatal rat islets to streptozotocin: limited B-cell regeneration and hyperglycemia.

    PubMed

    Bonner-Weir, S; Trent, D F; Honey, R N; Weir, G C

    1981-01-01

    Streptozotocin (SZ) was given to 2-day-old neonatal rats, and, during their subsequent development, the interrelationships between plasma glucose, plasma insulin, pancreatic islet morphology, and hormone content were examined. At 4 days of age, a peak of hyperglycemia was observed (SZ, 349 plus or minus 8 mg/dl versus control (C), 127 plus or minus 2) that was associated with a marked reduction of B-cell numbers (SZ, 26.5 plus or minus 2.6% B-cell per islet versus C, 72.8 plus or minus 0.8%). By 10 days of age the SZ animals became normoglycemia with partial recovery of the B-cell number (SZ, 39.6 plus or minus 2.1% versus, C, 64.0 plus or minus 2.6%). By six weeks hyperglycemia returned (SZ, 345 plus or minus 5.2 mg/dl versus C, 171 plus or minus 6.2) with B-cell number of the SZ being 72% of the C (SZ, 48.8 plus or minus 2.4% versus C, 67.5 plus or minus 1.5%). This hyperglycemia and reduced B-cell number persisted to at least 13 wk age. Despite a marked reduction of pancreatic insulin content observed during development, there was little effect upon glucagon or somatostatin content. At 6 wk of age, the plasma insulin concentration was only 30% of C, which suggests as insulin secretory defect beyond that which could be accounted for by the modest B-cell reduction. The present study indicates that even though active regeneration of B-cells occurred after early injury, the capacity for ultimate normalization was limited. The resultant moderate reduction in B-cell number may be associated with a functional defect in glucose-stimulated insulin secretion.

  20. Neonatal dexamethasone accelerates spreading depression in the rat, and antioxidant vitamins counteract this effect.

    PubMed

    Lopes-de-Morais, Andréia Albuquerque Cunha; Mendes-da-Silva, Rosângela Figueiredo; dos-Santos, Eryka Maria; Guedes, Rubem Carlos Araújo

    2014-12-01

    The use of dexamethasone (Dex) to treat chronic lung disease in preterm infants may produce adverse effects in the developing brain. Here, we evaluated the effects of neonatal Dex on the propagation of cortical spreading depression (CSD), and tested the action of vitamins C and E against the effect of Dex. Five groups of Wistar rats received, respectively: [1] no treatment (Naïve); [2] Vehicle (V); [3] tapering doses of Dex (Dex; 0.5mg/kg, 0.3mg/kg, and 0.1mg/kg) on postnatal day (PND) 1-3; [4] Dex plus 200mg/kg vitamin C and 100mg/kg vitamin E (DexCE); [5] only vitamins C and E (CE). Vehicle and vitamins were administered on PND 1-6. CSD was recorded after the pups reached maturity (PND 60-70). The Dex-treated group presented with higher CSD velocities (mean values ± SD, in mm/min: 4.14 ± 0.22, n=10) compared with the control groups (Naïve: 3.52 ± 0.13, n=8; V: 3.57 ± 0.18, n=10; CE: 3.51 ± 0.24, n=10; p<0.05 for all). Vitamins C and E antagonized this effect (DexCE group; CSD velocity: 3.43 ± 0.12, n=9). No intergroup difference was observed concerning P-wave amplitude and duration. In all groups, after the cortex underwent CSD, the electrocorticogram (ECoG) amplitude increased approximately 50% compared with the baseline amplitude for the same animal (CSD-induced ECoG potentiation); however, no intergroup difference was observed. Data suggest that coadministration of antioxidant vitamins with Dex may be a helpful therapeutic strategy to reduce brain adverse effects of dexamethasone.

  1. Retrograde labeling, enrichment, and characterization of retinal ganglion cells from the neonatal rat.

    PubMed

    Sarthy, P V; Curtis, B M; Catterall, W A

    1983-12-01

    We have developed a method for labeling retinal ganglion cells in neonatal rats by retrograde transport of the fluorescent dye, True Blue (TB), injected into the optic chiasm. Following proteolytic dissociation of labeled retinas into single cells, the labeled cells could be enriched 50- to 100-fold by centrifugation in a 5%/10% metrizamide gradient. When plated in Ham's F-10 medium in the presence of fetal calf serum and chick optic tectum-conditioned medium, the labeled cells could be maintained in vitro up to 48 hr. In these cultures, the ganglion cells (GCS) constituted 50 to 70% of the total cell population. When GC-rich fractions or GC cultures were stained with a monoclonal antibody to Thy-1 antigen, greater than 90% of the TB-labeled cells were reactive. In order to localize voltage-sensitive sodium channels, GC-rich cultures were reacted with 125I-scorpion toxin. Analysis of the autoradiograms showed that the density of silver grains was about 10-fold higher on TB-labeled cells than on nonfluorescent cells, or in controls which contained excess of unlabeled toxin. When GC cultures were incubated with micromolar concentrations of putative GC transmitters, aspartate and glutamate, the amino acids were accumulated by 15 to 20% of labeled cells. Several lectin receptors were also localized on TB-labeled cells in situ. Whereas the lectins wheat germ agglutinin, concanavalin A, peanut agglutinin, Dolichos biflorus agglutinin, and Limulus polyphemus agglutinin bound to TB-labeled cells, others such as Ricinus communis agglutinin I, Ulex, and Lotus lectins showed no binding. The lectin binding was specific since preincubation with the appropriate hapten sugar blocked lectin binding.

  2. Fetal asphyctic preconditioning modulates the acute cytokine response thereby protecting against perinatal asphyxia in neonatal rats

    PubMed Central

    2013-01-01

    Background Perinatal asphyxia (PA) is a major cause of brain damage and neurodevelopmental impairment in infants. Recent investigations have shown that experimental sublethal fetal asphyxia (FA preconditioning) protects against a subsequent more severe asphyctic insult at birth. The molecular mechanisms of this protection have, however, not been elucidated. Evidence implicates that inflammatory cytokines play a protective role in the induction of ischemic tolerance in the adult brain. Accordingly, we hypothesize that FA preconditioning leads to changes in the fetal cytokine response, thereby protecting the newborn against a subsequent asphyctic insult. Methods In rats, FA preconditioning was induced at embryonic day 17 by clamping the uterine vasculature for 30 min. At term birth, global PA was induced by placing the uterine horns, containing the pups, in a saline bath for 19 min. We assessed, at different time points after FA and PA, mRNA and protein expression of several cytokines and related receptor mRNA levels in total hemispheres of fetal and neonatal brains. Additionally, we measured pSTAT3/STAT3 levels to investigate cellular responses to these cytokines. Results Prenatally, FA induced acute downregulation in IL-1β, TNF-α and IL-10 mRNA levels. At 96 h post FA, IL-6 mRNA and IL-10 protein expression were increased in FA brains compared with controls. Two hours after birth, all proinflammatory cytokines and pSTAT3/STAT3 levels decreased in pups that experienced FA and/or PA. Interestingly, IL-10 and IL-6 mRNA levels increased after PA. When pups were FA preconditioned, however, IL-10 and IL-6 mRNA levels were comparable to those in controls. Conclusions FA leads to prenatal changes in the neuroinflammatory response. This modulation of the cytokine response probably results in the protective inflammatory phenotype seen when combining FA and PA and may have significant implications for preventing post-asphyctic perinatal encephalopathy. PMID:23351591

  3. Sertraline delays the somatic growth and reflex ontogeny in neonate rats.

    PubMed

    Deiró, T C B J; Manhães-de-Castro, R; Cabral-Filho, J E; Barreto-Medeiros, J M; Souza, S L; Marinho, S M O C; Castro, F M M; Toscano, A E; Jesus-Deiró, R A; Barros, K M F T

    2006-02-28

    This study investigated the somatic maturation and ontogeny of reflexes in neonate rats treated with sertraline (Sert) during the suckling period. The animals were divided into four groups; three that received daily doses of Sert (5, 10 or 15 mg/kg s.c.; groups Sert5, Sert10, and Sert15, respectively), and a fourth group that received distilled water (Dw) (1 ml/kg/b.w.). Growth indicators (body weight, axis of the head and tail length) were measured daily, from the 1st to the 21st postnatal day. The reflexes (righting, free-fall righting, negative geotaxis, cliff avoidance, auditory startle response, vibrissa placing and palm grasp) and physical-feature maturation (ear unfolding, auditory conduit opening, irruption of the lower incisors and eye opening) were recorded each day of the animal's life. All groups were compared to the Dw group. The body weight gain was reduced in all the Sert groups. Moreover, a delay in the growth of the body length was observed in all the Sert groups. Higher Sert doses reduced the speed of growth in the tail length. The medio-lateral head axis reduced in Sert15 and Sert5 doses. Otherwise, Sert10 had a temporary acceleration in this growth, but the growth of the anteroposterior head axis had a delay in all the Sert groups. The highest doses induced a delay in physical-feature maturation. The palm grasp reflex (disappearance) was retarded in Sert10; cliff avoidance advanced in Sert10; negative-geotaxis and free-fall righting retarded in Sert15. The findings suggest that altered serotonergic system activity induced by sertraline early in life could play a role in the retardation of the somatic growth ontogeny as well as a delay in the maturation of some reflexes.

  4. Regional alterations of repolarizing K+ currents among the left ventricular free wall of rats with ascending aortic stenosis

    PubMed Central

    Volk, Tilmann; Nguyen, Thi Hong-Diep; Schultz, Jobst-Hendrik; Faulhaber, Jörg; Ehmke, Heimo

    2001-01-01

    The effect of cardiac hypertrophy on electrocardiogram (ECG), action potential duration (APD) and repolarizing K+ currents was investigated in epicardial, midmyocardial and endocardial myocytes isolated from the rat left ventricular free wall. Cardiac hypertrophy was induced by stenosis of the ascending aorta (AS), which led to an increased pressure load (+85 ± 10 mm) of the left ventricle; sham-operated animals served as controls. In ECG recordings from AS rats, the QTc interval was prolonged and the main vectors of the QRS complex and the T-wave pointed in opposite directions, indicating an abnormal sequence of repolarization. APD and K+ currents were recorded using the whole-cell patch-clamp technique. In the AS group, APD90 (90 % repolarization) was significantly prolonged in epicardial and midmyocardial, but not endocardial myocytes. Corresponding to the increase in APD, the magnitude of the transient outward K+ current (Ito1) was significantly smaller (-30 %) in epicardial and midmyocardial, but not endocardial myocytes. Inactivation and steady-state inactivation of Ito1 were not affected by hypertrophy. Recovery from inactivation was slightly prolonged in endocardial myocytes from AS rats. No differences in delayed rectifier currents (IK) or inwardly rectifying K+ currents (IK1) were detected between myocytes of the three regions of sham-operated or AS animals. However, both currents were reduced by AS. The present data show that cardiac hypertrophy caused by pressure overload leads to an increase in APD and a decrease in Ito1 primarily in epicardial and midmyocardial myocytes, which implies a major role of alterations in Ito1 for the reduced gradient in APD. The effects of AS on IK1 and IK may slightly counteract the decrease in APD gradient. The observed changes in APD and underlying ionic currents could well explain the alterations in repolarization observed in the ECG induced by cardiac hypertrophy. PMID:11158275

  5. Investigation of infectivity of neonates and adults from different rat strains to Toxoplasma gondii Prugniaud shows both variation which correlates with iNOS and Arginase-1 activity and increased susceptibility of neonates to infection.

    PubMed

    Gao, Jiang-Mei; Yi, Si-Qi; Wu, Ming-Shui; Geng, Guo-Qing; Shen, Ji-Long; Lu, Fang-Li; Hide, Geoff; Lai, De-Hua; Lun, Zhao-Rong

    2015-02-01

    Mouse models differ considerably from humans with regard to clinical symptoms of toxoplasmosis caused by Toxoplasma gondii and, by comparison, the rat model is more representative of this disease in humans. In the present study, we found that different strains of adult and newborn rats (Lewis, Wistar, Sprague Dawley, Brown Norway and Fischer 344) exhibited remarkable variation in the number of brain cysts following inoculation with the T.gondii Prugniaud strain. In adult rats, large numbers of cysts (1231 ± 165.6) were observed in Fischer 344, but none in the other four. This situation was different in newborn rats aged from 5 to 20 days old. All Fischer 344 and Brown Norway newborns were cyst-positive while cyst-positive infection in Sprague Dawley neonates ranged from 54.5% to 60% depending on their age at infection. In Wistar and Lewis rat neonates, however, cyst-positivity rates of 0-42.9% and 0-25% were found respectively. To investigate whether rat strain differences in infectivity could be related to inherent strain and genetic differences in the host immune response, we correlated our data with previously reported strain differences in iNOS/Arginase ratio in adult rats and found them to be linked. These results show that interactions between host genetic background and age of rat influence T.gondii infection.

  6. Intermittent neonatal hypoxia elicits the upregulation of inflammatory-related genes in adult male rats through long-lasting programming effects.

