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Sample records for 6-ohda-lesioned rat model

  1. RGS4 is involved in the generation of abnormal involuntary movements in the unilateral 6-OHDA-lesioned rat model of Parkinson's disease.

    PubMed

    Ko, Wai Kin D; Martin-Negrier, Marie-Laure; Bezard, Erwan; Crossman, Alan R; Ravenscroft, Paula

    2014-10-01

    Regulators of G-protein signalling (RGS) proteins are implicated in striatal G-protein coupled receptor (GPCR) sensitisation in the pathophysiology of l-DOPA-induced abnormal involuntary movements (AIMs), also known as dyskinesia (LID), in Parkinson's disease (PD). In this study, we investigated RGS protein subtype 4 in the expression of AIMs in the unilateral 6-hydroxydopamine (6-OHDA)-lesioned rat model of LID. The effects of RGS4 antisense brain infusion on the behavioural and molecular correlates of l-DOPA priming in 6-OHDA-lesioned rats were assessed. In situ hybridisation revealed that repeated l-DOPA/benserazide treatment caused an elevation of RGS4 mRNA levels in the striatum, predominantly in the lateral regions. The increased expression of RGS4 mRNA in the rostral striatum was found to positively correlate with the behavioural (AIM scores) and molecular (pre-proenkephalin B, PPE-B expression) markers of LID. We found that suppressing the elevation of RGS4 mRNA in the striatum by continuous infusion of RGS4 antisense oligonucleotides, via implanted osmotic mini-pumps, during l-DOPA priming, reduced the induction of AIMs. Moreover, ex vivo analyses of the rostral dorsolateral striatum showed that RGS4 antisense infusion attenuated l-DOPA-induced elevations of PPE-B mRNA and dopamine-stimulated [(35)S]GTPγS binding, a marker used for measuring dopamine receptor super-sensitivity. Taken together, these data suggest that (i) RGS4 proteins play an important pathophysiological role in the development and expression of LID and (ii) suppressing the elevation of RGS4 mRNA levels in l-DOPA priming attenuates the associated pathological changes in LID, dampening its physiological expression. Thus, modulating RGS4 proteins could prove beneficial in the treatment of dyskinesia in PD. PMID:24969021

  2. Unprecedented Therapeutic Potential with a Combination of A2A/NR2B Receptor Antagonists as Observed in the 6-OHDA Lesioned Rat Model of Parkinson's Disease

    PubMed Central

    Michel, Anne; Downey, Patrick; Nicolas, Jean-Marie; Scheller, Dieter

    2014-01-01

    In Parkinson's disease, the long-term use of dopamine replacing agents is associated with the development of motor complications; therefore, there is a need for non-dopaminergic drugs. This study evaluated the potential therapeutic impact of six different NR2B and A2A receptor antagonists given either alone or in combination in unilateral 6-OHDA-lesioned rats without (monotherapy) or with (add-on therapy) the co-administration of L-Dopa: Sch-58261+ Merck 22; Sch-58261+Co-101244; Preladenant + Merck 22; Preladenant + Radiprodil; Tozadenant + Radiprodil; Istradefylline + Co-101244. Animals given monotherapy were assessed on distance traveled and rearing, whereas those given add-on therapy were assessed on contralateral rotations. Three-way mixed ANOVA were conducted to assess the main effect of each drug separately and to determine whether any interaction between two drugs was additive or synergistic. Additional post hoc analyses were conducted to compare the effect of the combination with the effect of the drugs alone. Motor activity improved significantly and was sustained for longer when the drugs were given in combination than when administered separately at the same dose. Similarly, when tested as add-on treatment to L-Dopa, the combinations resulted in higher levels of contralateral rotation in comparison to the single drugs. Of special interest, the activity observed with some combinations could not be described by a simplistic additive effect and involved more subtle synergistic pharmacological interactions. The combined administration of A2A/NR2B-receptor antagonists improved motor behaviour in 6-OHDA rats. Given the proven translatability of this model such a combination may be expected to be effective in improving motor symptoms in patients. PMID:25513815

  3. Alternative splicing of AMPA receptor subunits in the 6-OHDA-lesioned rat model of Parkinson's disease and L-DOPA-induced dyskinesia.

    PubMed

    Kobylecki, Christopher; Crossman, Alan R; Ravenscroft, Paula

    2013-09-01

    Abnormal corticostriatal plasticity is a key mechanism of L-DOPA-induced dyskinesia (LID) in Parkinson's disease (PD). Antagonists at glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, such as IEM 1460, reduce induction and expression of dyskinesia in rat and non-human primate models of PD. AMPA receptor function is regulated by post-transcriptional splicing of subunit mRNA to produce flip and flop isoforms, which may therefore influence corticostriatal plasticity. The aim of this work was to evaluate alterations in alternative splicing of striatal AMPA receptor subunits in the unilateral 6-hydroxydopamine (6-OHDA)-lesioned rat model of LID and PD. Male Sprague-Dawley rats received 12.5 μg 6-OHDA injections into the right medial forebrain bundle. In experiment 1, to assess acute dyskinesia, rats received L-DOPA/benserazide (6/15 mg/kg, i.p.) or vehicle for 21 days. In experiment 2, to assess dyskinesia priming, rats received vehicle, L-DOPA+vehicle or L-DOPA+IEM 1460 (3 mg/kg, i.p.) for 21 days. Animals were humanely killed 1h following final treatment in experiment 1, and 48 h following final treatment in experiment 2. Coronal sections of rostral striatum were processed for in situ hybridisation histochemistry, using oligonucleotide probes specific for the GluR1 and GluR2 subunits and their flip and flop isoforms. L-DOPA treatment increased GluR2-flip mRNA expression in the lesioned striatum of both groups; this was blocked by the Ca(2+)-permeable AMPA receptor antagonist IEM 1460. GluR1-flip expression was increased after 48 h drug washout but not in acute LID. There were no changes in expression of flop isoforms. Alternative splicing of AMPAR subunits contributes to abnormal striatal plasticity in the induction and expression of LID. Increases in GluR2-flip expression depend on activation of Ca(2+)-permeable AMPA receptors, which are a potential target of anti-dyskinetic therapies. PMID:23360800

  4. Embryonic MGE Precursor Cells Grafted into Adult Rat Striatum Integrate and Ameliorate Motor Symptoms in 6-OHDA-Lesioned Rats

    PubMed Central

    Martínez-Cerdeño, Verónica; Noctor, Stephen C.; Espinosa, Ana; Ariza, Jeanelle; Parker, Philip; Orasji, Samantha; Daadi, Marcel M.; Bankiewicz, Krystof; Alvarez-Buylla, Arturo; Kriegstein, Arnold R.

    2014-01-01

    SUMMARY We investigated a strategy to ameliorate the motor symptoms of rats that received 6-hydroxydopamine (6-OHDA) lesions, a rodent model of Parkinson’s disease, through transplantation of embryonic medial ganglionic eminence (MGE) cells into the striatum. During brain development, embryonic MGE cells migrate into the striatum and neocortex where they mature into GABAergic interneurons and play a key role in establishing the balance between excitation and inhibition. Unlike most other embryonic neurons, MGE cells retain the capacity for migration and integration when transplanted into the postnatal and adult brain. We performed MGE cell transplantation into the basal ganglia of control and 6-OHDA-lesioned rats. Transplanted MGE cells survived, differentiated into GABA+ neurons, integrated into host circuitry, and modifed motor behavior in both lesioned and control rats. Our data suggest that MGE cell transplantation into the striatum is a promising approach to investigate the potential benefits of remodeling basal ganglia circuitry in neurodegenerative diseases. PMID:20207227

  5. ACTIVATION OF PPAR GAMMA RECEPTORS REDUCES LEVODOPA-INDUCED DYSKINESIAS IN 6-OHDA-LESIONED RATS

    PubMed Central

    Martinez, A. A.; Morgese, M. G.; Pisanu, A.; Macheda, T.; Paquette, M. A.; Seillier, A.; Cassano, T.; Carta, A.R.; Giuffrida, A.

    2014-01-01

    Long-term administration of L-3,4-dihydroxyphenylalanine (levodopa), the mainstay treatment for Parkinson’s disease (PD), is accompanied by fluctuations in its duration of action and motor complications (dyskinesia) that dramatically affect the quality of life of patients. Levodopa-induced dyskinesias (LID) can be modeled in rats with unilateral 6-OHDA lesions via chronic administration of levodopa, which causes increasingly severe axial, limb and oro-facial abnormal involuntary movements (AIMs) over time. In previous studies, we showed that direct activation of CB1 cannabinoid receptors alleviated rat AIMs. Interestingly, elevation of the endocannabinoid anandamide by URB597 (URB), an inhibitor of endocannabinoid catabolism, produced an anti-dyskinetic response that was only partially mediated via CB1 receptors and required the concomitant blockade of transient receptor potential vanilloid type-1 (TRPV1) channels by capsazepine (CPZ) [1]. In this study, we showed that stimulation of peroxisome proliferator-activated receptors (PPAR), a family of transcription factors activated by anandamide, contributes to the anti-dyskinetic effects of URB+CPZ, and that direct activation of the PPARγ subtype by rosiglitazone (RGZ) alleviates levodopa-induced AIMs in 6-OHDA rats. AIM reduction was associated with an attenuation of levodopa-induced increase of dynorphin, zif-268 and of ERK phosphorylation in the denervated striatum. RGZ treatment did not decrease striatal levodopa and dopamine bioavailability, nor did it affect levodopa antiparkinsonian activity. Collectively, these data indicate that PPARγ may represent a new pharmacological target for the treatment of LID. PMID:25486547

  6. Behavioural Assessment of the A2a/NR2B Combination in the Unilateral 6-OHDA-Lesioned Rat Model: A New Method to Examine the Therapeutic Potential of Non-Dopaminergic Drugs.

    PubMed

    Michel, Anne; Downey, Patrick; Van Damme, Xavier; De Wolf, Catherine; Schwarting, Rainer; Scheller, Dieter

    2015-01-01

    In Parkinson's disease (PD), dopaminergic therapies are often associated with the development of motor complications. Attention has therefore been focused on the use of non-dopaminergic drugs. This study developed a new behavioural method capable of demonstrating the added value of combining adenosinergic and glutamatergic receptor antagonists in unilateral 6-OHDA lesioned rats. Rats were dosed orally with Tozadenant, a selective A2A receptor antagonist, and three different doses of Radiprodil, an NR2B-selective NMDA receptor antagonist. The drugs were given alone or in combination and rats were placed in an open-field for behavioural monitoring. Video recordings were automatically analysed. Five different behaviours were scored: distance traveled, ipsi- and contraversive turns, body position, and space occupancy. The results show that A2A or NR2B receptor antagonists given alone or in combination did not produce enhanced turning as observed with an active dose of L-Dopa/benserazide. Instead the treated rats maintained a straight body position, were able to shift from one direction to the other and occupied a significantly larger space in the arena. The highest "Tozadenant/Radiprodil" dose combination significantly increased all five behavioural parameters recorded compared to rats treated with vehicle or the same doses of the drugs alone. Our data suggest that the A2A/NR2B antagonist combination may be able to stimulate motor activity to a similar level as that achieved by L-Dopa but in the absence of the side-effects that are associated with dopaminergic hyperstimulation. If these results translate into the clinic, this combination could represent an alternative symptomatic treatment option for PD. PMID:26322641

  7. The effects of subthalamic deep brain stimulation on mechanical and thermal thresholds in 6OHDA-lesioned rats.

    PubMed

    Gee, Lucy E; Chen, Nita; Ramirez-Zamora, Adolfo; Shin, Damian S; Pilitsis, Julie G

    2015-08-01

    Chronic pain is a major complaint for up to 85% of Parkinson's disease patients; however, it often not identified as a symptom of Parkinson's disease. Adequate treatment of motor symptoms often provides analgesic effects in Parkinson's patients but how this occurs remains unclear. Studies have shown both Parkinson's patients and 6-hydroxydopamine-lesioned rats exhibit decreased sensory thresholds. In humans, some show improvements in these deficits after subthalamic deep brain stimulation, while others report no change. Differing methods of testing and response criteria may explain these varying results. We examined this effect in 6-hydroxydopamine-lesioned rats. Sprague-Dawley rats were unilaterally implanted with subthalamic stimulating electrodes in the lesioned right hemisphere and sensory thresholds were tested using von Frey, tail-flick and hot-plate tests. Tests were done during and off subthalamic stimulation at 50 and 150 Hz to assess its effects on sensory thresholds. The 6-hydroxydopamine-lesioned animals exhibited lower mechanical (left paw, P < 0.01) and thermal thresholds than shams (hot plate, P < 0.05). Both 50 and 150 Hz increased mechanical (left paw; P < 0.01) and thermal thresholds in 6-hydroxydopamine-lesioned rats (hot-plate test: 150 Hz, P < 0.05, 50 Hz, P < 0.01). Interestingly, during von Frey testing, low-frequency stimulation provided a more robust improvement in some 6OHDA lesioned rats, while in others, the magnitude of improvement on high-frequency stimulation was greater. This study shows that subthalamic deep brain stimulation improves mechanical allodynia and thermal hyperalgesia in 6-hydroxydopamine-lesioned animals at both high and low frequencies. Furthermore, we suggest considering using low-frequency stimulation when treating Parkinson's patients where pain remains the predominant complaint. PMID:26082992

  8. Nitrosative and cognitive effects of chronic L-DOPA administration in rats with intra-nigral 6-OHDA lesion.

    PubMed

    Ramírez-García, G; Palafox-Sánchez, V; Limón, I D

    2015-04-01

    Besides motor disturbances, other symptoms found in the early stage of Parkinson's disease (PD) are deficits in both learning and memory. The nigro-striatal-cortical pathway is affected in this pathology, with this neuronal circuit involved in cognitive processes such as spatial working memory (SWM). However, cognitive dysfunction appears even when the patients are receiving L-DOPA treatment. There is evidence that the dopamine metabolism formed by L-DOPA generates free radicals such as nitric oxide, which may cause damage through the nitrosative stress (NS). The aim of this study was to evaluate both the effects of chronic L-DOPA administration on SWM and the production of NS in rats using an intra-nigral lesion caused by 6-hydroxydopamine (6-OHDA). Post-lesion, the animals were administered orally with L-DOPA/Carbidopa (100-mg/kg) for 20 days. An SWM task in a Morris water maze was conducted post-treatment. Nitrite levels and immunoreactivity of 3-Nitrotyrosine (3-NT), Inducible Nitric Oxide Synthase (iNOS), Glial Fibrillary Acidic Protein (GFAP), and Tyrosine Hydroxylase (TH) were evaluated in the substantia nigra pars compacta, the dorsal striatum and the medial prefrontal cortex. Our results show that chronic L-DOPA administration in rats with intra-nigral 6-OHDA-lesion caused significant increases in SWM deficit, nitrite levels and the immunoreactivity of 3-NT, iNOS and GFAP in the nigro-striatal-cortical pathway. These facts suggest that as L-DOPA can induce NS in rats with dopaminergic intra-nigral lesion, it could play a key role in the impairment of the SWM, and thus can be considered as a toxic mechanism that induces cognitive deficit in PD patients. PMID:25644418

  9. Molsidomine, a nitric oxide donor, modulates rotational behavior and monoamine metabolism in 6-OHDA lesioned rats treated chronically with L-DOPA.

    PubMed

    Lorenc-Koci, Elżbieta; Czarnecka, Anna; Lenda, Tomasz; Kamińska, Kinga; Konieczny, Jolanta

    2013-12-01

    Some biochemical and histological studies of Parkinson's disease patients' brains and 6-OHDA-lesioned rats suggest that dopaminergic dennervation of the striatum leads to the nitrergic system hypofunction in this structure. Hence, recently the modulation of nitric oxide (NO)- soluble guanylyl cyclase-cyclic GMP signaling is considered to be a new target for the treatment of Parkinson's disease. The aim of our study was to examine the impact of chronic combined treatment with low doses of the NO donor molsidomine (2 and 4mg/kg) and L-DOPA (12.5 and 25mg/kg) on rotational behavior and monoamine metabolism in the striatum (STR) and substantia nigra (SN) of unilaterally 6-OHDA-lesioned rats. Chronic administration of molsidomine at a dose of 2mg/kg jointly with 25mg/kg of L-DOPA significantly decreased the number of contralateral rotations when compared to L-DOPA alone. Other combinations of the examined drug doses were less effective. The tissue DA levels in the ipsilateral STR and SN after the last chronic doses of molsidomine (2mg/kg) and L-DOPA (12.5 or 25mg/kg), were significantly higher than after L-DOPA alone. Chronic L-DOPA treatment alone or jointly with a lower dose of molsidomine decreased 5-HT levels and accelerated its catabolism in the examined structures. However, combination of a higher dose of molsidomine with L-DOPA (25mg/kg) did not reduce 5-HT content while its catabolism was less intensive. The obtained results show that low doses of molsidomine can modulate rotational behavior and tissue DA and 5-HT concentrations in the STR and SN of 6-OHDA-lesioned rats treated chronically with L-DOPA. PMID:24090640

  10. Temporal Dissociation of Striatum and Prefrontal Cortex Uncouples Anhedonia and Defense Behaviors Relevant to Depression in 6-OHDA-Lesioned Rats.

    PubMed

    Matheus, Filipe C; Rial, Daniel; Real, Joana I; Lemos, Cristina; Takahashi, Reinaldo N; Bertoglio, Leandro J; Cunha, Rodrigo A; Prediger, Rui D

    2016-08-01

    The dorsolateral striatum (DLS) processes motor and non-motor functions and undergoes extensive dopaminergic degeneration in Parkinson's disease (PD). The nigrostriatal dopaminergic degeneration also affects other brain areas including the pre-frontal cortex (PFC), which has been associated with the appearance of anhedonia and depression at pre-motor phases of PD. Using behavioral, neurochemical, and electrophysiological approaches, we investigated the temporal dissociation between the role of the DLS and PFC in the appearance of anhedonia and defense behaviors relevant to depression in rats submitted to bilateral DLS lesions with 6-hydroxydopamine (6-OHDA; 10 μg/hemisphere). 6-OHDA induced partial dopaminergic nigrostriatal damage with no gross motor impairments. Anhedonic-like behaviors were observed in the splash and sucrose consumption tests only 7 days after 6-OHDA lesion. By contrast, defense behaviors relevant to depression evaluated in the forced swimming test and social withdrawal only emerged 21 days after 6-OHDA lesion when anhedonia was no longer present. These temporally dissociated behavioral alterations were coupled to temporal- and structure-dependent alterations in dopaminergic markers such as dopamine D1 and D2 receptors and dopamine transporter, leading to altered dopamine sensitivity in DLS and PFC circuits, evaluated electrophysiologically. These results provide the first demonstration of a dissociated involvement of the DLS and PFC in anhedonic-like and defense behaviors relevant to depression in 6-OHDA-lesioned rats, which was linked with temporal fluctuations in dopaminergic receptor density, leading to altered dopaminergic system sensitivity in these two brain structures. This sheds new light to the duality between depressive and anhedonic symptoms in PD. PMID:26164273

  11. The CB1 cannabinoid receptor agonist reduces L-DOPA-induced motor fluctuation and ERK1/2 phosphorylation in 6-OHDA-lesioned rats

    PubMed Central

    Song, Lu; Yang, Xinxin; Ma, Yaping; Wu, Na; Liu, Zhenguo

    2014-01-01

    The dopamine precursor L-3,4-dihydroxyphenylalanine (L-DOPA) has been used as an effective drug for treating dopamine depletion-induced Parkinson’s disease (PD). However, long-term administration of L-DOPA produces motor complications. L-DOPA has also been found to modify the two key signaling cascades, protein kinase A/dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) and extracellular signal-regulated kinases 1 and 2 (ERK1/2), in striatal neurons, which are thought to play a pivotal role in forming motor complications. In the present study, we tested the possible effect of a CB1 cannabinoid receptor agonist on L-DOPA-stimulated abnormal behavioral and signaling responses in vivo. Intermittent L-DOPA administration for 3 weeks induced motor fluctuation in a rat model of PD induced by intrastriatal infusion of dopamine-depleting neurotoxin 6-hydroxydopamine (6-OHDA). A single injection of a CB1 cannabinoid receptor agonist WIN-55,212-2 had no effect on L-DOPA-induced motor fluctuation. However, chronic injections of WIN-55,212-2 significantly attenuated abnormal behavioral responses to L-DOPA in 6-OHDA-lesioned rats. Similarly, chronic injections of WIN-55,212-2 influence the L-DOPA-induced alteration of DARPP-32 and ERK1/2 phosphorylation status in striatal neurons. These data provide evidence for the active involvement of CB1 cannabinoid receptors in the regulation of L-DOPA action during PD therapy. PMID:25395834

  12. Counteraction by nitric oxide synthase inhibitor of neurochemical alterations of dopaminergic system in 6-OHDA-lesioned rats under L-DOPA treatment.