    PubMed

    Gehrand, Ashley L; Kaldunski, Mary L; Bruder, Eric D; Jia, Shuang; Hessner, Martin J; Raff, Hershel

    2015-12-01

    The long-term effects of neonatal intermittent hypoxia (IH), an accepted model of apnea-induced hypoxia, are unclear. We have previously shown lasting "programming" effects on the HPA axis in adult rats exposed to neonatal IH. We hypothesized that neonatal rat exposure to IH will subsequently result in a heightened inflammatory state in the adult. Rat pups were exposed to normoxia (control) or six cycles of 5% IH or 10% IH over one hour daily from postnatal day 2-6. Plasma samples from blood obtained at 114 days of age were analyzed by assessing the capacity to induce transcription in a healthy peripheral blood mononuclear cell (PBMC) population and read using a high-density microarray. The analysis of plasma from adult rats previously exposed to neonatal 5% IH versus 10% IH resulted in 2579 significantly regulated genes including increased expression of Cxcl1, Cxcl2, Ccl3, Il1a, and Il1b. We conclude that neonatal exposure to intermittent hypoxia elicits a long-lasting programming effect in the adult resulting in an upregulation of inflammatory-related genes. PMID:26660555

  7. Eyeblink classical conditioning and interpositus nucleus activity are disrupted in adult rats exposed to ethanol as neonates.

    PubMed

    Green, John T; Johnson, Timothy B; Goodlett, Charles R; Steinmetz, Joseph E

    2002-01-01

    Neonatal exposure to ethanol in rats, during the period of brain development comparable to that of the human third trimester, produces significant, dose-dependent cell loss in the cerebellum and deficits in coordinated motor performance. These rats are also impaired in eyeblink conditioning as weanlings and as adults. The current study examined single-unit neural activity in the interpositus nucleus of the cerebellum in adults following neonatal binge ethanol exposure. Group Ethanol received alcohol doses of 5.25 g/kg/day on postnatal days 4-9. Group Sham Intubated underwent acute intragastric intubation on postnatal days 4-9 but did not receive any infusions. Group Unintubated Control (from separate litters) did not receive any intubations. When rats were 3-7 mo old, pairs of extracellular microelectrodes were implanted in the region of the interpositus nucleus. Beginning 1 wk later, the rats were given either 100 paired or 190 unpaired trials per day for 10 d followed by 4 d of 100 conditioned stimulus (CS)-alone trials per day. As in our previous study, conditioned response acquisition in Group Ethanol rats was impaired. In addition, by session 5 of paired acquisition, Group Sham Intubated and Group Unintubated Control showed significant increases in interpositus nucleus activity, relative to baseline, in the CS-unconditioned stimulus interval. In contrast, Group Ethanol failed to show significant changes in interpositus nucleus activity until later in training. These results indicate that the disruption in eyeblink conditioning after early exposure to ethanol is reflected in alterations in interpositus nucleus activity.

  8. Cytoplasmic and nuclear estradiol receptors in the hypothalamus and cerebral cortex of female rats during the neonatal period

    SciTech Connect

    Shishkina, I.V.; Babichev, V.N.; Ozol', L.Y.

    1986-07-01

    The content of estradifol receptors (E/sub 2/) in the cytoplasmic and nuclear fractions of the hypothalamus and cerebral cortex of female rats was investigated in the course of neonatal development. In the cytosol of the hypothalamus and cortex, the E/sub 2/-binding proteins, which possess high capacity, include both the true estradiol receptors and proteins identical with ..cap alpha..-fetoprotein. True receptors E/sub 2/ were detected in the nuclear fraction; in the hypothalamus their concentration was virtually unchanged, while in the cortex it decreased from the first to fifth days of postnatal development.

  9. Characterization and agonist regulation of muscarinic ([3H]N-methyl scopolamine) receptors in isolated ventricular myocytes from rat.

    PubMed

    Horackova, M; Robinson, B; Wilkinson, M

    1990-11-01

    Cell surface muscarinic cholinergic receptors have been characterized and quantified for the first time, in intact, isolated adult rat cardiomyocytes. The cells were previously established as functionally fully compatible with cellular responses in intact cardiac tissue. The specific binding of the hydrophilic radioligand, [3H]-NMS, (N-methyl-[3H]-scopolamine methylchloride) was found to be stereo-specific, saturable, reversible and of high affinity. Binding of [3H]-NMS demonstrated appropriate drug specificity and was positively correlated with increasing cell concentrations. Bmax for [3H]-NMS binding to ventricular myocytes, enzymatically dissociated from adult male rats, was 15.8 +/- 1.03 fmol/25 x 10(3) cells (at 4 degrees C) and KD was 0.27 +/- 0.05 nM (n = 14). Binding assays performed at a higher incubation temperature (30 degrees C) yielded a higher Bmax value (22.1 +/- 1.6 fmol/25 x 10(3) cells; n = 11; P less than 0.005 vs. Bmax at 4 degrees C) but an unchanged KD (0.23 +/- 0.06 nM). Pretreatment of myocytes with the muscarinic agonist carbachol (1 mM) at 37 degrees C resulted in a reduction (down-regulation) in specific binding of the hydrophilic ligand [3H]-NMS. The magnitude of this reduction and its rate of recovery were dependent on the time of the exposure to carbachol. Exposures of 30-60 min elicited down-regulated by 35% (Bmax = 14.29 +/- 1.66 changed to 9.5 +/- 1.79 fmol/25 x 10(3) cells, without change in KD P less than 0.01, n = 4). The down-regulation of the muscarinic receptors by carbachol was insensitive to application of bacitracin - an inhibitor of endocytosis. On the other hand preincubation with 10(-9)M atropine, a muscarinic antagonist, hindered the agonist-induced receptor "loss" from the cell surface confirming the muscarinic nature of these receptors. We conclude that our preparation of intact, isolated ventricular cardiomyocytes is ideally suited for the study of cell surface muscarinic receptor regulation under physiological and

  10. Characterization and agonist regulation of muscarinic ([3H]N-methyl scopolamine) receptors in isolated ventricular myocytes from rat.

    PubMed

    Horackova, M; Robinson, B; Wilkinson, M

    1990-11-01

    Cell surface muscarinic cholinergic receptors have been characterized and quantified for the first time, in intact, isolated adult rat cardiomyocytes. The cells were previously established as functionally fully compatible with cellular responses in intact cardiac tissue. The specific binding of the hydrophilic radioligand, [3H]-NMS, (N-methyl-[3H]-scopolamine methylchloride) was found to be stereo-specific, saturable, reversible and of high affinity. Binding of [3H]-NMS demonstrated appropriate drug specificity and was positively correlated with increasing cell concentrations. Bmax for [3H]-NMS binding to ventricular myocytes, enzymatically dissociated from adult male rats, was 15.8 +/- 1.03 fmol/25 x 10(3) cells (at 4 degrees C) and KD was 0.27 +/- 0.05 nM (n = 14). Binding assays performed at a higher incubation temperature (30 degrees C) yielded a higher Bmax value (22.1 +/- 1.6 fmol/25 x 10(3) cells; n = 11; P less than 0.005 vs. Bmax at 4 degrees C) but an unchanged KD (0.23 +/- 0.06 nM). Pretreatment of myocytes with the muscarinic agonist carbachol (1 mM) at 37 degrees C resulted in a reduction (down-regulation) in specific binding of the hydrophilic ligand [3H]-NMS. The magnitude of this reduction and its rate of recovery were dependent on the time of the exposure to carbachol. Exposures of 30-60 min elicited down-regulated by 35% (Bmax = 14.29 +/- 1.66 changed to 9.5 +/- 1.79 fmol/25 x 10(3) cells, without change in KD P less than 0.01, n = 4). The down-regulation of the muscarinic receptors by carbachol was insensitive to application of bacitracin - an inhibitor of endocytosis. On the other hand preincubation with 10(-9)M atropine, a muscarinic antagonist, hindered the agonist-induced receptor "loss" from the cell surface confirming the muscarinic nature of these receptors. We conclude that our preparation of intact, isolated ventricular cardiomyocytes is ideally suited for the study of cell surface muscarinic receptor regulation under physiological and

  11. Testicular development in male rats is sensitive to a soy-based diet in the neonatal period.

    PubMed

    Napier, India D; Simon, Liz; Perry, Devin; Cooke, Paul S; Stocco, Douglas M; Sepehr, Estatira; Doerge, Daniel R; Kemppainen, Barbara W; Morrison, Edward E; Akingbemi, Benson T

    2014-02-01

    Approximately 30% of infants in the United States are exposed to high doses of isoflavones resulting from soy infant formula consumption. Soybeans contain the isoflavones genistin and daidzin, which are hydrolyzed in the gastrointestinal tract to their genistein and daidzein aglycones. Both aglycones possess hormonal activity and may interfere with male reproductive development. Testosterone, which supports male fertility, is mainly produced by testicular Leydig cells. Our previous studies indicated that perinatal exposure of male rats to isoflavones induced proliferative activity in Leydig cells and increased testosterone concentrations into adulthood. However, the relevance of the neonatal period as part of the perinatal window of isoflavone exposure remains to be established. The present study examined the effects of exposure to isoflavones on male offspring of dams maintained on a casein-based control or whole soybean diet in the neonatal period, that is, Days 2 to 21 postpartum. The results showed that the soybean diet stimulated proliferative activity in developing Leydig cells while suppressing their steroidogenic capacity in adulthood. In addition, isoflavone exposure decreased production of anti-Müllerian hormone by Sertoli cells. Similar to our previous in vitro studies of genistein action in Leydig cells, daidzein induced proliferation and interfered with signaling pathways to suppress steroidogenic activity. Overall, the data showed that the neonatal period is a sensitive window of exposure to isoflavones and support the view that both genistein and daidzein are responsible for biological effects associated with soy-based diets.

  12. Gender difference in alcohol-evoked hypothalamic-pituitary-adrenal activity in the rat: ontogeny and role of neonatal steroids.

    PubMed

    Ogilvie, K M; Rivier, C

    1996-04-01

    Alcohol administration results in activation of the hypothalamic-pituitary-adrenal (HPA) axis, with female rats secreting more adrenocorticotropin (ACTH) and corticosterone (B) than males in response to the same dose of alcohol. We first examined the ontogeny of the gender difference in HPA responsiveness to alcohol by administering four doses (0, 1, 2, or 3 g/kg body weight) to animals at 21, 41, and 61 days of age (prepubertal, peripubertal, and postpubertal, respectively). We then investigated the organizational role of steroids by manipulating the neonatal steroidal milieu. Rats of both genders were gonadectomized or injected with testosterone propionate within 24 hr of birth and the HPA response to 3 g/kg body weight alcohol was tested in adulthood (postpubertal period). Our data show that the gender difference in HPA responsiveness to alcohol administration arises peripubertally. In addition, HPA response to alcohol is quantitatively smaller in intact male rats than in feminized groups (gonadectomized males and females, intact females) and masculinized female rats. We conclude that the gender difference in HPA response to alcohol observed in postpubertal rats injected with alcohol depends on the activational role of testicular androgens, rather than on their organizational influence.

  13. Chronic cerebrolysin administration attenuates neuronal abnormalities in the basolateral amygdala induced by neonatal ventral hippocampus lesion in the rat.

    PubMed

    Vázquez-Roque, Rubén Antonio; Ubhi, Kiren; Masliah, Eliezer; Flores, Gonzalo

    2014-01-01

    The neonatal ventral hippocampal lesion (nVHL) has emerged as a model of schizophrenia-related behavior in the rat. Our previous report demonstrated that cerebrolysin (Cbl), a neuropeptide preparation which mimics the action of endogenous neurotrophic factors on brain protection and repair, promoted recovery of dendritic and neuronal damage of the prefrontal cortex and nucleus accumbens and behavioral improvements in postpubertal nVHL rats. We recently demonstrated that nVHL animals exhibit dendritic atrophy and spine loss in the basolateral amygdala (BLA). This study aimed to determine whether Cbl treatment was capable of reducing BLA neuronal alterations observed in nVHL rats. The morphological evaluation included examination of dendrites using the Golgi-Cox procedure and stereology to quantify the total cell number in BLA. Golgi-Cox staining revealed that nVHL induced dendritic retraction and spine loss in BLA pyramidal neurons. Stereological analysis demonstrated nVHL also produced a reduction in cells in BLA. Interestingly, repeated Cbl treatment ameliorated dendritic pathology and neuronal loss in the BLA of the nVHL rats. Our data show that Cbl may foster recovery of BLA damage in postpubertal nVHL rats and suggests that the use of neurotrophic agents for the management of some schizophrenia-related symptoms may present an alternative therapeutic pathway in these disorders.

  14. Differential effects of neonatal handling on anxiety, corticosterone response to stress, and hippocampal glucocorticoid and serotonin (5-HT)2A receptors in Lewis rats.

    PubMed

    Durand, M; Sarrieau, A; Aguerre, S; Mormède, P; Chaouloff, F

    1998-05-01

    Neonatal handling (during the first 3 weeks of age) has been reported by others to diminish the hypothalamo-pituitary-adrenal (HPA) responsivity to stress in adult Long Evans rats, an effect involving a serotonin (5-HT)2A receptor-mediated increase in glucocorticoid receptor (GR) gene expression in the frontal cortex and the hippocampus. In addition, handled animals may also display enduring reductions in anxiety-related behaviours, including in the elevated plus-maze. We have thus analysed the aforementioned neuroendocrine and behavioural consequences of neonatal stress in male and female adult Lewis rats, a strain characterised by its high anxiety and its hyporesponsive HPA axis. Plasma corticosterone, but not behavioural, responses to an elevated plus-maze test were decreased in handled rats. Besides, hippocampal mineralocorticoid receptor (MR) and GR binding capacities were not different between handled and non-handled Lewis rats, an observation which could be extended to our adult Long Evans rats. Lastly, neither hippocampal nor cortical 5-HT2A receptor binding capacities in adult Lewis rats were affected by prior handling. In keeping with the failure to detect early handling-induced increases in hippocampal GR binding in 3-week old Lewis and Long Evans rats, the present study reinforces past findings indicating that environmental and genetic factors are crucial variables in the neonatal handling paradigm.