    PubMed

    Del-Bel, Elaine; Padovan-Neto, Fernando Eduardo; Szawka, Raphael Escorsim; da-Silva, Célia Aparecida; Raisman-Vozari, Rita; Anselmo-Franci, Janete; Romano-Dutra, Angélica Caroline; Guimaraes, Francisco Silveira

    2014-01-01

    Nitric oxide synthase inhibitors reduce L-3, (Del-Bel et al., Cell Mol Neurobiol 25(2):371-392, 2005) 4-dihydroxyphenylalanine (L-DOPA)-induced abnormal motor effects subsequent to depletion of dopaminergic neurons in rodents and non-human primates. The present study used quantitative high-performance liquid chromatography to analyze, for the first time, dopamine metabolism in striatum of rats in order to elucidate the mechanism of action of the nitric oxide synthase inhibitors. Adult male Wistar rats received unilateral microinjection of saline (sham) or 6-hydroxydopamine (6-OHDA-lesioned) in the medial forebrain bundle. Past 3 weeks, rats were treated during 21 days with L-DOPA/benserazide (30 mg/kg/7.5 mg/kg, respectively, daily). On the 22nd day rats received an intraperitoneal (i.p.) injection of either vehicle or 7-nitroindazole, a preferential neuronal nitric oxide synthase inhibitor before L-DOPA. Abnormal involuntary movements and rotarod test were assessed as behavioral correlate of motor responses. Lesion intensity was evaluated through tyrosine hydroxylase immunohystochemical reaction. Dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and an extent of dopamine striatal tissue levels/dopamine metabolism were measured in the striatum. Lesion with 6-OHDA decreased dopamine, DOPAC, and DOPAC/dopamine ratio in the lesioned striatum. L-DOPA treatment induced abnormal involuntary movements and increased DOPAC/dopamine ratio (nearly five times) in the lesioned striatum. L-DOPA-induced dyskinesia was mitigated by 7-nitroindazole, which also decreased dopamine turnover, dopamine and DOPAC levels. Our results revealed an almost two times increase in dopamine content in the non-lesioned striatum of 6-OHDA-lesioned rats. Reduction of striatal DOPAC/dopamine ratio in dyskinetic rats may suggest an increase in the dopamine availability. Our data confirm contribution of nitrergic transmission in the pathogenesis of L-DOPA-induced dyskinesia with potential

  13. The effect of additional noradrenergic and serotonergic depletion on a lateralised choice reaction time task in rats with nigral 6-OHDA lesions.

    PubMed

    Lindgren, Hanna S; Demirbugen, Merve; Bergqvist, Filip; Lane, Emma L; Dunnett, Stephen B

    2014-03-01

    Parkinson's disease (PD) patients often suffer from visuospatial deficits, which have been considered a disruption of the representation of external space. The lateralised choice reaction time (CRT) task is an operant task for rodents in which similar deficits can be assessed. It has been demonstrated that specific parameters in this task is disrupted after unilateral injections of 6-hydroxydopamine (6-OHDA), which have been associated with the dopamine (DA) depletion that inevitably follows this type of lesion. However, studies have demonstrated that this type of lesion also affects the serotonergic (5HT) and noradrenergic (NA) systems. However, the impact of these systems on parameters in the CRT task had not yet been investigated. To this end, rats were pretrained on the CRT task before receiving selective lesions of the DAergic system, either alone or in combination with depletion of the NA or 5HT system. All rats with a 6-OHDA lesion displayed a gradual decline in the selection, initiation and execution of lateralised movements compared to sham-lesion controls on the side contralateral to the lesion. They also displayed a reduced number of useable trials as well as an increased number of procedural errors. Interestingly, the group with an additional noradrenergic lesion was significantly slower in reacting to lateralised stimuli throughout the testing period compared to the other two groups with a 6-OHDA lesion. There was however no difference between the three different lesion groups in the other parameters assessed in the task. These data confirm previous findings demonstrating that the majority of the parameters assessed in the lateralised CRT task are strongly dependent on DA. However, this study has also shown that the NAergic system may play an important role in contributing to the attentive performance influencing the capacity to react to the presented lateralised stimuli. PMID:24333808

  14. LPA signaling is required for dopaminergic neuron development and is reduced through low expression of the LPA1 receptor in a 6-OHDA lesion model of Parkinson's disease.

    PubMed

    Yang, Xiao-Yun; Zhao, Ethan Y; Zhuang, Wen-Xin; Sun, Feng-Xiang; Han, Hai-Lin; Han, Hui-Rong; Lin, Zhi-Juan; Pan, Zhi-Fang; Qu, Mei-Hua; Zeng, Xian-Wei; Ding, Yuchuan

    2015-11-01

    Lysophosphatidic acid (LPA) is a bioactive phospholipid that activates at least five known G-protein-coupled receptors (GPCRs): LPA1-LPA5. The nervous system is a major locus for LPA1 expression. LPA has been shown to regulate neuronal proliferation, migration, and differentiation during central nervous system development as well as neuronal survival. Furthermore, deficient LPA signaling has been implicated in several neurological disorders including neuropathic pain and schizophrenia. Parkinson's disease (PD) is a neurodegenerative movement disorder that results from the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). The specific molecular pathways that lead to DA neuron degeneration, however, are poorly understood. The influence of LPA in the differentiation of mesenchymal stem cells (MSCs) into DA neurons in vitro and LPA1 expression in a 6-hydroxydopamine (6-OHDA) lesion model of PD in vivo were examined in the present study. LPA induced neuronal differentiation in 80.2 % of the MSC population. These MSCs developed characteristic neuronal morphology and expressed the neuronal marker, neuron-specific enolase (NSE), while expression of the glial marker, glial fibrillary acidic protein (GFAP), was absent. Moreover, 27.6 % of differentiated MSCs were positive for tyrosine hydroxylase (TH), a marker for DA neurons. In the 6-OHDA PD rat model, LPA1 expression in the substantia nigra was significantly reduced compared to control. These results suggest LPA signaling via activation of LPA1 may be necessary for DA neuron development and survival. Furthermore, reduced LPA/LPA1 signaling may be involved in DA neuron degeneration thus contributing to the pathogenesis of PD. PMID:26169757

  15. COMPARISON OF THE D1-DOPAMINE AGONIST SKF-38393 AND A-68930 IN NEONATAL 6-OHDA-LESIONED RATS: BEHAVIORAL EFFECTS AND INDUCTION OF C-FOS-LIKE IMMUNOREACTIVITY

    EPA Science Inventory

    Previous studies from this laboratory and others have found that neonatal 6-OHDA-lesioned rats exhibit profound behavioral manifestations, and significant induction of striatal c-fos-like immunoreactivity (FLI), when administered the selective D1-dopamine agonist SKF-38393. ith t...

  16. Decreased synaptic plasticity in the medial prefrontal cortex underlies short-term memory deficits in 6-OHDA-lesioned rats.

    PubMed

    Matheus, Filipe C; Rial, Daniel; Real, Joana I; Lemos, Cristina; Ben, Juliana; Guaita, Gisele O; Pita, Inês R; Sequeira, Ana C; Pereira, Frederico C; Walz, Roger; Takahashi, Reinaldo N; Bertoglio, Leandro J; Da Cunha, Cláudio; Cunha, Rodrigo A; Prediger, Rui D

    2016-03-15

    Parkinson's disease (PD) is characterized by motor dysfunction associated with dopaminergic degeneration in the dorsolateral striatum (DLS). However, motor symptoms in PD are often preceded by short-term memory deficits, which have been argued to involve deregulation of medial prefrontal cortex (mPFC). We now used a 6-hydroxydopamine (6-OHDA) rat PD model to explore if alterations of synaptic plasticity in DLS and mPFC underlie short-term memory impairments in PD prodrome. The bilateral injection of 6-OHDA (20μg/hemisphere) in the DLS caused a marked loss of dopaminergic neurons in the substantia nigra (>80%) and decreased monoamine levels in the striatum and PFC, accompanied by motor deficits evaluated after 21 days in the open field and accelerated rotarod. A lower dose of 6-OHDA (10μg/hemisphere) only induced a partial degeneration (about 60%) of dopaminergic neurons in the substantia nigra with no gross motor impairments, thus mimicking an early premotor stage of PD. Notably, 6-OHDA (10μg)-lesioned rats displayed decreased monoamine levels in the PFC as well as short-term memory deficits evaluated in the novel object discrimination and in the modified Y-maze tasks; this was accompanied by a selective decrease in the amplitude of long-term potentiation in the mPFC, but not in DLS, without changes of synaptic transmission in either brain regions. These results indicate that the short-term memory dysfunction predating the motor alterations in the 6-OHDA model of PD is associated with selective changes of information processing in PFC circuits, typified by persistent changes of synaptic plasticity. PMID:26707254