  15. Celecoxib reduces brain dopaminergic neuronaldysfunction, and improves sensorimotor behavioral performance in neonatal rats exposed to systemic lipopolysaccharide

    PubMed Central

    2013-01-01

    Background Cyclooxygenase-2 (COX-2) is induced in inflammatory cells in response to cytokines and pro-inflammatory molecules, suggesting that COX-2 has a role in the inflammatory process. The objective of the current study was to examine whether celecoxib, a selective COX-2 inhibitor, could ameliorate lipopolysaccharide (LPS)-induced brain inflammation, dopaminergic neuronal dysfunction and sensorimotor behavioral impairments. Methods Intraperitoneal (i.p.) injection of LPS (2 mg/kg) was performed in rat pups on postnatal Day 5 (P5), and celecoxib (20 mg/kg) or vehicle was administered (i.p.) five minutes after LPS injection. Sensorimotor behavioral tests were carried out 24 h after LPS exposure, and brain injury was examined on P6. Results Our results showed that LPS exposure resulted in impairment in sensorimotor behavioral performance and injury to brain dopaminergic neurons, as indicated by loss of tyrosine hydroxylase (TH) immunoreactivity, as well as decreases in mitochondria activity in the rat brain. LPS exposure also led to increases in the expression of α-synuclein and dopamine transporter proteins and enhanced [3H]dopamine uptake. Treatment with celecoxib significantly reduced LPS-induced sensorimotor behavioral disturbances and dopaminergic neuronal dysfunction. Celecoxib administration significantly attenuated LPS-induced increases in the numbers of activated microglia and astrocytes and in the concentration of IL-1β in the neonatal rat brain. The protective effect of celecoxib was also associated with an attenuation of LPS-induced COX-2+ cells, which were double labeled with TH + (dopaminergic neuron) or glial fibrillary acidic protein (GFAP) + (astrocyte) cells. Conclusion Systemic LPS administration induced brain inflammatory responses in neonatal rats; these inflammatory responses included induction of COX-2 expression in TH neurons and astrocytes. Application of the COX-2 inhibitor celecoxib after LPS treatment attenuated the inflammatory

  16. Maternal iron deficiency alters circulating thyroid hormone levels in developing neonatal rats

    EPA Science Inventory

    Thyroid hormone insufficiency and iron deficiency (FeD) during fetal and neonatal life are both similarly deleterious to mammalian development suggesting a possible linkage between iron and thyroid hormone insufficiencies. Recent published data from our laboratory demonstrate a r...

  17. Combustion derived ultrafine particles induce cytochrome P-450 expression in specific lung compartments in the developing neonatal and adult rat

    PubMed Central

    Chan, Jackie K. W.; Vogel, Christoph F.; Baek, Jaeeun; Kodani, Sean D.; Uppal, Ravi S.; Bein, Keith J.; Anderson, Donald S.

    2013-01-01

    Vehicle exhaust is rich in polycyclic aromatic hydrocarbons (PAH) and can be a dominant contributor to ultrafine urban particulate matter (PM). Exposure to ultrafine PM is correlated with respiratory infections and asthmatic symptoms in young children. The lung undergoes substantial growth, alveolarization, and cellular maturation within the first years of life, which may be impacted by environmental pollutants such as PM. PAHs in PM can serve as ligands for the aryl hydrocarbon receptor (AhR) that induces expression of certain isozymes in the cytochrome P-450 superfamily, such as CYP1A1 and CYP1B1, localized in specific lung cell types. Although AhR activation and induction has been widely studied, its context within PM exposure and impact on the developing lung is poorly understood. In response, we have developed a replicable ultrafine premixed flame particle (PFP) generating system and used in vitro and in vivo models to define PM effects on AhR activation in the developing lung. We exposed 7-day neonatal and adult rats to a single 6-h PFP exposure and determined that PFPs cause significant parenchymal toxicity in neonates. PFPs contain weak AhR agonists that upregulate AhR-xenobiotic response element activity and expression and are capable inducers of CYP1A1 and CYP1B1 expression in both ages with different spatial and temporal patterns. Neonatal CYP1A1 expression was muted and delayed compared with adults, possibly because of differences in the enzyme maturation. We conclude that the inability of neonates to sufficiently adapt in response to PFP exposure may, in part, explain their susceptibility to PFP and urban ultrafine PM. PMID:23502512

  18. Environmental neurotoxin interaction with proteins: Dose-dependent increase of free and protein-associated BMAA (β-N-methylamino-L-alanine) in neonatal rat brain.

    PubMed

    Karlsson, Oskar; Jiang, Liying; Ersson, Lisa; Malmström, Tim; Ilag, Leopold L; Brittebo, Eva B

    2015-01-01

    β-Methylamino-L-alanine (BMAA) is implicated in the aetiology of neurodegenerative disorders. Neonatal exposure to BMAA induces cognitive impairments and progressive neurodegenerative changes including intracellular fibril formation in the hippocampus of adult rats. It is unclear why the neonatal hippocampus is especially vulnerable and the critical cellular perturbations preceding BMAA-induced toxicity remains to be elucidated. The aim of this study was to compare the level of free and protein-associated BMAA in neonatal rat brain and peripheral tissues after different exposures to BMAA. Ultra-high performance liquid chromatography-tandem mass spectrometry analysis revealed that BMAA passed the neonatal blood-brain barrier and was distributed to all studied brain areas. BMAA was also associated to proteins in the brain, especially in the hippocampus. The level in the brain was, however, considerably lower compared to the liver that is not a target organ for BMAA. In contrast to the liver there was a significantly increased level of protein-association of BMAA in the hippocampus and other brain areas following repeated administration suggesting that the degradation of BMAA-associated proteins may be lower in neonatal brain than in the liver. Additional evidence is needed in support of a role for protein misincorporation in the neonatal hippocampus for long-term effects of BMAA.

  19. Environmental neurotoxin interaction with proteins: Dose-dependent increase of free and protein-associated BMAA (β-N-methylamino-L-alanine) in neonatal rat brain

    PubMed Central

    Karlsson, Oskar; Jiang, Liying; Ersson, Lisa; Malmström, Tim; Ilag, Leopold L.; Brittebo, Eva B.

    2015-01-01

    β-Methylamino-L-alanine (BMAA) is implicated in the aetiology of neurodegenerative disorders. Neonatal exposure to BMAA induces cognitive impairments and progressive neurodegenerative changes including intracellular fibril formation in the hippocampus of adult rats. It is unclear why the neonatal hippocampus is especially vulnerable and the critical cellular perturbations preceding BMAA-induced toxicity remains to be elucidated. The aim of this study was to compare the level of free and protein-associated BMAA in neonatal rat brain and peripheral tissues after different exposures to BMAA. Ultra-high performance liquid chromatography-tandem mass spectrometry analysis revealed that BMAA passed the neonatal blood-brain barrier and was distributed to all studied brain areas. BMAA was also associated to proteins in the brain, especially in the hippocampus. The level in the brain was, however, considerably lower compared to the liver that is not a target organ for BMAA. In contrast to the liver there was a significantly increased level of protein-association of BMAA in the hippocampus and other brain areas following repeated administration suggesting that the degradation of BMAA-associated proteins may be lower in neonatal brain than in the liver. Additional evidence is needed in support of a role for protein misincorporation in the neonatal hippocampus for long-term effects of BMAA. PMID:26498001

  20. Thymbra capitata essential oil prevents cell death induced by 4-hydroxy-2-nonenal in neonatal rat cardiac myocytes.

    PubMed

    Hortigón-Vinagre, María P; Blanco, José; Ruiz, Trinidad; Henao, Fernando

    2014-10-01

    An interdisciplinary experimental investigation on the antioxidant activity of Thymbra capitata essential oil was made. This plant is a Mediterranean culinary herb, whose essential oil antioxidant power has recently been demonstrated in vitro as one of the highest in nature. We tested if this in vitro antioxidant capacity was reproducible on biological systems using as model system primary cultures of neonatal rat cardiomyocytes treated with the lipid peroxidation product 4-hydroxy-2-nonenal. The composition and the in vitro antioxidant activity of the T. capitata essential oil were also assessed. Cell viability, mitochondrial membrane potential, and reactive oxygen species level were measured in cells treated with pathophysiologic doses of 4-hydroxy-2-nonenal (< 10 µM) or vehicle after being pre-incubated with small concentrations of the T. capitata essential oil, and the ability of small doses (< 40 ppm) to prevent the death of neonatal rat cardiomyocytes proved very remarkable. Long-term pre-incubation (12 h) with 20 ppm prevented 4-hydroxy-2-nonenal-induced cell death and avoided mitochondrial membrane potential loss and reactive oxygen species generation caused by 4-hydroxy-2-nonenal. A deleterious effect was shown at doses higher than 40 ppm. The results of this study pave the way to further analysis in animal models to achieve a deeper understanding of the in vivo antioxidant power of T. capitata essential oil. PMID:25203731

  1. Effects of acute changes in neonatal leptin levels on food intake and long-term metabolic profiles in rats.

    PubMed

    Granado, Miriam; García-Cáceres, Cristina; Fuente-Martín, Esther; Díaz, Francisca; Mela, Virginia; Viveros, Maria-Paz; Argente, Jesús; Chowen, Julie A

    2011-11-01

    In rodents there is a rise in serum leptin levels between postnatal days (PND) 5 and 14, with this neonatal leptin surge reported to modulate the maturation of hypothalamic circuits involved in appetite regulation. We hypothesized that acute changes in neonatal leptin levels have different long-term metabolic effects depending on how and when this surge is modified. To advance the timing of the normal leptin peak, male Wistar rats were injected with leptin (sc, 3 μg/g) on PND 2. To ablate the leptin peak on PND 10, a pegylated leptin antagonist (sc, 9 μg/g) was injected. Controls received vehicle. All rats were allowed to eat ad libitum until PND 150. Increased leptin on PND 2 reduced food intake (P<0.01) after 3 months of age with no effect on body weight. Levels of total ghrelin were reduced (P<0.001) and acylated ghrelin increased (P<0.05), with no other modifications in metabolic hormones. In contrast, treatment with the leptin antagonist on PND 9 did not affect food intake but reduced body weight beginning around PND 60 (P<0.02). This was associated with a reduction in fat mass, insulin (P<0.01), and leptin (P<0.007) levels and an increase in testosterone levels (P<0.01). Hypothalamic neuropeptide Y (P<0.05) and leptin receptor (P<0.005) mRNA levels were reduced, whereas mRNA levels for uncoupling protein 2 (P<0.005) were increased in visceral fat, which may indicate an increase in energy expenditure. In conclusion, acute changes in neonatal leptin levels induce different metabolic profiles depending on how and when leptin levels are modified.

  2. Optimal dose-setting study of curcumin for improvement of left ventricular systolic function after myocardial infarction in rats.

    PubMed

    Sunagawa, Yoichi; Sono, Shogo; Katanasaka, Yasufumi; Funamoto, Masafumi; Hirano, Sae; Miyazaki, Yusuke; Hojo, Yuya; Suzuki, Hidetoshi; Morimoto, Eriko; Marui, Akira; Sakata, Ryuzo; Ueno, Morio; Kakeya, Hideaki; Wada, Hiromichi; Hasegawa, Koji; Morimoto, Tatsuya

    2014-01-01

    A natural p300-specific histone acetyltransferase inhibitor, curcumin, may have a therapeutic potential for heart failure. However, a study of curcumin to identify an appropriate dose for heart failure has yet to be performed. Rats were subjected to a left coronary artery ligation. One week later, rats with a moderate severity of myocardial infarction (MI) were randomly assigned to 4 groups receiving the following: a solvent as a control, a low dose of curcumin (0.5 mg∙kg(-1)∙day(-1)), a medium dose of curcumin (5 mg∙kg(-1)∙day(-1)), or a high dose of curcumin (50 mg∙kg(-1)∙day(-1)). Daily oral treatment was continued for 6 weeks. After treatment, left ventricular (LV) fractional shortening was dose-dependently improved in the high-dose (25.2% ± 1.6%, P < 0.001 vs. vehicle) and medium-dose (19.6% ± 2.4%) groups, but not in the low-dose group (15.5% ± 1.4%) compared with the vehicle group (15.1% ± 0.8%). The histological cardiomyocyte diameter and perivascular fibrosis as well as echocardiographic LV posterior wall thickness dose-dependently decreased in the groups receiving high and medium doses. The beneficial effects of oral curcumin on the post-MI LV systolic function are lower at 5 compared to 50 mg∙kg(-1)∙day(-1) and disappear at 0.5 mg∙kg(-1)∙day(-1). To clinically apply curcumin therapy for heart failure patients, a precise, optimal dose-setting study is required.

  3. An endogenous protectant effect of cardiac cyclic GMP against reperfusion-induced ventricular fibrillation in the rat heart.

    PubMed Central

    Pabla, R.; Bland-Ward, P.; Moore, P. K.; Curtis, M. J.

    1995-01-01

    1. After a period of myocardial ischaemia, reperfusion of the myocardium can elicit cardiac arrhythmias. Susceptibility to these arrhythmias declines with time, such that a preceding period of more than approximately 40 min ischaemia is associated with few reperfusion-induced arrhythmias. We have tested the hypothesis that this decline in susceptibility occurs, in part, because of protection by endogenous guanosine 3':5'-cyclic monophosphate (cyclic GMP). 2. Rat isolated hearts were subjected to 60 min left regional ischaemia followed by reperfusion (n = 10 per group). Methylene blue (20 microM), a soluble guanylate cyclase inhibitor, raised the incidence of reperfusion-induced ventricular fibrillation (VF) from 10% in control hearts to 80% (P < 0.05). This effect of methylene blue was abolished by co-perfusion with zaprinast (100 microM), a phosphodiesterase inhibitor which, in the rat heart, is cyclic GMP-specific (specific for the type-V phosphodiesterase isozyme). 3. Methylene blue reduced cyclic GMP levels in the ischaemic, non-ischaemic and reperfused myocardium (P < 0.05) to 50 +/- 10, 52 +/- 12 and 70 +/- 7 fmol mg-1 tissue wet weight, respectively from control values of 143 +/- 38, 147 +/- 43 and 156 +/- 15 fmol mg-1. Co-perfusion with zaprinast prevented this effect, and cyclic GMP levels were actually elevated (P < 0.05) to 366 +/- 102, 396 +/- 130 and 293 +/- 22 fmol mg-1 in ischaemic, non-ischaemic and reperfused myocardium, respectively. Zaprinast by itself also elevated cyclic GMP content. Cyclic AMP levels were not affected by zaprinast or methylene blue. 4. In conclusion, when endogenous cardiac cyclic GMP synthesis is reduced, susceptibility to reperfusion-induced VF after sustained ischaemia is substantially increased. The effect is prevented by inhibiting cyclic GMP degradation. Therefore cyclic GMP appears to be an endogenous intracellular cardioprotectant, and its actions may account for the low susceptibility to VF normally encountered in

  4. IMPACT OF ISOPRENALINE AND CAFFEINE ON DEVELOPMENT OF LEFT VENTRICULAR HYPERTROPHY AND RENAL HEMODYNAMIC IN WISTAR KYOTO RATS.

    PubMed

    Ahmad, Ashfaq; Sattar, Munavvar Z A; Rathore, Hassaan A; Khan, Safia Akhtar; Lazhari, Mohammed A; Hashmi, Fayaz; Abdullah, Nor A; Johns, Edward J

    2015-01-01

    Left ventricular hypertrophy (LVH) is a compensatory mechanism in response to an increased work load on the heart. This study investigated the impact of chronic isoprenaline and caffeine (I/C model) administration on cardiac geometry, systemic hemodynamic and physiological data in rats as LVH develops. LVH was induced by administering isoprenaline (5 mg/kg s.c. every 72 h) and caffeine (62 mg/L) in drinking water for 14 days to Wistar Kyoto (WKY) rats. Mean arterial pressure (MAP), systolic blood pressure (SBP), heart weight, LV weight, LV chamber diameter and thickness of myocardium were observed as LVH indicators. MAP was significantly higher (142 ± 13 vs. 119 ± 2 mmHg, respectively) while heart rate (HR) in LVH was lower (314 ± 9 vs. 264 ± 18 BPM) compared to control WKY. Heart weight, LV weight and kidney weight were 31%, 38% and 7%, respectively, greater in the LVH group as compared to the control WKY (all p < 0.05).The myocardium thickness was 101% greater while LV chamber diameter was 44% smaller in the LVH group as compared to the control WKY (p < 0.05). The superoxide dismutase (SOD), glutathione reductase (GSH) and total antioxidant capacity (T-AOC) levels were significantly reduced while malonodialdehyde (MDA) level increased in LVH as compared to control WKY (all p < 0.05). In conclusion, isoprenaline and caffeine (I/C) induces LVH and cardiac hypertrophy with increases in blood pressure, fluid excretion and reduced renal hemodynamics. Prooxidant mechanism of the body and arterial stiffness are dominant in this disease model. This model of LVH is easily generated and associated with low mortality. PMID:26665409

  5. IMPACT OF ISOPRENALINE AND CAFFEINE ON DEVELOPMENT OF LEFT VENTRICULAR HYPERTROPHY AND RENAL HEMODYNAMIC IN WISTAR KYOTO RATS.

    PubMed

    Ahmad, Ashfaq; Sattar, Munavvar Z A; Rathore, Hassaan A; Khan, Safia Akhtar; Lazhari, Mohammed A; Hashmi, Fayaz; Abdullah, Nor A; Johns, Edward J

    2015-01-01

    Left ventricular hypertrophy (LVH) is a compensatory mechanism in response to an increased work load on the heart. This study investigated the impact of chronic isoprenaline and caffeine (I/C model) administration on cardiac geometry, systemic hemodynamic and physiological data in rats as LVH develops. LVH was induced by administering isoprenaline (5 mg/kg s.c. every 72 h) and caffeine (62 mg/L) in drinking water for 14 days to Wistar Kyoto (WKY) rats. Mean arterial pressure (MAP), systolic blood pressure (SBP), heart weight, LV weight, LV chamber diameter and thickness of myocardium were observed as LVH indicators. MAP was significantly higher (142 ± 13 vs. 119 ± 2 mmHg, respectively) while heart rate (HR) in LVH was lower (314 ± 9 vs. 264 ± 18 BPM) compared to control WKY. Heart weight, LV weight and kidney weight were 31%, 38% and 7%, respectively, greater in the LVH group as compared to the control WKY (all p < 0.05).The myocardium thickness was 101% greater while LV chamber diameter was 44% smaller in the LVH group as compared to the control WKY (p < 0.05). The superoxide dismutase (SOD), glutathione reductase (GSH) and total antioxidant capacity (T-AOC) levels were significantly reduced while malonodialdehyde (MDA) level increased in LVH as compared to control WKY (all p < 0.05). In conclusion, isoprenaline and caffeine (I/C) induces LVH and cardiac hypertrophy with increases in blood pressure, fluid excretion and reduced renal hemodynamics. Prooxidant mechanism of the body and arterial stiffness are dominant in this disease model. This model of LVH is easily generated and associated with low mortality.

  6. Neonatal olfactory bulbectomy enhances locomotor activity, exploratory behavior and binding of NMDA receptors in pre-pubertal rats.

    PubMed

    Flores, G; Ibañez-Sandoval, O; Silva-Gómez, A B; Camacho-Abrego, I; Rodríguez-Moreno, A; Morales-Medina, J C

    2014-02-14

    In this study, we investigated the effect of neonatal olfactory bulbectomy (nOBX) on behavioral paradigms related to olfaction such as exploratory behavior, locomotor activity in a novel environment and social interaction. We also studied the effect of nOBX on the activity of the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors during development. The behavioral effects of nOBX (postnatal day 7, PD7) were investigated in pre- (PD30) and post-pubertal (PD60) Wistar rats. NMDA receptor activity was measured with [(125)I]MK-801 in the brain regions associated with the olfactory circuitry. A significant increase in the novelty-induced locomotion was seen in the pre-pubertal nOBX rats. Although the locomotor effect was less marked than in pre-pubertal rats, the nOBX rats tested post-pubertally failed to habituate to the novel situation as quickly as the sham- and normal- controls. Pre-pubertally, the head-dipping behavior was enhanced in nOBX rats compared with sham-operated and normal controls, while normal exploratory behavior was observed between groups in adulthood. In contrast, social interaction was increased in post-pubertal animals that underwent nOBX. Both pre- and post-pubertal nOBX rats recovered olfaction. Interestingly, pre-pubertal rats showed a significant increase in the [(125)I]MK-801 binding in the piriform cortex, dorsal hippocampus, inner and outer layers of the frontal cortex and outer layer of the cingulate cortex. At post-pubertal age, no significant differences in [(125)I]MK-801 binding were observed between groups at any of the brain regions analyzed. These results suggest that nOBX produces pre-pubertal behavioral disturbances and NMDA receptor changes that are transitory with recovery of olfaction early in adulthood. PMID:24295633

  7. Neonatal olfactory bulbectomy enhances locomotor activity, exploratory behavior and binding of NMDA receptors in pre-pubertal rats.

    PubMed

    Flores, G; Ibañez-Sandoval, O; Silva-Gómez, A B; Camacho-Abrego, I; Rodríguez-Moreno, A; Morales-Medina, J C

    2014-02-14

    In this study, we investigated the effect of neonatal olfactory bulbectomy (nOBX) on behavioral paradigms related to olfaction such as exploratory behavior, locomotor activity in a novel environment and social interaction. We also studied the effect of nOBX on the activity of the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors during development. The behavioral effects of nOBX (postnatal day 7, PD7) were investigated in pre- (PD30) and post-pubertal (PD60) Wistar rats. NMDA receptor activity was measured with [(125)I]MK-801 in the brain regions associated with the olfactory circuitry. A significant increase in the novelty-induced locomotion was seen in the pre-pubertal nOBX rats. Although the locomotor effect was less marked than in pre-pubertal rats, the nOBX rats tested post-pubertally failed to habituate to the novel situation as quickly as the sham- and normal- controls. Pre-pubertally, the head-dipping behavior was enhanced in nOBX rats compared with sham-operated and normal controls, while normal exploratory behavior was observed between groups in adulthood. In contrast, social interaction was increased in post-pubertal animals that underwent nOBX. Both pre- and post-pubertal nOBX rats recovered olfaction. Interestingly, pre-pubertal rats showed a significant increase in the [(125)I]MK-801 binding in the piriform cortex, dorsal hippocampus, inner and outer layers of the frontal cortex and outer layer of the cingulate cortex. At post-pubertal age, no significant differences in [(125)I]MK-801 binding were observed between groups at any of the brain regions analyzed. These results suggest that nOBX produces pre-pubertal behavioral disturbances and NMDA receptor changes that are transitory with recovery of olfaction early in adulthood.

  8. ATP-sensitive K+ channels in rat ventricular myocytes are blocked and inactivated by internal divalent cations.

    PubMed

    Findlay, I

    1987-10-01

    K+ currents were recorded from ATP-sensitive channels in inside-out patches from isolated rat ventricular myocytes. In the absence of internal divalent cations the current voltage relationship could be described by constant-field assumptions with a permeability of 1.25 X 10(-13) cm2/s; outward currents saturated under a high driving force for K+ movement. Internal 0.1-5.0 mM Mg2+, 0.1 microM Ca2+ and 10 mM Na+ each depressed the flux of K+ ions moving outwards through open channels. Internal 0.1-5.0 mM Mg2+, 0.1-1.0 microM Ca2+ and 1-10 microM Ba2+ and Sr2+ blocked K+ channel activity in a dose- and voltage-dependent manner. Run-down channels could be reactivated by Mg-ATP, but not by AMP-PNP, ATP gamma S or Mg-free ATP which suggested that phosphorylation of the channels was involved in their activity. Ca2+ (greater than = 1 microM) and Sr2+ (1 mM) markedly inactivated K+ ATP channels, millimolar Ba2+ or Mg2+ were less effective. This suggested that the run down of the channels was a Ca2+-dependent dephosphorylation of the K+ channel protein.

  9. Hypoxia-inducible factor-1α and erythropoietin expression in the hippocampus of neonatal rats following hypoxia-ischemia.