  17. Intranasally applied L-DOPA alleviates parkinsonian symptoms in rats with unilateral nigro-striatal 6-OHDA lesions.

    PubMed

    Chao, Owen Y; Mattern, Claudia; Silva, Angelica M De Souza; Wessler, Janet; Ruocco, Lucia A; Nikolaus, Susanne; Huston, Joseph P; Pum, Martin E

    2012-02-10

    l-3,4-Dihydroxyphenylalanine (L-DOPA) remains the most effective drug for therapy of Parkinson's disease. However, the current clinical route of L-DOPA administration is variable and unreliable because of problems with drug absorption and first-pass metabolism. Administration of drugs via the nasal passage has been proven an effective alternate route for a number of medicinal substances. Here we examined the acute behavioral and neurochemical effects of intranasally (IN) applied L-DOPA in rats bearing unilateral lesions of the medial forebrain bundle, with severe depletion (97%) of striatal dopamine. Turning behavior in an open field, footslips on a horizontal grid and postural motor asymmetry in a cylinder were assessed following IN L-DOPA or vehicle administration with, or without, benserazide pre-treatment. IN L-DOPA without benserazide pre-treatment mildly decreased ipsilateral turnings and increased contralateral turnings 10-20 min after the treatment. IN L-DOPA with saline pre-treatment reduced contralateral forelimb-slips on the grid while no effects were evident in the cylinder test. These results support the hypothesis that L-DOPA can bypass the blood-brain barrier by the IN route and alleviate behavioral impairments in the hemiparkinsonian animal model. PMID:22108632

  18. Neuropathology and behavioral impairments in Wistar rats with a 6-OHDA lesion in the substantia nigra compacta and exposure to a static magnetic field.

    PubMed

    Bertolino, Guilherme; Dutra Souza, Hugo Celso; de Araujo, João Eduardo

    2013-12-01

    Studies have sought to assess various potential neuroprotective therapeutics in Parkinson's disease. The aim of this study was to evaluate the effects of static magnetic field stimulation 14 days after a 6-Hydroxydopamine (6-OHDA) substantia nigra compacta (SNc) lesion on motor behavior, as assessed by the rotarod (RR) test and brain tissue morphology. Forty male Wistar rats were used and were divided into five groups: control group, sham group (SG), lesion group (LG), lesion north pole group (LNPG) and lesion south pole group (LSPG). In groups with magnetic stimulation, a 3200-gauss magnet was fixed to the skull. After the experiments, the animals were anesthetized for brain perfusion. Coronal sections of the SNc were stained with Nissl. The RR test showed a decrease in the time spent on the apparatus in the LG compared with all groups. The LNPG and LSPG had significant increases in the time spent when compared to the LG. A morphometric analysis revealed a significant reduction in the number of neurons in the LG, LNPG and LSPG in relation to the SG. There were a higher number of neurons in the LNPG and LSPG than the LG, and a higher number of neurons in the LSPG than the LNPG. We observed that the LG, LNPG and LSPG showed a higher number of glial cells than the SG, and the LNPG and LSPG showed a lower number of glial cells than the LG. Our results demonstrate a potential therapeutic use of static magnetic fields for the preservation of motor behavior and brain morphology in the SNc after 14 days with 6-OHDA lesion. PMID:23631668

  19. Ontogenetic manganese exposure with perinatal 6-OHDA lesioning alters behavioral responses of rats to dopamine D₁ and D2 agonist treatments.

    PubMed

    Szkilnik, Ryszard; Brus, Ryszard; Malinowska-Borowska, Jolanta; Nowak, Damian; Waliczek, Martyna; Kostrzewa, Richard M; Nowak, Przemyslaw

    2014-01-01

    The effect of neonatal manganese (Mn) exposure in a 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease was investigated. Pregnant Wistar rats were given drinking water with 10,000 ppm of Manganese (MnCl₂.4H₂O) from the time of conception until weaning on the 21st day after delivery. Control rats consumed tap water. Three days after the birth, other groups of neonatal rat pups were pretreated with desipramine (20 mg/kg ip 1h) prior to bilateral ICV administration of 6-OHDA or its vehicle, saline-ascorbic (0.1%) (control). Two months after the birth, striatal dopamine and homovanilic acid efflux measured by an in vivo microdialysis method were reduced in rats lesioned with 6-OHDA. Co-exposure to perinatal Mn did not modify neurotransmission alterations. However, there were prominent abnormalities in behavioral testing in rats perinatally exposed to Mn and treated neonatally with 6-OHDA. These findings demonstrate that although Mn did not further damage neurotransmitter activity in the neostriatum, ontogenetic exposure to Mn enhances the behavioral toxicity to 6-OHDA. PMID:24295730

  20. Retigabine, a K(V)7 (KCNQ) potassium channel opener, attenuates L-DOPA-induced dyskinesias in 6-OHDA-lesioned rats.

    PubMed

    Sander, S E; Lemm, C; Lange, N; Hamann, M; Richter, A

    2012-02-01

    L-DOPA-induced dyskinesias (LID) represent a severe complication of long-time pharmacotherapy in Parkinson's disease that necessitates novel therapeutics. The acute and chronic effects of K(V)7.2-7.5 channel openers (retigabine, flupirtine) on the severity of LID and parkinsonian signs were examined in comparison to the glutamate receptor antagonist amantadine (positive control) in a rat model of LID. Acute treatment with retigabine (2.5, 5 mg/kg i.p.) and flupirtine (5, 10 mg/kg i.p.) significantly reduced the severity of abnormal involuntary movements (AIM) to a comparable extent as amantadine (20, 40 mg/kg s.c.), but flupirtine delayed the disappearance of AIM. Chronic treatment with retigabine (daily 5 mg/kg i.p. over 19 days combined with l-DOPA 10 mg i.p.) did not prevent or delay the development of LID, but reduced the severity of AIM, while antidyskinetic effects of amantadine (40 mg/kg i.p.) were restricted to the first day of treatment. Retigabine caused sedation and ataxia which declined during the chronic treatment, but did not reduce the antiparkinsonian effects of l-DOPA in these experiments. Acute co-injections of retigabine (5 mg) together with l-DOPA (10 mg/kg) neither reduced the motor performance in the rotarod test nor exerted negative effects on the antiparkinsonian efficacy of l-DOPA in the block and stepping test. Nevertheless, the sedative effects of retigabine may limit its therapeutic potential for the treatment of LID. The present data indicate that K(V)7 channels deserve attention in the research of the pathophysiology of dyskinesias. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'. PMID:22079161

  1. RNAi-mediated silencing of HLA A2 suppressed acute rejection against human fibroblast xenografts in the striatum of 6-OHDA lesioned rats.

    PubMed

    Liang, Caixia; Xu, Yunzhi; Zheng, Deyu; Sun, Xiaohong; Xu, Qunyuan; Duan, Deyi

    2016-08-15

    Major histocompatibility complex class l (MHC I) molecules play a role in determining whether transplanted cells will be accepted or rejected, and masking of MHC I on donor cells has been found useful for immunoprotection of neural xenografts. In the present study, primary human embryonic lung fibroblasts (HELF), HELF treated with lentivirus-mediated small interfering RNAs (siRNAs) targeting human leukocyte antigen A2 (HLA A2, MHC I in humans) (siHELF), and rat embryonic lung fibroblasts (RELF) were stereotaxically grafted into the striatum of 6-hydroxydopamine lesioned rats to explore whether knockdown of HLA A2 could reduce host immune responses against xenografts. Before lentiviral infection, the cells were transduced with retroviruses harboring tyrosine hydroxylase cDNA. Knockdown of HLA A2 protein was examined by Western blotting. The immune responses (the number of CD4 and CD8 T-cells in the brain and peripheral blood), glial reaction, and survival of human fibroblasts were quantitatively evaluated by flow cytometry and immunohistochemistry at 4d, 2w, and 6w post-graft. Animal behaviors were assessed by counting apomorphine-induced rotations pre- and post-grafts. It was shown that a lower level of HLA A2 was observed in siHELF grafts than in HELF grafts, and knockdown of HLA A2 decreased rat immune responses, as indicated by less remarkable increases in the number of CD8 and CD4 T-cells in the brain and the ratio of CD4:CD8 T-cells in the peripheral blood in rats grafted with siHELF. Rats grafted with siHELF exhibited a significant improvement in motor asymmetry post-transplantation and a better survival of human fibroblasts at 2w. The increasing number of activated microglia and the decreasing number of astrocytes were found in three groups of rats post-implantation. These data suggested that RNAi-mediated knockdown of HLA A2 could suppress acute rejection against xenogeneic human cell transplants in the rat brain. PMID:27397073

  2. Carbidopa-Based Modulation of the Functional Effect of the AAV2-hAADC Gene Therapy in 6-OHDA Lesioned Rats

    PubMed Central

    Forsayeth, John; Bankiewicz, Krystof

    2015-01-01

    Progressively blunted response to L-DOPA in Parkinson’s disease (PD) is a critical factor that complicates long-term pharmacotherapy in view of the central importance of this drug in management of the PD-related motor disturbance. This phenomenon is likely due to progressive loss of one of the key enzymes involved in the biosynthetic pathway for dopamine in the basal ganglia: aromatic L-amino acid decarboxylase (AADC). We have developed a gene therapy based on an adeno-associated virus encoding human AADC (AAV2-hAADC) infused into the Parkinsonian striatum. Although no adverse clinical effects of the AAV2-hAADC gene therapy have been observed so far, the ability to more precisely regulate transgene expression or transgene product activity could be an important long-term safety feature. The present study was designed to define pharmacological regulation of the functional activity of AAV2-hAADC transgene product by manipulating L-DOPA and carbidopa (AADC inhibitor) administration in hemi-parkinsonian rats. Thirty days after unilateral striatal infusion of AAV2-hAADC, animals displayed circling behavior and acceleration of dopamine metabolism in the lesioned striatum after administration of a low dose of L-DOPA (5 mg/kg) co-administered with 1.25 mg/kg of carbidopa. This phenomenon was not observed in control AAV2-GFP-treated rats. Withdrawal of carbidopa from a daily L-DOPA regimen decreased the peripheral L-DOPA pool, resulting in almost total loss of L-DOPA-induced behavioral response in AAV2-hAADC rats and a significant decline in striatal dopamine turnover. The serum L-DOPA level correlated with the magnitude of circling behavior in AAV2-hAADC rats. Additionally, AADC activity in homogenates of lesioned striata transduced by AAV2-AADC was 10-fold higher when compared with AAV2-GFP-treated control striata, confirming functional transduction. Our data suggests that the pharmacological regulation of circulating L-DOPA might be effective in the controlling of

  3. Carbidopa-based modulation of the functional effect of the AAV2-hAADC gene therapy in 6-OHDA lesioned rats.

    PubMed

    Ciesielska, Agnieszka; Sharma, Nitasha; Beyer, Janine; Forsayeth, John; Bankiewicz, Krystof

    2015-01-01

    Progressively blunted response to L-DOPA in Parkinson's disease (PD) is a critical factor that complicates long-term pharmacotherapy in view of the central importance of this drug in management of the PD-related motor disturbance. This phenomenon is likely due to progressive loss of one of the key enzymes involved in the biosynthetic pathway for dopamine in the basal ganglia: aromatic L-amino acid decarboxylase (AADC). We have developed a gene therapy based on an adeno-associated virus encoding human AADC (AAV2-hAADC) infused into the Parkinsonian striatum. Although no adverse clinical effects of the AAV2-hAADC gene therapy have been observed so far, the ability to more precisely regulate transgene expression or transgene product activity could be an important long-term safety feature. The present study was designed to define pharmacological regulation of the functional activity of AAV2-hAADC transgene product by manipulating L-DOPA and carbidopa (AADC inhibitor) administration in hemi-parkinsonian rats. Thirty days after unilateral striatal infusion of AAV2-hAADC, animals displayed circling behavior and acceleration of dopamine metabolism in the lesioned striatum after administration of a low dose of L-DOPA (5 mg/kg) co-administered with 1.25 mg/kg of carbidopa. This phenomenon was not observed in control AAV2-GFP-treated rats. Withdrawal of carbidopa from a daily L-DOPA regimen decreased the peripheral L-DOPA pool, resulting in almost total loss of L-DOPA-induced behavioral response in AAV2-hAADC rats and a significant decline in striatal dopamine turnover. The serum L-DOPA level correlated with the magnitude of circling behavior in AAV2-hAADC rats. Additionally, AADC activity in homogenates of lesioned striata transduced by AAV2-AADC was 10-fold higher when compared with AAV2-GFP-treated control striata, confirming functional transduction. Our data suggests that the pharmacological regulation of circulating L-DOPA might be effective in the controlling of

  4. Selective blockade of mGlu5 metabotropic glutamate receptors is protective against hepatic mitochondrial dysfunction in 6-OHDA lesioned Parkinsonian rats.

    PubMed

    Ferrigno, Andrea; Vairetti, Mariapia; Ambrosi, Giulia; Rizzo, Vittoria; Richelmi, Plinio; Blandini, Fabio; Fuzzati-Armentero, Marie-Therese

    2015-06-01

    Non-motor symptoms including those involving the splanchnic district are present in Parkinson's disease (PD). The authors previously reported that PD-like rats, bearing a lesion of the nigrostriatal pathway induced by the injection of 6-hydroxydopamine (6-OHDA), have impaired hepatic mitochondrial function. Glutamate intervenes at multiple levels in PD and liver pathophysiologies. The metabotropic glutamate receptor 5 (mGluR5) is abundantly expressed in brain and liver and may represent a pharmacological target for PD therapy. This study investigated whether and how chronic treatment with 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a well-characterized mGluR5 antagonist, may influence hepatic function with regard to neuronal cell loss in PD-like rats. Chronic treatment with MPEP was started immediately (Early) or 4 weeks after (Delayed) intrastriatal injection of 6-OHDA and lasted 4 weeks. Early MPEP treatment significantly prevented the decrease in adenosine triphosphate (ATP) production/content and counteracted increased reactive oxygen species (ROS) formation in isolated hepatic mitochondria of PD-like animals. Early MPEP administration also reduced the toxin-induced neurodegenerative process; improved survival of nigral dopaminergic neurons correlated with enhanced mitochondrial ATP content and production. ATP content/production, in turn, negatively correlated with ROS formation suggesting that the MPEP-dependent improvement in hepatic function positively influenced neuronal cell survival. Delayed MPEP treatment had no effect on hepatic mitochondrial function and neuronal cell loss. Antagonizing mGluR5 may synergistically act against neuronal cell loss and PD-related hepatic mitochondrial alterations and may represent an interesting alternative to non-dopaminergic therapeutic strategies for the treatment of PD. PMID:25904005

  5. The preferential nNOS inhibitor 7-nitroindazole and the non-selective one N(G)-nitro-L-arginine methyl ester administered alone or jointly with L-DOPA differentially affect motor behavior and monoamine metabolism in sham-operated and 6-OHDA-lesioned rats.

    PubMed

    Czarnecka, Anna; Konieczny, Jolanta; Lenda, Tomasz; Lorenc-Koci, Elżbieta

    2015-11-01

    Reciprocal interactions between nitrergic and dopaminergic systems play a key role in the control of motor behavior. In the present study, we performed a comparative analysis of motor behavior (locomotor activity, catalepsy, rotational behavior) and monoamine metabolism in the striatum and substantia nigra of unilaterally sham-operated and 6-OHDA-lesioned rats treated with the preferential neuronal nitric oxide synthase (nNOS) inhibitor 7-nitroindazole (7-NI) or the non-selective one N(G)-nitro-L-arginine methyl ester (L-NAME), alone or in combination with L-DOPA. Each NOS inhibitor given alone (50mg/kg) induced a distinct catalepsy 30 min after injection but only 7-NI impaired spontaneous locomotion after 10 min. In 6-OHDA-lesioned rats, chronic L-DOPA (25mg/kg) induced 2.5-h long contralateral rotations. 7-NI (30 and 50mg/kg) markedly reduced the intensity of L-DOPA-induced contralateral rotations while extending their duration until 4.5h whereas L-NAME (50 and 100mg/kg) only tended to attenuate their intensity without affecting the duration. 7-NI but not L-NAME significantly increased endogenous tissue DA levels in the nigrostriatal system of both sham-operated and 6-OHDA-lesioned rats. In L-DOPA-treated group, 7-NI significantly enhanced the L-DOPA-derived tissue DA content in this system and decreased the level of the intracellular DA metabolite DOPAC produced by monoamine oxidase (MAO). In contrast to 7-NI, L-NAME decreased markedly DA content and did not affect DOPAC level in the ipsilateral striatum. It means that the differences in 7-NI and L-NAME-mediated modulation of L-DOPA-induced behavioral and biochemical effects resulted not only from the inhibition of NOS activity but also from differences in their ability to inhibit MAO. PMID:26319690

  6. Neurotoxic effects of berberine on long-term L-DOPA administration in 6-hydroxydopamine-lesioned rat model of Parkinson's disease.

    PubMed

    Shin, Keon Sung; Choi, Hyun Sook; Zhao, Ting Ting; Suh, Kwang Hoon; Kwon, Ik Hyun; Choi, Soon Ok; Lee, Myung Koo

    2013-06-01

    The effects of berberine on long-term administration of L-DOPA in 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease (PD) were investigated. Rat models of PD were prepared by 6-OHDA lesions in the ipsilateral sides, and then were treated with berberine (5 and 15 mg/kg) and/or L-DOPA (10 mg/kg) once daily for 21 days. Treatments with either concentration of berberine (5 and 15 mg/kg) in 6-OHDA-lesioned groups decreased the numbers of tyrosine hydroxylase (TH)-immunopositive neurons in the substantia nigra and the levels of dopamine, norepinephrine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum as compared to 6-OHDA-lesioned groups. In addition, dopaminergic neuronal cell death of the ipsilateral sides in 6-OHDA-lesioned groups was attenuated by L-DOPA administration. However, both concentrations of berberine in 6-OHDA-lesioned groups treated with L-DOPA aggravated the numbers of TH-immunopositive neurons in the substantia nigra and the levels of dopamine, norepinephrine, DOPAC and HVA in the striatum as compared to rats not treated with berberine. These results suggest that berberine leads to the degeneration of dopaminergic neuronal cells in the substantia nigra in the rat model of PD with chronic L-DOPA administration. Long-term L-DOPA therapy that may involve possibly neurotoxic isoquinoline agents including berberine should involve monitoring for adverse symptoms. PMID:23539311

  7. Subtle Cardiovascular Dysfunction in the Unilateral 6-Hydroxydopamine-Lesioned Rat

    PubMed Central

    Slack, K.; Billing, R.; Matthews, S.; Allbutt, H. N.; Einstein, R.; Henderson, J. M.

    2010-01-01

    The present study evaluated whether the unilateral 6-hydroxydopamine (6-OHDA) model of Parkinson's disease produces autonomic deficits. Autonomic parameters were assessed by implanting a small radiofrequency telemetry device which measured heart rate variability (HRV), diurnal rhythms of heart rate (HR), core body temperature (cBT) and locomotor activity (LA). Rats then received 6-OHDA lesion or sham surgery. 6-OHDA lesioned rats exhibited head and body axis biases, defective sensorimotor function (“disengage” test), and prominent apomorphine rotation (all P < .05 versus controls). Diurnal rhythm of HR was lower for 6-OHDA lesioned rats (n = 8) versus controls (n = 6; P < .05). Whilst HR decreased similarly in both groups during the day, there was a greater decrease in HR for the 6-OHDA lesioned rats at night (by 38 b.p.m. relative to 17 b.p.m. for controls). LA and cBT did not differ between surgery groups. This study indicates the unilateral 6-OHDA model of PD shows subtle signs of cardiovascular autonomic dysfunction. PMID:20976085

  8. Intraventricular administration of endoneuraminidase-N facilitates ectopic migration of subventricular zone-derived neural progenitor cells into 6-OHDA lesioned striatum of mice.