    PubMed

    Lu, Junjie; Jiang, Li; Zhu, Huan; Zhang, Long; Wang, Ting

    2014-08-01

    In some regions of the hippocampus, neurogenesis persists throughout life and is upregulated following hypoxia/ischemia. The mechanisms underlying the upregulation of neurogenesis, however, are not known. Here we examined the expression of two factors thought to be involved in hypoxia-related neurogenesis, hypoxia-inducible factor-1α (HIF-1α) and brain-derived erythropoietin (EPO), in the hippocampus of neonatal rats following hypoxia-ischemia. Sprague-Dawley rat pups were exposed to hypoxia-ischemia conditions or hypoxia conditions only. For the hypoxia-ischemia experiment, the left common carotid artery of Sprague-Dawley rat pups was ligated on postnatal day 7. The pups were exposed to hypoxic conditions and then returned to normoxia for re-oxygenation. Immunohistochemical staining was performed to evaluate EPO and HIF-1α expression at various time points after re-oxygenation (1 h, 6 h, 16 h, 1 d, 3 d, and 7 d). EPO expression in the hippocampus was verified using Western blot studies. For the hypoxia-only experiment, postnatal day 7 rat pups were continuously exposed to hypoxic conditions for different durations (0.5 h, 1 h, 2 h, 3 h, and 5 h). HIF-1α expression in the hippocampus was evaluated by immunohistochemical staining. In the hypoxia-ischemia group, EPO expression was significantly altered. The EPO expression increased during re-oxygenation, peaked at 16 h, and decreased thereafter. In the hypoxia-only group, the EPO protein was not detectable. When the rat pups were returned to normoxia for re-oxygenation, there was no HIF-1α expression. HIF-1α immunoreactivity was present in the hypoxia-only group and peaked in rats exposed to continuous hypoxic conditions for 3 h. In addition, endogenous EPO increased in the neonatal rats after the hypoxia-ischemia event. Furthermore, HIF-1α was induced as a result of hypoxia. We postulate that disruption of homeostasis triggers and enhances hippocampal neurogenesis. Thus, HIF-1α/EPO hypoxic signal

  10. Acute third ventricular administration of leptin decreases protein and fat in self-selecting rats.

    PubMed

    Wetzler, Sandrine; Jean-Joseph, Gwladys; Even, Patrick; Tomé, Daniel; Larue-Achagiotis, Christiane

    2005-04-15

    The peripheral administration of leptin reduces food intake (FI) body weight gain (BWG) and modifies food choice. The aim of this study was to examine the effect of acute cerebral injections of leptin on food selection in rats. Male rats were first adapted to the food choice paradigm (protein, carbohydrate, fat) for 3 weeks. They were then implanted with a cannula in the third ventricle. Leptin (leptin group=L) or saline (control group=C) injections were performed at either the beginning or the end of the night at 4-day intervals. FI was recorded continuously, 3 days before, during and then after injections. Rats were sacrificed 86 h after the second injection. After both injections, BWG and FI were reduced. The reduction in FI concerned only nocturnal intake, whatever the timing of the injection. When the injection was given at the beginning of the night, the reductions after a 1-h latency period were -45% and -27.5% during the first and second days, respectively. Following the second injection, the same effects were observed immediately (-16% and -41%, respectively). Only the fat and protein intakes were significantly reduced. This lower FI was due to a reduction in meal size and duration. The reduction resulted in a lower BWG and total white adipose tissue mass. At the time of sacrifice, 6 h after food deprivation, leptinemia and insulinemia were reduced in leptin-treated rats. Glycemia values were identical. It was thus demonstrated that central leptin was a satiation factor rather than a satiety factor.

  11. Traditional formula, modern application: chinese medicine formula sini tang improves early ventricular remodeling and cardiac function after myocardial infarction in rats.

    PubMed

    Liu, Jiangang; Peter, Karoline; Shi, Dazhuo; Zhang, Lei; Dong, Guoju; Zhang, Dawu; Breiteneder, Heimo; Jakowitsch, Johannes; Ma, Yan

    2014-01-01

    SINI TANG (SNT) IS A TRADITIONAL CHINESE HERBAL FORMULA CONSISTING OF FOUR DIFFERENT HERBS: the root of Aconitum carmichaelii, the bark of Cinnamomum cassia, the rhizome of Zingiber officinale, and the root of Glycyrrhiza uralensis. This study aims to evaluate the improvement of early ventricular remodeling and cardiac function in myocardial infarction (MI) rats by SNT. A MI model was established by ligation of the left anterior descending coronary artery. Following treatment for 4 weeks, ultrasonic echocardiography was performed. Myocardial histopathological changes were observed using haematoxylin and eosin staining. Collagens (type I and type III), transforming growth factor- β 1 (TGF- β 1), and Toll-like receptors (TLR-2 and TLR-4) were measured in plasma, serum, and myocardial tissue. SNT treatment decreased the infarct size, the left ventricular cavity area/heart cavity area ratio, and the left ventricle dimension at end systole and increased the left ventricular ejection fraction. SNT reduced the levels of TLR-2 and TLR-4 in myocardial tissue significantly and decreased the collagens content in serum and in myocardial tissue. SNT could partially reduce the level of TGF- β 1 in serum and in myocardial tissue. Our data suggest that the Chinese medicine formula SNT has the potential to improve early ventricular remodeling and cardiac function after MI.

  12. Effects of Single Drug and Combined Short-term Administration of Sildenafil, Pimobendan, and Nicorandil on Right Ventricular Function in Rats With Monocrotaline-induced Pulmonary Hypertension

    PubMed Central

    Tanaka, Ryou; Yoshiyuki, Rieko; Fukayama, Toshiharu; Goya, Seijiro; Fukushima, Ryuji

    2015-01-01

    Abstract: This study was designed to assess the progression of pulmonary arterial hypertension (PAH) and the effectiveness of therapy using recently investigated echocardiographic parameters. PAH is characterized by the progressive elevation of pulmonary artery pressure and right ventricular hypertrophy and dysfunction, which ultimately results in right-sided heart failure and death. Echocardiography results and invasive measurements of right and left ventricular systolic pressures were compared after 3-week administrations of sildenafil (S group), pimobendan (P group), nicorandil (N group), and their combinations (SP and SPN groups) in male rats with monocrotaline (MCT)-induced pulmonary hypertension (M group) and without this condition (C group). The groups that received pimobendan alone and in combinations (SP and SPN groups) showed improvement in their echocardiographic parameters of systolic function. A significant improvement of diastolic function was achieved in the SPN group. Invasive measurements showed the most significant decreases of right ventricular systolic pressure in the N and SPN groups, and the use of pimobendan resulted in a comparatively low risk of adverse hemodynamic effects (left ventricular systolic pressure). Although our results suggested the attenuation of PAH severity in all treatment groups, PAH could not be reversed. PMID:25806612

  13. Effects of Single Drug and Combined Short-term Administration of Sildenafil, Pimobendan, and Nicorandil on Right Ventricular Function in Rats With Monocrotaline-induced Pulmonary Hypertension.

    PubMed

    Nakata, Telma M; Tanaka, Ryou; Yoshiyuki, Rieko; Fukayama, Toshiharu; Goya, Seijiro; Fukushima, Ryuji

    2015-06-01

    This study was designed to assess the progression of pulmonary arterial hypertension (PAH) and the effectiveness of therapy using recently investigated echocardiographic parameters. PAH is characterized by the progressive elevation of pulmonary artery pressure and right ventricular hypertrophy and dysfunction, which ultimately results in right-sided heart failure and death. Echocardiography results and invasive measurements of right and left ventricular systolic pressures were compared after 3-week administrations of sildenafil (S group), pimobendan (P group), nicorandil (N group), and their combinations (SP and SPN groups) in male rats with monocrotaline (MCT)-induced pulmonary hypertension (M group) and without this condition (C group). The groups that received pimobendan alone and in combinations (SP and SPN groups) showed improvement in their echocardiographic parameters of systolic function. A significant improvement of diastolic function was achieved in the SPN group. Invasive measurements showed the most significant decreases of right ventricular systolic pressure in the N and SPN groups, and the use of pimobendan resulted in a comparatively low risk of adverse hemodynamic effects (left ventricular systolic pressure). Although our results suggested the attenuation of PAH severity in all treatment groups, PAH could not be reversed.

  14. Alterations in stress-associated behaviors and neurochemical markers in adult rats after neonatal short-lasting local inflammatory insult.

    PubMed

    Anseloni, V C Z; He, F; Novikova, S I; Turnbach Robbins, M; Lidow, I A; Ennis, M; Lidow, M S

    2005-01-01

    Recently, there has been a growing interest in long-term consequences of neonatal pain because modern neonatal intensive care units routinely employ procedures that cause considerable pain and may be followed by local inflammation and hyperalgesia lasting for several hours or even days. To address this question, we developed a rat model of short lasting (<2 days) early local inflammatory insult produced by a single injection of 0.25% carrageenan (CAR) into the plantar surface of a hindpaw. Previously, we demonstrated that rats receiving this treatment within the first week after birth grow into adults with a global reduction in responsiveness to acute pain. Here, we report that these animals also manifest a low anxiety trait associated with reduced emotional responsiveness to stress. This conclusion is based in the following observations: (a) rats in our model display reduced anxiety on an elevated plus-maze; (b) in the forced swim test, these rats exhibit behavioral characteristics associated with stronger ability for stress coping; and (c) these animals have reduced basal and stress-induced plasma levels of such stress-related neuroendocrine markers as corticotropin-releasing factor, vasopressin, and adrenocorticotrophic hormone. In addition, we used DNA microarray and real-time reverse-transcriptase polymerase chain reaction to profile long-term changes in gene expression in the midbrain periaqueductal gray (PAG; a region involved in both stress and pain modulation) in our animal model. Among the affected genes, serotonergic receptors were particularly well represented. Specifically, we detected increase in the expression of 5-HT1A, 5-HT1D, 5-HT2A, 5-HT2C and 5-HT4 receptors. Several of these receptors are known to be involved in the anxiolytic and analgesic activity of the PAG. Finally, to determine whether neonatal inflammatory insult induces elevation in maternal care, which may play a role in generating long-term behavioral alterations seen in our model, we

  15. Influence of neonatal sevoflurane exposure on nerve development-related microRNAs and behavior of rats.

    PubMed

    Fujimoto, Saiko; Ishikawa, Masashi; Nagano, Masatoshi; Sakamoto, Atsuhiro

    2015-01-01

    Commonly used anesthetics adversely affect the developing brain, but the mechanisms remain unknown. We previously showed that the expressions of microRNAs (miRNAs) in major organs are affected by anesthetics. Therefore, we used TaqMan low-density array (TLDA) to analyze gene expression in the hippocampus of neonatal rats exposed to sevoflurane and performed behavioral tests after they reached adulthood to evaluate cognitive and memory function. Rat male pups at postnatal day 7 were exposed to 1.9% sevoflurane for 3 h, and the hippocampus-miRNA expression profile on postnatal day 8 was determined. Open field and fear conditioning tests conducted during postnatal weeks 7 and 8 indicated that sevoflurane-exposed rats, but not controls, exhibited anxiety-like disorders. TLDA analysis identified 20 differentially expressed miRNAs, which were not shared between postnatally and maturely sevoflurane-exposed rats. The level of rno-miR-632, which targets brain-derived neurotrophic factor and calcium channel, voltage-dependent, alpha 2/delta subunit 2, increased by 10-fold, indicating that exposure to sevoflurane during early neural development alters hippocampus-miRNA expression and may induce subsequent behavioral disorders. PMID:26700589

  16. TRPV1-mediated presynaptic transmission in basolateral amygdala contributes to visceral hypersensitivity in adult rats with neonatal maternal deprivation

    PubMed Central

    Xiao, Ying; Chen, Xiaoqi; Zhang, Ping-An; Xu, Qiya; Zheng, Hang; Xu, Guang-Yin

    2016-01-01

    The central mechanisms of visceral hypersensitivity remain largely unknown. It’s reported that there are highest densities of TRPV1 labeled neurons within basolateral amygdala (BLA). The aim of this study was to explore the role and mechanisms of TRPV1 in BLA in development of visceral hypersensitivity. Visceral hypersensitivity was induced by neonatal maternal deprivation (NMD) and was quantified by abdominal withdrawal reflex. Expression of TRPV1 was determined by Western blot. The synaptic transmission of neurons in BLA was recorded by patch clamping. It was found that the expression of TRPV1 in BLA was significantly upregulated in NMD rats; glutamatergic synaptic activities in BLA were increased in NMD rats; application of capsazepine (TRPV1 antagonist) decreased glutamatergic synaptic activities of BLA neurons in NMD slices through a presynaptic mechanism; application of capsaicin (TRPV1 agonist) increased glutamatergic synaptic activities of BLA neurons in control slices through presynaptic mechanism without affecting GABAergic synaptic activities; microinjecting capsazepine into BLA significantly increased colonic distension threshold both in control and NMD rats. Our data suggested that upregulation of TRPV1 in BLA contributes to visceral hypersensitivity of NMD rats through enhancing excitation of BLA, thus identifying a potential target for treatment of chronic visceral pain. PMID:27364923

  17. IN VITRO CONAZOLE EXPOSURE INHIBITS TESTOSTERONE PRODUCTION IN THE ADULT AND NEONATAL RAT TESTIS THROUGH THE INHIBITION OF CYP17 ACTIVITY

    EPA Science Inventory

    IN VITRO CONAZOLE EXPOSURE INHIBITS TESTOSTERONE PRODUCTION IN THE ADULT AND NEONATAL RAT TESTIS THROUGH THE INHIBITION OF CYP17 ACTIVITY

    Chad R. Blystone1, David J. Dix2, and John C. Rockett2
    1Department of Environmental and Molecular Toxicology, NC State University, R...

  18. NEONATAL LOW- AND HIGH-DOSE EXPOSURE TO ESTRADIOL BENZOATE IN THE MALE RAT: II. EFFECTS ON THE MALE PUBERTY AND THE REPRODUCTIVE TRACT

    EPA Science Inventory

    NEONATAL LOW- AND HIGH-DOSE EXPOSURE TO ESTRADIOL BENZOATE IN THE MALE RAT: II. EFFECTS ON MALE PUBERTY AND THE REPRODUCTIVE TRACT. Oliver Putz, Christian B. Schwartz, Gerald A. LeBlanc, Ralph L. Cooper, Gail S. Prins

    ABSTRACT
    Environmental contaminants with estrogen...