    PubMed

    Li, Chen; Zhang, Yong-Xin; Yang, Chun; Hao, Fei; Chen, Sha-Sha; Hao, Qiang; Lu, Tao; Qu, Ting-Yu; Zhao, Li-Ru; Duan, Wei-Ming

    2016-03-01

    Polysialic acid (PSA), a carbohydrate polymer associated with the neural cell adhesion molecule (NCAM), plays an important role in the migration, differentiation and maturation of neuroblasts. Endoneuraminidase-N (Endo-N) can specifically cleave PSA from NCAM. The objective of the present study was to examine: the effect of Endo-N on characteristics of subventricular zone (SVZ)-derived neural progenitor cells (NPCs) in vitro; whether intraventricular administration of Endo-N could increase ectopic migration of SVZ-derived NPCs into 6-hydroxydopamine (6-OHDA)-lesioned striatum, and whether migrated NPCs could differentiate into neuronal and glial cells. In in vitro study, Endo-N was found to inhibit the migration of NPCs, and to enhance the differentiation of NPCs. In in vivo study, mice sequentially received injections of 6-OHDA into the right striatum, Endo-N into the right lateral ventricle, and bromodeoxyuridine (BrdU) intraperitoneally. The data showed that intraventricular injections of Endo-N disorganized the normal structure of the rostral migratory stream (RMS), and drastically increased the number of BrdU-immunoreactive (IR) cells in 6-OHDA-lesioned striatum. In addition, a number of BrdU-IR cells were double labeled for doublecortin (DCX), NeuN or glial fibrillary acidic protein (GFAP). The results suggest that interruption of neuroblast chain pathway with Endo-N facilitates ectopic migration of SVZ-derived NPCs into the lesioned striatum, and migrated NPCs can differentiate into neurons and astrocytes. PMID:26724216

  9. Interhemispheric modulation of dopamine receptor interactions in unilateral 6-OHDA rodent model.

    PubMed

    Lawler, C P; Gilmore, J H; Watts, V J; Walker, Q D; Southerland, S B; Cook, L L; Mathis, C A; Mailman, R B

    1995-12-01

    A critical assumption in the unilateral 6-hydroxydopamine (6-OHDA) model is that interactions between the intact and denervated hemispheres do not influence the response to insult. The present study examined this issue by assessing the effects of unilateral substantia nigra 6-OHDA lesions in rats that previously had received corpus callosum transections, a treatment designed to minimize interhemispheric influences. Quantitative autoradiography in the caudate-putamen ipsilateral to the lesion revealed that corpus callosum transection did not alter the increase in D2-like receptors ([125I]-epidepride-labeled sites) that is induced by unilateral 6-OHDA lesion. There were no effects of either 6-OHDA lesion or transection on D1 receptor density ([125I]-SCH23982 autoradiography). As a functional endpoint, dopamine-stimulated cAMP efflux was measured in superfused striatal slices. In this paradigm, the net effect of dopamine (DA) represents a combination of D1 receptor-mediated stimulation and D2 receptor-mediated inhibition. 6-OHDA lesion increased cAMP efflux induced by exposure to 100 microM DA alone; corpus callosum transection did not alter this effect. An interaction between 6-OHDA lesion and transection status was revealed, however, by comparison of results obtained with DA alone vs. DA plus the D2 antagonist sulpiride (to block the D2 inhibitory effects of 100 microM DA). This comparison revealed two important effects of 6-OHDA lesion in rats with an intact corpus callosum: 1) a moderate decrease in dopamine D1 receptor-mediated stimulation; and 2) a dramatic decrease in the ability of D2 receptors to inhibit this stimulation. Corpus callosum transection prevented these effects of 6-OHDA. These results provide a biochemical demonstration of D1:D2 receptor uncoupling in unilateral 6-OHDA lesioned rats, and suggest that interhemispheric influences (e.g., contralateral cortico-striatal glutamatergic projections) may contribute to lesion-induced alterations in D1:D2

  10. ALCAR Exerts Neuroprotective and Pro-Neurogenic Effects by Inhibition of Glial Activation and Oxidative Stress via Activation of the Wnt/β-Catenin Signaling in Parkinsonian Rats.

    PubMed

    Singh, Sonu; Mishra, Akanksha; Shukla, Shubha

    2016-09-01

    Oxidative stress and neuroinflammation are known causative factors in progressive degeneration of dopaminergic (DAergic) neurons in Parkinson's disease (PD). Neural stem cells (NSCs) contribute in maintaining brain plasticity; therefore, survival of NSCs and neuroblasts during neurodegenerative process becomes important in replenishing the pool of mature neuronal population. Acetyl-L-carnitine (ALCAR), present in almost all body cells, increases endogenous antioxidants and regulates bioenergetics. Currently, no information is available about the putative mechanism and neuroprotective effects of ALCAR in 6-hydroxydopamine (6-OHDA)-induced rat model of PD-like phenotypes. Herein, we investigated the effect of ALCAR on death/survival of DAergic neurons, neuroblasts and NSCs and associates mechanism of neuroprotection in 6-OHDA-induced rat model of PD-like phenotypes. ALCAR (100 mg/kg/day, intraperitoneal (i.p.)) treatment started 3 days prior to 6-OHDA lesioning and continued for another 14 day post-lesioning. We found that ALCAR pretreatment in 6-OHDA-lesioned rats increased expression of neurogenic and the Wnt pathway genes in the striatum and substantia nigra pars compacta (SNpc) region. It suppressed the glial cell activation, improved antioxidant status, increased NSC/neuroblast population and rescued the DAergic neurons in nigrostriatal pathway. ALCAR pretreatment in 6-OHDA-lesioned rats decreased GSK-3β activation and increased nuclear translocation of β-catenin. Functional deficits were restored following ALCAR pretreatment in 6-OHDA-lesioned rats as demonstrated by improved motor coordination and rotational behaviour, confirming protection of DAergic innervations in lesioned striatum. These results indicate that ALCAR exerts neuroprotective effects through the activation of Wnt/β-catenin pathway, suggesting its therapeutic use to treat neurodegenerative diseases by enhancing regenerative capacity. PMID:26223802

  11. Intracranial application of near-infrared light in a hemi-parkinsonian rat model: the impact on behavior and cell survival.

    PubMed

    Reinhart, Florian; Massri, Nabil El; Chabrol, Claude; Cretallaz, Celine; Johnstone, Daniel M; Torres, Napoleon; Darlot, Fannie; Costecalde, Thomas; Stone, Jonathan; Mitrofanis, John; Benabid, Alim-Louis; Moro, Cécile

    2016-06-01

    OBJECT The authors of this study used a newly developed intracranial optical fiber device to deliver near-infrared light (NIr) to the midbrain of 6-hydroxydopamine (6-OHDA)-lesioned rats, a model of Parkinson's disease. The authors explored whether NIr had any impact on apomorphine-induced turning behavior and whether it was neuroprotective. METHODS Two NIr powers (333 nW and 0.16 mW), modes of delivery (pulse and continuous), and total doses (634 mJ and 304 J) were tested, together with the feasibility of a midbrain implant site, one considered for later use in primates. Following a striatal 6-OHDA injection, the NIr optical fiber device was implanted surgically into the midline midbrain area of Wistar rats. Animals were tested for apomorphine-induced rotations, and then, 23 days later, their brains were aldehyde fixed for routine immunohistochemical analysis. RESULTS The results showed that there was no evidence of tissue toxicity by NIr in the midbrain. After 6-OHDA lesion, regardless of mode of delivery or total dose, NIr reduced apomorphine-induced rotations at the stronger, but not at the weaker, power. The authors found that neuroprotection, as assessed by tyrosine hydroxylase expression in midbrain dopaminergic cells, could account for some, but not all, of the observed behavioral improvements; the groups that were associated with fewer rotations did not all necessarily have a greater number of surviving cells. There may have been other "symptomatic" elements contributing to behavioral improvements in these rats. CONCLUSIONS In summary, when delivered at the appropriate power, delivery mode, and dosage, NIr treatment provided both improved behavior and neuroprotection in 6-OHDA-lesioned rats. PMID:26613166

  12. Neuroprotective Properties of the Standardized Extract from Camellia sinensis (Green Tea) and Its Main Bioactive Components, Epicatechin and Epigallocatechin Gallate, in the 6-OHDA Model of Parkinson's Disease

    PubMed Central

    Bitu Pinto, Natália; da Silva Alexandre, Bruno; Neves, Kelly Rose Tavares; Silva, Aline Holanda; Leal, Luzia Kalyne A. M.; Viana, Glauce S. B.

    2015-01-01

    Camellia sinensis (green tea) is largely consumed, mainly in Asia. It possesses several biological effects such as antioxidant and anti-inflammatory properties. The objectives were to investigate the neuroprotective actions of the standardized extract (CS), epicatechin (EC) and epigallocatechin gallate (EGCG), on a model of Parkinson's disease. Male Wistar rats were divided into SO (sham-operated controls), untreated 6-OHDA-lesioned and 6-OHDA-lesioned treated for 2 weeks with CS (25, 50, or 100 mg/kg), EC (10 mg/kg), or EGCG (10 mg/kg) groups. One hour after the last administration, animals were submitted to behavioral tests and euthanized and their striata and hippocampi were dissected for neurochemical (DA, DOPAC, and HVA) and antioxidant activity determinations, as well as immunohistochemistry evaluations (TH, COX-2, and iNOS). The results showed that CS and catechins reverted behavioral changes, indicating neuroprotection manifested as decreased rotational behavior, increased locomotor activity, antidepressive effects, and improvement of cognitive dysfunction, as compared to the untreated 6-OHDA-lesioned group. Besides, CS, EP, and EGCG reversed the striatal oxidative stress and immunohistochemistry alterations. These results show that the neuroprotective effects of CS and its catechins are probably and in great part due to its powerful antioxidant and anti-inflammatory properties, pointing out their potential for the prevention and treatment of PD. PMID:26167188

  13. Valproic Acid Neuroprotection in the 6-OHDA Model of Parkinson's Disease Is Possibly Related to Its Anti-Inflammatory and HDAC Inhibitory Properties.

    PubMed

    Ximenes, José Christian Machado; Neves, Kelly Rose Tavares; Leal, Luzia Kalyne A M; do Carmo, Marta Regina Santos; Brito, Gerly Anne de Castro; Naffah-Mazzacoratti, Maria da Graça; Cavalheiro, Ésper Abrão; Viana, Glauce Socorro de Barros

    2015-01-01

    Parkinson's disease is a neurodegenerative disorder where the main hallmark is the dopaminergic neuronal loss. Besides motor symptoms, PD also causes cognitive decline. Although current therapies focus on the restoration of dopamine levels in the striatum, prevention or disease-modifying therapies are urgently needed. Valproic acid (VA) is a wide spectrum antiepileptic drug, exerting many biochemical and physiological effects. It has been shown to inhibit histone deacetylase which seems to be associated with the drug neuroprotective action. The objectives were to study the neuroprotective properties of VA in a model of Parkinson's disease, consisting in the unilateral striatal injection of the neurotoxin 6-OHDA. For that, male Wistar rats (250 g) were divided into the groups: sham-operated (SO), untreated 6-OHDA-lesioned, and 6-OHDA-lesioned treated with VA (25 or 50 mg/kg). Oral treatments started 24 h after the stereotaxic surgery and continued daily for 2 weeks, when the animals were subjected to behavioral evaluations (apomorphine-induced rotations and open-field tests). Then, they were sacrificed and had their mesencephalon, striatum, and hippocampus dissected for neurochemical (DA and DOPAC determinations), histological (Fluoro-Jade staining), and immunohistochemistry evaluations (TH, OX-42, GFAP, TNF-alpha, and HDAC). The results showed that VA partly reversed behavioral and neurochemical alterations observed in the untreated 6-OHDA-lesioned rats. Besides, VA also decreased neuron degeneration in the striatum and reversed the TH depletion observed in the mesencephalon of the untreated 6-OHDA groups. This neurotoxin increased the OX-42 and GFAP immunoreactivities in the mesencephalon, indicating increased microglia and astrocyte reactivities, respectively, which were reversed by VA. In addition, the immunostainings for TNF-alpha and HDAC demonstrated in the untreated 6-OHDA-lesioned rats were also decreased after VA treatments. These results were

  14. Valproic Acid Neuroprotection in the 6-OHDA Model of Parkinson's Disease Is Possibly Related to Its Anti-Inflammatory and HDAC Inhibitory Properties

    PubMed Central

    Ximenes, José Christian Machado; Neves, Kelly Rose Tavares; Leal, Luzia Kalyne A. M.; do Carmo, Marta Regina Santos; Brito, Gerly Anne de Castro; Naffah-Mazzacoratti, Maria da Graça; Cavalheiro, Ésper Abrão; Viana, Glauce Socorro de Barros

    2015-01-01

    Parkinson's disease is a neurodegenerative disorder where the main hallmark is the dopaminergic neuronal loss. Besides motor symptoms, PD also causes cognitive decline. Although current therapies focus on the restoration of dopamine levels in the striatum, prevention or disease-modifying therapies are urgently needed. Valproic acid (VA) is a wide spectrum antiepileptic drug, exerting many biochemical and physiological effects. It has been shown to inhibit histone deacetylase which seems to be associated with the drug neuroprotective action. The objectives were to study the neuroprotective properties of VA in a model of Parkinson's disease, consisting in the unilateral striatal injection of the neurotoxin 6-OHDA. For that, male Wistar rats (250 g) were divided into the groups: sham-operated (SO), untreated 6-OHDA-lesioned, and 6-OHDA-lesioned treated with VA (25 or 50 mg/kg). Oral treatments started 24 h after the stereotaxic surgery and continued daily for 2 weeks, when the animals were subjected to behavioral evaluations (apomorphine-induced rotations and open-field tests). Then, they were sacrificed and had their mesencephalon, striatum, and hippocampus dissected for neurochemical (DA and DOPAC determinations), histological (Fluoro-Jade staining), and immunohistochemistry evaluations (TH, OX-42, GFAP, TNF-alpha, and HDAC). The results showed that VA partly reversed behavioral and neurochemical alterations observed in the untreated 6-OHDA-lesioned rats. Besides, VA also decreased neuron degeneration in the striatum and reversed the TH depletion observed in the mesencephalon of the untreated 6-OHDA groups. This neurotoxin increased the OX-42 and GFAP immunoreactivities in the mesencephalon, indicating increased microglia and astrocyte reactivities, respectively, which were reversed by VA. In addition, the immunostainings for TNF-alpha and HDAC demonstrated in the untreated 6-OHDA-lesioned rats were also decreased after VA treatments. These results were

  15. T-Lymphocyte Deficiency Exacerbates Behavioral Deficits in the 6-OHDA Unilateral Lesion Rat Model for Parkinson’s Disease

    PubMed Central

    Wheeler, Christopher J; Seksenyan, Akop; Koronyo, Yosef; Rentsendorj, Altan; Sarayba, Danielle; Wu, Henry; Gragg, Ashley; Siegel, Emily; Thomas, Deborah; Espinosa, Andres; Thompson, Kerry; Black, Keith; Koronyo-Hamaoui, Maya; Pechnick, Robert; Irvin, Dwain K

    2014-01-01

    T-lymphocytes have been previously implicated in protecting dopaminergic neurons in the substantianigra from induced cell death. However, the role of T-cells in neurodegenerative models such as Parkinson’s disease (PD) has not been fully elucidated. To examine the role of T-lymphocytes on motor behavior in the 6-hydroxydopamine (6-OHDA) unilateral striatal partial lesion PD rat model, we assessed progression of hemi-parkinsonian lesions in the substantia nigra, induced by 6-OHDA striatal injections, in athymic rats (RNU−/−, T-lymphocyte-deficient) as compared to RNU−/+ rats (phenotypically normal). Motor skills were determined by the cylinder and D-amphetamine sulfate-induced rotational behavioral tests. Cylinder behavioral test showed no significant difference between unilaterally lesioned RNU−/− and RNU−/+ rats. However both unilaterally lesioned RNU−/− and RNU−/+ rats favored the use of the limb ipsilateral to lesion. Additionally, amphetamine-induced rotational test revealed greater rotational asymmetry in RNU−/− rats compared to RNU−/+ rats at two- and six-week post-lesion. Quantitative immunohistochemistry confirmed loss of striatal TH-immunopositive fibers in RNU−/− and RNU−/+ rat, as well as blood-brain-barrier changes associated with PD that may influence passage of immune cells into the central nervous system in RNU−/− brains. Specifically, GFAP immunopositive cells were decreased, as were astrocytic end-feet (AQP4) contacting blood vessels (laminin) in the lesioned relative to contralateral striatum. Flow cytometric analysis in 6-OHDA lesioned RNU−/+rats revealed increased CD4+ and decreased CD8+ T cells specifically within lesioned brain. These results suggest that both major T cell subpopulations are significantly and reciprocally altered following 6-OHDA-lesioning, and that global T cell deficiency exacerbates motor behavioral defects in this rat model of PD. PMID:25346865

  16. Neuroprotection in a rat Parkinson model by GDNF gene therapy using EIAV vector.

    PubMed

    Azzouz, Mimoun; Ralph, Scott; Wong, Liang-Fong; Day, Denise; Askham, Zoe; Barber, Robert D; Mitrophanous, Kyriacos A; Kingsman, Susan M; Mazarakis, Nicholas D

    2004-04-29

    Vectors based on lentiviruses are opening up new approaches for the treatment of neurodegenerative diseases. Currently, the equine infectious anaemia virus (EIAV) vector is one of the most attractive gene delivery systems with respect to neuronal tropism. The aim was to validate EIAV-lentiviral vectors as a gene delivery system for neurotrophic factor genes in an animal model of Parkinson's disease. EIAV carrying the glial cell line-derived neurotrophic factor (GDNF) gene was unilaterally injected into rat striatum and above the substantia nigra (SN). One week later, the rats received a 6-OHDA lesion into the ipsilateral striatum. GDNF delivery led to extensive expression of GDNF protein within the striatum. In addition, near complete protection against dopaminergic cell death was observed in the GDNF-treated group. PMID:15076720

  17. In vivo extracellular recording of striatal neurons in the awake rat following unilateral 6-hydroxydopamine lesions.

    PubMed

    Chen, M T; Morales, M; Woodward, D J; Hoffer, B J; Janak, P H

    2001-09-01

    The purpose of this study was to further understand the functional effects of dopaminergic input to the dorsal striatum and to compare the effects of dopaminergic lesions in awake and anesthetized animals. We examined the effects of unilateral 6-hydroxydopamine (6-OHDA) lesions of the ascending dopaminergic bundle on the firing properties of dorsal striatal neurons in the awake freely moving rat using chronically implanted microwire electrode arrays. We recorded extracellular activity of striatal neurons under baseline conditions and following the systemic injection of apomorphine in awake and anesthetized subjects. Firing rates were higher in the hemisphere ipsilateral to the 6-OHDA lesion compared to rates of neurons from the contralateral unlesioned hemisphere. Striatal firing rates from sham and no-surgery control rats were, in general, higher than those from the contralateral unlesioned striatum of experimental subjects. Apomorphine (0.05 mg/kg, sc) normalized the differences in firing rates in lesioned animals by increasing firing of neurons within the contralateral unlesioned side, while simultaneously decreasing firing of neurons within the ipsilateral lesioned side. Mean firing rates were substantially higher in awake animals than in subjects anesthetized with chloral hydrate, perhaps reflecting anesthesia-induced decreases in excitatory input to striatal neurons. Chloral hydrate anesthesia decreased firing rates of neurons in the lesioned, unlesioned, and control striata to a similar degree, although absolute firing rates of neurons from the 6-OHDA-lesioned striata remained elevated over all other groups. Unilateral 6-OHDA lesions also altered the pattern of spike output in the awake animal as indicated by an increase in the number of bursts per minute following dopaminergic deafferentation. This and other burst parameters were altered by apomorphine. Our findings show that effects of dopaminergic deafferentation can be measured in the awake behaving

  18. Development of a Unilaterally-lesioned 6-OHDA Mouse Model of Parkinson's Disease

    PubMed Central

    Thiele, Sherri L.; Warre, Ruth; Nash, Joanne E.