  19. Ramipril attenuates left ventricular remodeling by regulating the expression of activin A-follistatin in a rat model of heart failure

    PubMed Central

    Wei, Qun; Liu, Haiyan; Liu, Miao; Yang, Chunyan; Yang, Jie; Liu, Zhonghui; Yang, Ping

    2016-01-01

    Prior studies have shown that overexpression of ACT A can lead to ventricular remodeling in rat models of heart failure. Furthermore, recently work studying demonstrated that stimulation of activin An expression in rat aortic smooth muscle (RASM) cells by angiotensin II (Ang II). Ramipril is a recently developed angiotensin converting enzyme (ACE) inhibitor. To investigate the effects of Ramipril on expression of ACT A-FS, we established the rat model of heart failure after myocardial infarction (MI), and divided into either a sham operation (SO), MI, or MI-Ramipril group. We found that Ramipril significantly attenuates collagen-I and III deposition (col-I and III). Notably, we determined that expression of ACT A and II activin receptor (ActRII) were significantly down-regulated in the non-infarcted area of the left ventricle in the Ramipril group, whereas the mRNA and protein levels of FS were markedly up-regulated. Our data suggested that Ramipril benefited left ventricular remodeling by reducing fibrosis and collagen accumulation in the left ventricle of rats after myocardial infarction. This observation was also associated with down-regulation of ACT A expression. This study elucidated a new protective mechanism of Ramipril and suggests a novel strategy for treatment of post-infarct remodeling and subsequent heart failure. PMID:27642098

  20. Ramipril attenuates left ventricular remodeling by regulating the expression of activin A-follistatin in a rat model of heart failure.

    PubMed

    Wei, Qun; Liu, Haiyan; Liu, Miao; Yang, Chunyan; Yang, Jie; Liu, Zhonghui; Yang, Ping

    2016-01-01

    Prior studies have shown that overexpression of ACT A can lead to ventricular remodeling in rat models of heart failure. Furthermore, recently work studying demonstrated that stimulation of activin An expression in rat aortic smooth muscle (RASM) cells by angiotensin II (Ang II). Ramipril is a recently developed angiotensin converting enzyme (ACE) inhibitor. To investigate the effects of Ramipril on expression of ACT A-FS, we established the rat model of heart failure after myocardial infarction (MI), and divided into either a sham operation (SO), MI, or MI-Ramipril group. We found that Ramipril significantly attenuates collagen-I and III deposition (col-I and III). Notably, we determined that expression of ACT A and II activin receptor (ActRII) were significantly down-regulated in the non-infarcted area of the left ventricle in the Ramipril group, whereas the mRNA and protein levels of FS were markedly up-regulated. Our data suggested that Ramipril benefited left ventricular remodeling by reducing fibrosis and collagen accumulation in the left ventricle of rats after myocardial infarction. This observation was also associated with down-regulation of ACT A expression. This study elucidated a new protective mechanism of Ramipril and suggests a novel strategy for treatment of post-infarct remodeling and subsequent heart failure. PMID:27642098

  1. The influences of rearing environment and neonatal choline dietary supplementation on spatial learning and memory in adult rats.

    PubMed

    Tees, R C

    1999-11-15

    The facilitative effects of early environmental enrichment and perinatal choline chloride dietary supplementation on adult rat spatial learning and memory were examined using delayed match-to-place (DMTP) and delayed spatial win-shift (DSWSh) discrimination tasks. Animals were either maintained in a standard lighted colony (LR) or were given supplementary exposure to a complex environment (CR) for 2-h daily from 20 to 90 days of age. In each case, half the animals were exposed to the choline supplementation both prenatally (through the diet of pregnant rats) and postnatally (subcutaneous injection) for 24 days. In the first experiment, all 90-day-old rats were given trials in which they first found a hidden platform in a Morris water maze (MWM) in a particular location (acquisition trial), and then were required to remember that position 10 min later (test trial). Both environmental enrichment and early diet had significant impacts on performance. CR animals, given neonatal choline pretreatment, found the platform on test trials significantly faster than any of the other groups. CR animals exposed to the control saline diet showed better retention than did the LR animals given the early choline diet, which in turn, were superior to animals given neither environmental enrichment nor choline. All animals were subsequently tested in the same paradigm immediately following atropine sulfate injections. The atropine eliminated the difference between the four groups of animals on test trials. In a second experiment, both CR, and neonatal choline treatment facilitated performance on a DSWSh radial arm maze (RAM) task previously found to be sensitive to hippocampal and/or medial prefrontal lesions. Performance differences between groups were facilitated by the anticholinesterase drug, tacrine and attenuated by the cholinergic antagonist, Atropine. The present study extends the descriptions of long-term functional enhancements produced by perinatal choline supplementation

  2. Exposure to nitrous oxide stimulates a nitric oxide-dependent neuronal release of beta-endorphin in ventricular-cisternally-perfused rats.

    PubMed

    Zelinski, Lisa M; Ohgami, Yusuke; Quock, Raymond M

    2009-12-01

    We have previously shown that the antinociceptive effect of nitrous oxide (N(2)O) in the rat hot plate test is sensitive to antagonism by antisera against the endogenous opioid peptide beta-endorphin. Moreover, N(2)O-induced antinociception is reduced by inhibition of nitric oxide (NO) production in the brain. To test the hypothesis that N(2)O might stimulate an NO-dependent neuronal release of beta-endorphin, we conducted a ventricular-cisternal perfusion with artificial cerebrospinal fluid (aCSF) in urethane-anesthetized Sprague-Dawley rats. Ten-minute fractions of aCSF perfusate were collected from separate groups of room air-exposed rats, N(2)O-exposed rats, and L-NAME-pretreated, N(2)O-exposed rats; they were then analyzed for their content of NO metabolites and beta-endorphin. Compared to room air control, exposure to 70% N(2)O increased perfusate levels of the NO metabolites nitrite and nitrate as well as beta-endorphin. Pretreatment of rats with L-N(G)-nitro arginine methyl ester, an inhibitor of NO synthase, prevented the N(2)O-induced increases in nitrite, nitrate and beta-endorphin. These findings demonstrate in an in vivo rat model that N(2)O may stimulate an NO-dependent neuronal release of beta-endorphin. PMID:19747467

  3. Dehydroepiandrosterone reverses chronic hypoxia/reoxygenation-induced right ventricular dysfunction in rats.

    PubMed

    Dumas de La Roque, Eric; Bellance, Nadège; Rossignol, Rodrigue; Begueret, Hugues; Billaud, Marie; dos Santos, Pierre; Ducret, Thomas; Marthan, Roger; Dahan, Diana; Ramos-Barbón, David; Amor-Carro, Óscar; Savineau, Jean-Pierre; Fayon, Michael

    2012-12-01

    Dehydroepiandrosterone (DHEA) prevents chronic hypoxia-induced pulmonary hypertension and associated right ventricle dysfunction in rats. In this animal model, reoxygenation following hypoxia reverses pulmonary hypertension but not right ventricle dysfunction. We thus studied the effect of DHEA on the right ventricle after reoxygenation, i.e. after a normoxic recovery phase secondary to chronic hypoxia in rats. Right ventricle function was assessed in vivo by Doppler echocardiography and in vitro by the isolated perfused heart technique in three groups of animals: control, recovery (21 days of hypoxia followed by 21 days of normoxia) and recovery DHEA (30 mg · kg(-1) every 2 days during the recovery phase). Right ventricle tissue was assessed by optical and electron microscopy. DHEA abolished right ventricle diastolic dysfunction, as the echographic E wave remained close to that of controls (mean ± SD 76.5 ± 2.4 and 79.7 ± 1.7 cm · s(-1), respectively), whereas it was diminished to 40.3 ± 3.7 in the recovery group. DHEA also abolished right ventricle systolic dysfunction, as shown by the inhibition of the increase in the slope of the pressure-volume curve in isolated heart. The DHEA effect was related to cardiac myocytes proliferation. In conclusion, DHEA prevents right ventricle dysfunction in this animal model by preventing cardiomyocyte alteration.

  4. Enhancement of contraction and L-type Ca(2+) current by murrayafoline-A via protein kinase C in rat ventricular myocytes.

    PubMed

    Chidipi, Bojjibabu; Son, Min-Jeong; Kim, Joon-Chul; Lee, Jeong Hyun; Toan, Tran Quoc; Cuong, Nguyen Manh; Lee, Byung Ho; Woo, Sun-Hee

    2016-08-01

    We previously reported that murrayafoline-A (1-methoxy-3-methyl-9H-carbazole, Mu-A) increases the contractility of ventricular myocytes, in part, via enhancing Ca(2+) influx through L-type Ca(2+) channels, and that it increases the Ca(2+) transients by activation of protein kinase C (PKC). In the present study, we further examined the cellular mechanisms for the enhancement of contractility and L-type Ca(2+) current (ICa,L) by Mu-A. Cell shortening and ICa,L were measured in rat ventricular myocytes using a video edge detection method and perforated patch-clamp technique, respectively. We found that the positive inotropic effect of Mu-A was not affected by pre-exposure to the β-adrenoceptor antagonist propranolol, the protein kinase A (PKA) inhibitors KT5720 or H-89, or the phospholipase C inhibitor U73122. Interestingly, the Mu-A-mediated increases in cell shortening and in the rate of contraction were completely suppressed by pre-treatment with the PKC inhibitor GF109203X. The stimulatory effect of Mu-A on ICa,L was not altered by inhibition of PKA (KT5720), G-protein coupled receptors (suramin), or α1-adrenoceptor (prazosin). However, pre-exposure to the PKC inhibitor, GF109203X or chelerythrine, abolished the Mu-A-induced increase in ICa,L. Pre-exposure to the Ca(2+)-calmodulin-dependent protein kinase II (CaMKII) inhibitor KN93 slightly reduced the stimulatory effects on contraction and ICa,L by Mu-A. Phosphorylation of PKC was enhanced by Mu-A in ventricular myocytes. These data suggest that Mu-A increases contraction and ICa,L via PKC in rat ventricular myocytes, and that the PKC-mediated responses in the presence of Mu-A may be partly mediated by CaMKII.

  5. Are there gender differences in left ventricular remodeling after myocardial infarction in rats?

    PubMed Central

    Antonio, Ednei Luiz; Serra, Andrey Jorge; dos Santos, Alexandra Alberta; Vieira, Stella Sousa; Silva, Jairo Montemor Augusto; Yoshizaki, Amanda; Sofia, Renato Rodrigues; Tucci, Paulo José Ferreira

    2015-01-01

    Objective An unclear issue is whether gender may influence at cardiac remodeling after myocardial infarction (MI). We evaluated left ventricle remodeling in female and male rats post-MI. Methods Rats were submitted to anterior descending coronary occlusion. Echocardiographic evaluations were performed on the first and sixth week post-occlusion to determine myocardial infarction size and left ventricle systolic function (FAC, fractional area change). Pulsed Doppler was applied to analyze left ventricle diastolic function using the following parameters: E wave, A wave, E/A ratio. Two-way ANOVA was applied for comparisons, complemented by the Bonferroni test. A P≤=0.05 was considered significant. Results There were no significant differences between genders for morphometric parameters on first (MI [Female (FE): 44.0±5.0 vs. Male (MA): 42.0±3.0%]; diastolic [FE: 0.04±0.003 vs. MA: 0.037±0.005, mm/g] and systolic [FE: 0.03±0.0004 vs. MA: 0.028±0.005, mm/g] diameters of left ventricle) and sixth (MI [FE: 44.0±5.0 vs. MA: 42.0±3.0, %]; diastolic [FE: 0.043±0.01 vs. MA: 0.034±0.005, mm/g] and systolic [FE: 0.035±0.01 vs. MA: 0.027±0.005, mm/g] of LV) week. Similar findings were reported for left ventricle functional parameters on first (FAC [FE: 34.0±6.0 vs. MA: 32.0±4.0, %]; wave E [FE: 70.0±18.0 vs. MA: 73.0±14.0, cm/s]; wave A [FE: 20.0±12.0 vs. MA: 28.0±13.0, cm/s]; E/A [FE: 4.9±3.4 vs. MA: 3.3±1.8]) and sixth (FAC [FE: 29.0±7.0 vs. MA: 31.0±7.0, %]; wave E [FE: 85.0±18.0 vs. MA: 87.0±20.0, cm/s]; wave A [FE: 20.0±11.0 vs. MA: 28.0±17.0, cm/s]; E/A [FE: 6.2±4.0 vs. MA: 4.6±3.4]) week. Conclusion Gender does not influence left ventricle remodeling post-MI in rats. PMID:25859870

  6. Neonatal handling and environmental enrichment increase the expression of GAP-43 in the hippocampus and promote cognitive abilities in prenatally stressed rat offspring.

    PubMed

    Zhang, Zhengyu; Zhang, Hua; Du, Baoling; Chen, Zhiqiang

    2012-07-26

    Neonatal handling and environmental enrichment have been used to aid the treatment and recovery of a diverse variety of brain dysfunctions. However, the underlying mechanism and the effects on cognitive function following neonatal handling and environmental enrichment are still unclear. In this study, we investigated GAP-43 protein levels in the hippocampus of prenatally stressed rat pups by Western blot on postnatal day (P) 10, P20 and P45. The cognitive ability of prenatally stressed rat pups was tested by using the Morris water maze on P45. GAP-43 protein levels were upregulated on P10 in the prenatal restraint stress (RS) group and the prenatal restraint stress plus neonatal handling and environmental enrichment (RE) group compared to the negative control (NC) group. However, the expression of GAP-43 in RS pups was lower on P20 and P45 than that in NC and RE pups. Exposure to prenatal stress prolonged average latency and total swim distance, but neonatal handling and environmental enrichment could reverse the change. Differences were also observed in the selection of search strategies. These results indicate that neonatal handling and environmental enrichment can improve the spatial learning and memory ability of prenatally stressed offspring, and the possible mechanism is the upregulation of GAP-43.

  7. Glutamate and glycine modulation of 3H-MK801 binding to the NMDA receptor-ion channel complex in the vitamin B-6 deficient neonatal rat brain

    SciTech Connect

    Guilarte, T.R. )

    1990-02-26

    The authors have previously shown that the concentrations of the neuroactive amino acids glutamate (GLU) and glycine (GLY) are significantly altered in the seizure-prone vitamin B-6 deficient neonatal rat brain. Recently, it has been shown that GLU and GLY modulate the binding of {sup 3}H-MK801 to the ion channel associated with the N-methyl-D-aspartate (NMDA)-glutamate receptor subtype. The present investigation was undertaken to determine if GLU or GLY modulation of {sup 3}H-MK801 binding was altered in B-6 deficient neonatal rat brain. Preparation of cortical membranes from control and deficient 14 day old rats and {sup 3}H-MK801 binding assay were done as described by Ransom and Stec. The results show a significant reduction in the potency and efficacy of GLU modulation of {sup 3}H-MK801 binding, as well as a reduction in the efficacy of GLY, in membrane preparations from deficient rats compared to controls. These results indicate a reduced ability of GLU and GLY to potentiate the binding of {sup 3}H-MK801 to the NMDA receptor-ion channel in the B-6 deficient neonatal rat brain.

  8. The consequences of prenatal and/or postnatal methamphetamine exposure on neonatal development and behaviour in rat offspring.

    PubMed

    McDonnell-Dowling, Kate; Kelly, John P

    2015-12-01

    Methamphetamine (MA) has become a popular drug of abuse in recent years not only in the general population but also amongst pregnant women. Although there is a growing body of preclinical investigations of MA exposure during pregnancy, there has been little investigation of the consequences of such exposure via the breast milk during the neonatal period. Therefore, the aim of this study was to determine the consequences of MA exposure during pregnancy and lactation on neurodevelopment and behaviour in the rat offspring. Pregnant Sprague-Dawley dams received MA (3.75 mg/kg) or control (distilled water) once daily via oral gavage from gestation day 7-21, postnatal day 1-21 or gestation day 7- postnatal day 21. A range of well-recognised neurodevelopmental parameters were examined in the offspring. Prenatal MA significantly reduced maternal weight gain, with a concomitant reduction in food intake. A significant increase in neonatal pup mortality was observed, being most marked in the prenatal/postnatal MA group. Significant impairments in neurodevelopmental parameters were also evident in all MA treatment groups including somatic development (e.g. pinna unfolding, fur appearance, eye opening) and behavioural development (e.g. surface righting, inclined plane test, forelimb grip). In conclusion, this study demonstrates that exposure to MA during any of these exposure periods (prenatal and/or postnatal) can have a profound effect on neonatal outcome, suggesting that regardless of the exposure period MA is associated with detrimental consequences in the offspring. These results indicate that in the clinical scenario, exposure during lactation needs to be considered when assessing the potential harmful effects of MA on offspring development. PMID:26391019

  9. The consequences of prenatal and/or postnatal methamphetamine exposure on neonatal development and behaviour in rat offspring.

    PubMed

    McDonnell-Dowling, Kate; Kelly, John P

    2015-12-01

    Methamphetamine (MA) has become a popular drug of abuse in recent years not only in the general population but also amongst pregnant women. Although there is a growing body of preclinical investigations of MA exposure during pregnancy, there has been little investigation of the consequences of such exposure via the breast milk during the neonatal period. Therefore, the aim of this study was to determine the consequences of MA exposure during pregnancy and lactation on neurodevelopment and behaviour in the rat offspring. Pregnant Sprague-Dawley dams received MA (3.75 mg/kg) or control (distilled water) once daily via oral gavage from gestation day 7-21, postnatal day 1-21 or gestation day 7- postnatal day 21. A range of well-recognised neurodevelopmental parameters were examined in the offspring. Prenatal MA significantly reduced maternal weight gain, with a concomitant reduction in food intake. A significant increase in neonatal pup mortality was observed, being most marked in the prenatal/postnatal MA group. Significant impairments in neurodevelopmental parameters were also evident in all MA treatment groups including somatic development (e.g. pinna unfolding, fur appearance, eye opening) and behavioural development (e.g. surface righting, inclined plane test, forelimb grip). In conclusion, this study demonstrates that exposure to MA during any of these exposure periods (prenatal and/or postnatal) can have a profound effect on neonatal outcome, suggesting that regardless of the exposure period MA is associated with detrimental consequences in the offspring. These results indicate that in the clinical scenario, exposure during lactation needs to be considered when assessing the potential harmful effects of MA on offspring development.

  10. Developmental changes in choline acetyltransferase and glutamate decarboxylase activity in various regions of the brain of the male, female, and neonatally androgenized female rat.

    PubMed

    Brown, R; Brooksbank, B W

    1979-04-01

    In attempt to discern effects of sex hormones on the development of neurotransmitter systems in the rat brain, choline acetyltransferase (ChAT) and glutamate decarboxylase (GAD) have been measured at postnatal days 8, 12, 25, and 60 in five regions (amygdala, anterior hypothalamus, hippocampus, olfactory bulbs, and cerebral cortex) of the brains of normal male, normal female, and neonatally androgen-treated female rats. Essentially no association between sex or of neonatal "androgenization" on either enzymol were found. The data, however, provide new information on the relative rates of development of ChAT and GAD in five regions of the rat brain which supplement the limited information already available in the literature. ChAT activity was highest in amygdala and hypothalamus, but developed most rapidly in hippocampus and cerebral cortex. The relative activities and patterns of development of GAD activity were similar to those of ChAT.

  11. Cardiotoxic Electrophysiological Effects of the Herbicide Roundup(®) in Rat and Rabbit Ventricular Myocardium In Vitro.

    PubMed

    Gress, Steeve; Lemoine, Sandrine; Puddu, Paolo-Emilio; Séralini, Gilles-Eric; Rouet, René

    2015-10-01

    Roundup (R), a glyphosate (G)-based herbicide (GBH), containing unknown adjuvants is widely dispersed around the world. Used principally by farmers, intoxications have increasingly been reported. We have studied R effects (containing 36 % of G) on right ventricular tissues (male Sprague-Dawley rats, up to 20,000 ppm and female New Zealand rabbits, at 25 and 50 ppm), to investigate R cardiac electrophysiological actions in vitro. We tested the reduced Ca(++) intracellular uptake mechanism as one potential cause of the electrical abnormalities after GBH superfusion, using the Na(+)/K(+)-ATPase inhibitor ouabain or the 1,4-dihydropyridine L-type calcium channel agonist BAY K 8644 which increases I Ca. R concentrations were selected based on human blood ranges found after acute intoxication. The study showed dose-dependent V max, APD50 and APD90 variations during 45 min of R superfusion. At the highest concentrations tested, there was a high incidence of conduction blocks, and 30-min washout with normal Tyrode solution did not restore excitability. We also observed an increased incidence of arrhythmias at different doses of R. Ouabain and BAY K 8644 prevented V max decrease, APD90 increase and the cardiac inexcitability induced by R 50 ppm. Glyphosate alone (18 and 180 ppm) had no significant electrophysiological effects. Thus, the action potential prolonging effect of R pointing to I Ca interference might explain both conduction blocks and proarrhythmia in vitro. These mechanisms may well be causative of QT prolongation, atrioventricular conduction blocks and arrhythmias in man after GBH acute intoxications as reported in retrospective hospital records.

  12. Simultaneous recording of ATP-sensitive K+ current and intracellular Ca2+ in anoxic rat ventricular myocytes. Effects of glibenclamide.

    PubMed

    Russ, U; Englert, H; Schölkens, B A; Gögelein, H

    1996-05-01

    We investigated the temporal relationship between the adenosine triphosphate-sensitive K current (KATP current), hypoxic shortening and Ca accumulation in cardiomyocytes exposed to anoxia or metabolic inhibition. Whole-cell, patch-clamp experiments were performed with nonstimulated isolated rat heart ventricular muscle cells loaded with the Ca-sensitive fluorescent dye 1-[2-(5-carboxyoxazol-2-yl)-6-aminobenzofuran-5-oxy]-2-(2'- amino-5'-methylphenoxy) ethane-N,N,N',N'-tetraacetic acid (fura-2) via the patch pipette. After approximately 8 min anoxia, the KATP current started to rise and reached a maximum of 21.3 +/- 3.7 nA (n = 5, recorded at 0 mV clamp potential) within 1-3 min. At that time hypoxic contracture also occurred. Resting cytoplasmic free calcium (Cai) did not change significantly before hypoxic shortening. After hypoxic contracture, the KATP current decreased and Cai started to rise, reaching about 1 micromol/l. The presence of glibenclamide (10 micromol/l) in the bath reduced the anoxia-induced KATP current by more than 50%, but did not significantly influence the time dependence of current, hypoxic shortening and Cai, or the magnitude of Cai. Metabolic inhibition with 1.5 mmol/l CN resulted in KATP current increase and hypoxic shortening, occurring somewhat earlier than under anoxia, but all other parameters were comparable. In non-patch-clamped cells loaded with fura-2 AM ester and field-stimulated with 1 Hz, 1 micronol/l glibenclamide had no significant effect on the magnitude of the Cai increase caused by exposure of the cells to 1.5 mmol/l CN-. After CN- wash-out in non-patch-clamped cells, Cai declined, oscillated and finally returned to control values. It can be concluded that glibenclamide inhibits anoxia-induced KATP currents only partially and has no significant effect on anoxia-induced rise in resting Cai.

  13. Changes of SERCA activity have only modest effects on sarcoplasmic reticulum Ca2+ content in rat ventricular myocytes.

    PubMed

    Bode, E F; Briston, S J; Overend, C L; O'Neill, S C; Trafford, A W; Eisner, D A

    2011-10-01

    Changes of the activity of the sarco-endoplasmic reticulum Ca(2+)-ATPase (SERCA) affect the amplitude of the systolic Ca(2+) transient and thence cardiac contractility. This is thought to be due to alterations of SR Ca(2+) content. Recent work on mice in which the expression of SERCA is decreased found that a large reduction of SERCA expression resulted in a proportionately much smaller decrease of SR Ca(2+) content. The aim of the current work was to investigate the quantitative nature of the dependence of both the amplitude of the systolic Ca(2+) transient and SR Ca(2+) content on SERCA activity during acute partial inhibition of SERCA. Experiments were performed on rat ventricular myocytes. Brief application of thapsigargin (1 μm) resulted in a decrease of SERCA activity as measured from the rate of decay of the systolic Ca(2+) transient. This was accompanied by a decrease in the amplitude of the systolic Ca(2+) transient which was linearly related to that of SERCA activity. However, the fractional decrease in the SR Ca(2+) content was much less than that of SERCA activity. On average SR Ca(2+) content was proportional to SERCA activity raised to the 0.38 ± 0.07 power. This shallow dependence of SR content on SERCA activity arises because Ca(2+) release is a steep function of SR Ca(2+) content. In contrast SR Ca(2+) content was increased 4.59 ± 0.40 (n = 8)-fold by decreasing ryanodine receptor opening with tetracaine (1 mm). Therefore a modest decrease of SR Ca(2+) content results in a proportionately larger fall of Ca(2+) release from the SR which can balance a larger initiating decrease of SERCA. In conclusion, the shallow dependence of SR Ca(2+) content on SERCA activity is expected for a system in which small changes of SR Ca(2+) content produce larger effects on the amplitude of the systolic Ca(2+) transient.

  14. Bumetanide enhances phenobarbital efficacy in a rat model of hypoxic neonatal seizures.

    PubMed

    Cleary, Ryan T; Sun, Hongyu; Huynh, Thanhthao; Manning, Simon M; Li, Yijun; Rotenberg, Alexander; Talos, Delia M; Kahle, Kristopher T; Jackson, Michele; Rakhade, Sanjay N; Berry, Gerard T; Berry, Gerard; Jensen, Frances E

    2013-01-01

    Neonatal seizures can be refractory to conventional anticonvulsants, and this may in part be due to a developmental increase in expression of the neuronal Na(+)-K(+)-2 Cl(-) cotransporter, NKCC1, and consequent paradoxical excitatory actions of GABAA receptors in the perinatal period. The most common cause of neonatal seizures is hypoxic encephalopathy, and here we show in an established model of neonatal hypoxia-induced seizures that the NKCC1 inhibitor, bumetanide, in combination with phenobarbital is significantly more effective than phenobarbital alone. A sensitive mass spectrometry assay revealed that bumetanide concentrations in serum and brain were dose-dependent, and the expression of NKCC1 protein transiently increased in cortex and hippocampus after hypoxic seizures. Importantly, the low doses of phenobarbital and bumetanide used in the study did not increase constitutive apoptosis, alone or in combination. Perforated patch clamp recordings from ex vivo hippocampal slices removed following seizures revealed that phenobarbital and bumetanide largely reversed seizure-induced changes in EGABA. Taken together, these data provide preclinical support for clinical trials of bumetanide in human neonates at risk for hypoxic encephalopathy and seizures.

  15. Effects of NaCl and sultopride on striatal [(3)H]spiperone binding in neonatal, adult and senescent rats.

    PubMed

    Makihata, J; Nomura, Y

    1984-01-01

    Effects of NaCl, (+)-and (-)-sultopride on striatal [(3)H]spiperone binding was investigated in 7-day, 70-day and 2-year-old rats. The amount of specific [(3)H]spiperone binding was the highest at 70 days and the value at adult stage was significantly (P < 0.001) higher than those at 7 days and 2 years. NaCl (100 mM) significantly increased [(3)H]spiperone binding in neonatal (P < 0.01), adult (P < 0.05) and senescent (P < 0.05) animals. Scatchard analysis showed that the Bmax of low-affinity [(3)H]spiperone binding was significantly elevated by 100 mM NaCl compared to the value in control of adult animals. More potent inhibition of (-)-sultopride for [(3)H]spiperone binding than that of the (+)-enantiomer at adult stage was also observed at neonatal and senescent stages. NaCl (100 mM) significantly enhanced inhibitory activities of (+)- and (-)-sultopride at every stage. It is suggested that stabilizing effect of Na(+) on dopamine (DA) receptor complexes and increasing effect of Na(+) on binding affinity of benzamide to DA2 receptors keep functions through development and aging.

  16. Maternal immune activation produces neonatal excitability defects in offspring hippocampal neurons from pregnant rats treated with poly I:C

    PubMed Central

    Patrich, Eti; Piontkewitz, Yael; Peretz, Asher; Weiner, Ina; Attali, Bernard

    2016-01-01

    Maternal immune activation (MIA) resulting from prenatal exposure to infectious pathogens or inflammatory stimuli is increasingly recognized to play an important etiological role in neuropsychiatric disorders with neurodevelopmental features. MIA in pregnant rodents induced by injection of the synthetic double-stranded RNA, Poly I:C, a mimic of viral infection, leads to a wide spectrum of behavioral abnormalities as well as structural and functional defects in the brain. Previous MIA studies using poly I:C prenatal treatment suggested that neurophysiological alterations occur in the hippocampus. However, these investigations used only juvenile or adult animals. We postulated that MIA-induced alterations could occur earlier at neonatal/early postnatal stages. Here we examined the neurophysiological properties of cultured pyramidal-like hippocampal neurons prepared from neonatal (P0-P2) offspring of pregnant rats injected with poly I:C. Offspring neurons from poly I:C-treated mothers exhibited significantly lower intrinsic excitability and stronger spike frequency adaptation, compared to saline. A similar lower intrinsic excitability was observed in CA1 pyramidal neurons from hippocampal slices of two weeks-old poly I:C offspring. Cultured hippocampal neurons also displayed lower frequency of spontaneous firing, higher charge transfer of IPSCs and larger amplitude of miniature IPSCs. Thus, maternal immune activation leads to strikingly early neurophysiological abnormalities in hippocampal neurons. PMID:26742695

  17. Minocycline Transiently Reduces Microglia/Macrophage Activation but Exacerbates Cognitive Deficits Following Repetitive Traumatic Brain Injury in the Neonatal Rat.

    PubMed

    Hanlon, Lauren A; Huh, Jimmy W; Raghupathi, Ramesh

    2016-03-01

    Elevated microglial/macrophage-associated biomarkers in the cerebrospinal fluid of infant victims of abusive head trauma (AHT) suggest that these cells play a role in the pathophysiology of the injury. In a model of AHT in 11-day-old rats, 3 impacts (24 hours apart) resulted in spatial learning and memory deficits and increased brain microglial/macrophage reactivity, traumatic axonal injury, neuronal degeneration, and cortical and white-matter atrophy. The antibiotic minocycline has been effective in decreasing injury-induced microglial/macrophage activation while simultaneously attenuating cellular and functional deficits in models of neonatal hypoxic ischemia, but the potential for this compound to rescue deficits after impact-based trauma to the immature brain remains unexplored. Acute minocycline administration in this model of AHT decreased microglial/macrophage reactivity in the corpus callosum of brain-injured animals at 3 days postinjury, but this effect was lost by 7 days postinjury. Additionally, minocycline treatment had no effect on traumatic axonal injury, neurodegeneration, tissue atrophy, or spatial learning deficits. Interestingly, minocycline-treated animals demonstrated exacerbated injury-induced spatial memory deficits. These results contrast with previous findings in other models of brain injury and suggest that minocycline is ineffective in reducing microglial/macrophage activation and ameliorating injury-induced deficits following repetitive neonatal traumatic brain injury. PMID:26825312

  18. Rat model of exercise-induced cardiac hypertrophy: hemodynamic characterization using left ventricular pressure-volume analysis.

    PubMed

    Radovits, Tamás; Oláh, Attila; Lux, Árpád; Németh, Balázs Tamás; Hidi, László; Birtalan, Ede; Kellermayer, Dalma; Mátyás, Csaba; Szabó, Gábor; Merkely, Béla

    2013-07-01

    Long-term exercise training is associated with characteristic structural and functional changes of the myocardium, termed athlete's heart. Several research groups investigated exercise training-induced left ventricular (LV) hypertrophy in animal models; however, only sporadic data exist about detailed hemodynamics. We aimed to provide functional characterization of exercise-induced cardiac hypertrophy in a rat model using the in vivo method of LV pressure-volume (P-V) analysis. After inducing LV hypertrophy by swim training, we assessed LV morphometry by echocardiography and performed LV P-V analysis using a pressure-conductance microcatheter to investigate in vivo cardiac function. Echocardiography showed LV hypertrophy (LV mass index: 2.41 ± 0.09 vs. 2.03 ± 0.08 g/kg, P < 0.01), which was confirmed by heart weight data and histomorphometry. Invasive hemodynamic measurements showed unaltered heart rate, arterial pressure, and LV end-diastolic volume along with decreased LV end-systolic volume, thus increased stroke volume and ejection fraction (73.7 ± 0.8 vs. 64.1 ± 1.5%, P < 0.01) in trained versus untrained control rats. The P-V loop-derived sensitive, load-independent contractility indexes, such as slope of end-systolic P-V relationship or preload recruitable stroke work (77.0 ± 6.8 vs. 54.3 ± 4.8 mmHg, P = 0.01) were found to be significantly increased. The observed improvement of ventriculoarterial coupling (0.37 ± 0.02 vs. 0.65 ± 0.08, P < 0.01), along with increased LV stroke work and mechanical efficiency, reflects improved mechanoenergetics of exercise-induced cardiac hypertrophy. Despite the significant hypertrophy, we observed unaltered LV stiffness (slope of end-diastolic P-V relationship: 0.043 ± 0.007 vs. 0.040 ± 0.006 mmHg/μl) and improved LV active relaxation (τ: 10.1 ± 0.6 vs. 11.9 ± 0.2 ms, P < 0.01). According to our knowledge, this is the first study that provides characterization of functional changes and hemodynamic relations in

  19. Mechanisms of induction and expression of long-term depression at GABAergic synapses in the neonatal rat hippocampus.

    PubMed

    Caillard, O; Ben-Ari, Y; Gaïarsa, J L

    1999-09-01

    Synaptic plasticity at excitatory glutamatergic synapses is believed to be instrumental in the maturation of neuronal networks. Using whole-cell patch-clamp recordings, we have studied the mechanisms of induction and expression of long-term depression at excitatory GABAergic synapses in the neonatal rat hippocampus (LTD(GABA-A)). We report that the induction of LTD(GABA-A) requires a GABA(A) receptor-mediated membrane depolarization, which is necessary to remove the Mg(2+) block from postsynaptic NMDA receptors. LTD(GABA-A) is associated with an increase in the coefficient of variation of evoked GABA(A) receptor-mediated synaptic currents and a decrease in the frequency, but not amplitude, of Sr(2+)-induced asynchronous GABA(A) quantal events. We conclude that LTD(GABA-A) induction requires the activation of both GABA(A) and NMDA postsynaptic receptors and that its expression is likely presynaptic.

  20. Intravenous Glial Growth Factor 2 (GGF2) Isoform of Neuregulin-1β Improves Left Ventricular Function, Gene and Protein Expression in Rats after Myocardial Infarction

    PubMed Central

    Murphy, Abigail; Smith, Holly M.; Galindo, Cristi L.; Pentassuglia, Laura; Peng, Xuyang; Lenneman, Carrie G.; Odiete, Oghenerukevwe; Friedman, David B.; Kronenberg, Marvin W.; Zheng, Siyuen; Zhao, Zhongming; Song, Yanna; Harrell, Frank E.; Srinivas, Maya; Ganguly, Anindita; Iaci, Jennifer; Parry, Tom J.; Caggiano, Anthony O.; Sawyer, Douglas B.

    2013-01-01

    Aims Recombinant Neuregulin (NRG)-1β has multiple beneficial effects on cardiac myocytes in culture, and has potential as a clinical therapy for heart failure (HF). A number of factors may influence the effect of NRG-1β on cardiac function via ErbB receptor coupling and expression. We examined the effect of the NRG-1β isoform, glial growth factor 2 (GGF2), in rats with myocardial infarction (MI) and determined the impact of high-fat diet as well as chronicity of disease on GGF2 induced improvement in left ventricular systolic function. Potential mechanisms for GGF2 effects on the remote myocardium were explored using microarray and proteomic analysis. Methods and Results Rats with MI were randomized to receive vehicle, 0.625 mg/kg, or 3.25 mg/kg GGF2 in the presence and absence of high-fat feeding beginning at day 7 post-MI and continuing for 4 weeks. Residual left ventricular (LV) function was improved in both of the GGF2 treatment groups compared with the vehicle treated MI group at 4 weeks of treatment as assessed by echocardiography. High-fat diet did not prevent the effects of high dose GGF2. In experiments where treatment was delayed until 8 weeks after MI, high but not low dose GGF2 treatment was associated with improved systolic function. mRNA and protein expression analysis of remote left ventricular tissue revealed a number of changes in myocardial gene and protein expression altered by MI that were normalized by GGF2 treatment, many of which are involved in energy production. Conclusions This study demonstrates that in rats with MI induced systolic dysfunction, GGF2 treatment improves cardiac function. There are differences in sensitivity of the myocardium to GGF2 effects when administered early vs. late post-MI that may be important to consider in the development of GGF2 in humans. PMID:23437060

  1. Effects of neonatal allopregnanolone manipulations and early maternal separation on adult alcohol intake and monoamine levels in ventral striatum of male rats.

    PubMed

    Llidó, Anna; Bartolomé, Iris; Darbra, Sònia; Pallarès, Marc

    2016-06-01

    Changes in endogenous neonatal levels of the neurosteroid allopregnanolone (AlloP) as well as a single 24h period of early maternal separation (EMS) on postnatal day (PND) 9 affect the development of the central nervous system (CNS), causing adolescent/adult alterations including systems and behavioural traits that could be related to vulnerability to drug abuse. In rats, some behavioural alterations caused by EMS can be neutralised by previous administration of AlloP. Thus, the aim of the present work is to analyse if manipulations of neonatal AlloP could increase adult alcohol consumption, and if EMS could change these effects. We administered AlloP or finasteride, a 5α-reductase inhibitor, from PND5 to PND9, followed by 24h of EMS at PND9. At PND70 we measured alcohol consumption using a two-bottle free-choice model (ethanol 10% (v/v)+glucose 3% (w/v), and glucose 3% (w/v)) for 15days. Ventral striatum samples were obtained to determine monoamine levels. Results revealed that neonatal finasteride increased both ethanol and glucose consumption, and AlloP increased alcohol intake compared with neonatal vehicle-injected animals. The differences between neonatal groups in alcohol consumption were not found in EMS animals. In accordance, both finasteride and AlloP animals that did not suffer EMS showed lower levels of dopamine and serotonin in ventral striatum. Taken together, these results reveal that neonatal neurosteroids alterations affect alcohol intake; an effect which can be modified by subsequent EMS. Thus, these data corroborate the importance of the relationship between neonatal neurosteroids and neonatal stress for the correct CNS development.

  2. Effects of neonatal allopregnanolone manipulations and early maternal separation on adult alcohol intake and monoamine levels in ventral striatum of male rats.

    PubMed

    Llidó, Anna; Bartolomé, Iris; Darbra, Sònia; Pallarès, Marc

    2016-06-01

    Changes in endogenous neonatal levels of the neurosteroid allopregnanolone (AlloP) as well as a single 24h period of early maternal separation (EMS) on postnatal day (PND) 9 affect the development of the central nervous system (CNS), causing adolescent/adult alterations including systems and behavioural traits that could be related to vulnerability to drug abuse. In rats, some behavioural alterations caused by EMS can be neutralised by previous administration of AlloP. Thus, the aim of the present work is to analyse if manipulations of neonatal AlloP could increase adult alcohol consumption, and if EMS could change these effects. We administered AlloP or finasteride, a 5α-reductase inhibitor, from PND5 to PND9, followed by 24h of EMS at PND9. At PND70 we measured alcohol consumption using a two-bottle free-choice model (ethanol 10% (v/v)+glucose 3% (w/v), and glucose 3% (w/v)) for 15days. Ventral striatum samples were obtained to determine monoamine levels. Results revealed that neonatal finasteride increased both ethanol and glucose consumption,