    2012-01-01

    The unilaterally lesioned 6-hyroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease (PD) has proved to be invaluable in advancing our understanding of the mechanisms underlying parkinsonian symptoms, since it recapitulates the changes in basal ganglia circuitry and pharmacology observed in parkinsonian patients1-4. However, the precise cellular and molecular changes occurring at cortico-striatal synapses of the output pathways within the striatum, which is the major input region of the basal ganglia remain elusive, and this is believed to be site where pathological abnormalities underlying parkinsonian symptoms arise3,5. In PD, understanding the mechanisms underlying changes in basal ganglia circuitry following degeneration of the nigro-striatal pathway has been greatly advanced by the development of bacterial artificial chromosome (BAC) mice over-expressing green fluorescent proteins driven by promoters specific for the two striatal output pathways (direct pathway: eGFP-D1; indirect pathway: eGFP-D2 and eGFP-A2a)8, allowing them to be studied in isolation. For example, recent studies have suggested that there are pathological changes in synaptic plasticity in parkinsonian mice9,10. However, these studies utilised juvenile mice and acute models of parkinsonism. It is unclear whether the changes described in adult rats with stable 6-OHDA lesions also occur in these models. Other groups have attempted to generate a stable unilaterally-lesioned 6-OHDA adult mouse model of PD by lesioning the medial forebrain bundle (MFB), unfortunately, the mortality rate in this study was extremely high, with only 14% surviving the surgery for 21 days or longer11. More recent studies have generated intra-nigral lesions with both a low mortality rate >80% loss of dopaminergic neurons, however expression of L-DOPA induced dyskinesia11,12,13,14 was variable in these studies. Another well established mouse model of PD is the MPTP-lesioned mouse15. Whilst this model has proven

  19. Effects of (-)-sesamin on 6-hydroxydopamine-induced neurotoxicity in PC12 cells and dopaminergic neuronal cells of Parkinson's disease rat models.

    PubMed

    Park, Hyun Jin; Zhao, Ting Ting; Lee, Kyung Sook; Lee, Seung Ho; Shin, Keon Sung; Park, Keun Hong; Choi, Hyun Sook; Lee, Myung Koo

    2015-01-01

    The present study investigated the effects of (-)-sesamin on 6-hydroxydopamine (6-OHDA)-induced neurotoxicity using PC12 cells and dopaminergic neuronal cells of 6-OHDA-lesioned rat model of Parkinson's disease (PD). In PC12 cells, treatment with (-)-sesamin (25 µM) reduced 6-OHDA (100 µM)-induced cell death and induced transient extracellular signal-regulated kinase (ERK1/2) phosphorylation and Bad phosphorylation at Ser112 (BadSer112). In contrast, sustained ERK1/2 phosphorylation, p38 mitogen-activated protein kinase (p38MAPK) and c-Jun N-terminal kinase (JNK1/2) phosphorylation, and cleaved-caspase-3 activity, all of which were induced by 6-OHDA (100 µM), were inhibited by treatment with (-)-sesamin (25 µM). Furthermore, co-treatment with (-)-sesamin (30 mg/kg, p.o.) once a day for 28 days significantly increased the number of tyrosine hydroxylase-immunopositive neuronal cells and the levels of dopamine, norepinephrine, 3,4-dihydroxyphenylacetic acid, and homovanillic acid in the substantia nigra-striatum of 6-OHDA-lesioned rat model of PD with or without L-DOPA treatment. These results suggest that (-)-sesamin protects 6-OHDA-induced cytotoxicity via the activation of transient ERK1/2-BadSer112 system and the inhibition of sustained ERK-p38MAPK-JNK1/2-caspase-3 system in PC12 cells. (-)-Sesamin also shows protective effects on long-term L-DOPA therapy in dopaminergic neuronal cells of PD rat models. (-)-Sesamin may serve as adjuvant therapeutics in PD. PMID:25747493

  20. Assessment of the Protection of Dopaminergic Neurons by an α7 Nicotinic Receptor Agonist, PHA 543613 Using [(18)F]LBT-999 in a Parkinson's Disease Rat Model.

    PubMed

    Sérrière, Sophie; Doméné, Aurélie; Vercouillie, Johnny; Mothes, Céline; Bodard, Sylvie; Rodrigues, Nuno; Guilloteau, Denis; Routier, Sylvain; Page, Guylène; Chalon, Sylvie

    2015-01-01

    The inverse association between nicotine intake and Parkinson's disease (PD) is well established and suggests that this molecule could be neuroprotective through anti-inflammatory action mediated by nicotinic receptors, including the α7-subtype (α7R). The objective of this study was to evaluate the effects of an agonist of α7R, PHA 543613, on striatal dopaminergic neurodegeneration and neuroinflammation in a rat model of PD induced by 6-hydroxydopamine (6-OHDA) lesion. Adult male Wistar rats were lesioned in the right striatum and assigned to either the PHA group (n = 7) or the Sham group (n = 5). PHA 543613 hydrochloride at the concentration of 6 mg/kg (PHA group) or vehicle (Sham group) was intra-peritoneally injected 2 h before 6-OHDA lesioning and then at days 2, 4, and 6 post-lesion. Positron emission tomography (PET) imaging was performed at 7 days post-lesion using [(18)F]LBT-999 to quantify the striatal dopamine transporter (DAT). After PET imaging, neuroinflammation was evaluated in same animals in vitro through the measurement of the microglial activation marker 18 kDa translocator protein (TSPO) by quantitative autoradiography with [(3)H]PK-11195. The DAT density reflecting the integrity of dopaminergic neurons was significantly decreased while the intensity of neuroinflammation measured by TSPO density was significantly increased in the lesioned compared to intact striatum in both groups. However, these both modifications were partially reversed in the PHA group compared to Sham. In addition, a significant positive correlation between the degree of lesion and the intensity of neuroinflammation was evidenced. These findings indicate that PHA 543613 exerts neuroprotective effects on the striatal dopaminergic neurons associated with a reduction in microglial activation in this model of PD. This reinforces the hypothesis that an α7R agonist could provide beneficial effects for the treatment of PD. PMID:26389120

  1. Altered extracellular striatal in vivo biotransformation of the opioid neuropeptide dynorphin A(1-17) in the unilateral 6-OHDA rat model of Parkinson's disease.

    PubMed

    Klintenberg, Rebecka; Andrén, Per E

    2005-02-01

    The in vivo biotransformation of dynorphin A(1-17) (Dyn A) was studied in the striatum of hemiparkinsonian rats by using microdialysis in combination with nanoflow reversed-phase liquid chromatography/electrospray time-of-flight mass spectrometry. The microdialysis probes were implanted into both hemispheres of unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats. Dyn A (10 pmol microl(-1)) was infused through the probes at 0.4 microl min(-1) for 2 h. Samples were collected every 30 min and analyzed by mass spectrometry. The results showed for the first time that there was a difference in the Dyn A biotransformation when comparing the two corresponding sides of the brain. Dyn A metabolites 1-8, 1-16, 5-17, 10-17, 7-10 and 8-10 were detected in the dopamine-depleted striatum but not in the untreated striatum. Dyn A biotransformed fragments found in both hemispheres were N-terminal fragments 1-4, 1-5, 1-6, 1-11, 1-12 and 1-13, C-terminal fragments 2-17, 3-17, 4-17, 7-17 and 8-17 and internal fragments 2-5, 2-10, 2-11, 2-12, and 8-15. The relative levels of these fragments were lower in the dopamine-depleted striatum. The results imply that the extracellular in vivo processing of the dynorphin system is being disturbed in the 6-OHDA-lesion animal model of Parkinson's disease. PMID:15706626

  2. Antagonism of quercetin against tremor induced by unilateral striatal lesion of 6-OHDA in rats.

    PubMed

    Mu, Xin; Yuan, Xia; Du, Li-Da; He, Guo-Rong; Du, Guan-Hua

    2016-01-01

    Quercetin, a flavonoid present in many plants, is reported to be effective in models of neurodegenerative diseases. The aim of the present study was to evaluate the anti-tremor effects of quercetin in 6-hydroxydopamine (6-OHDA)-induced rat model of Parkinson's disease. In rats, quercetin had no effect on apomorphine-induced rotations, but it could significantly attenuate muscle tremor of 6-OHDA lesioned rats. Interestingly, quercetin could decrease the burst frequency in a dose- and time-dependent manner. These results suggest that quercetin may have a protective effect on models to mimic muscle tremors of Parkinson's disease. This effect of quercetin may be associated with serotonergic system, but further study is needed. PMID:26217978

  3. Short-Term Treatment with Silymarin Improved 6-OHDA-Induced Catalepsy and Motor Imbalance in Hemi-Parkisonian Rats

    PubMed Central

    Haddadi, Rasool; Eyvari Brooshghalan, Shahla; Farajniya, Safar; Mohajjel Nayebi, Alireza; Sharifi, Hamdolah

    2015-01-01

    Purpose: Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by disabling motor abnormalities, which include tremor, muscle stiffness, paucity of voluntary movements, and postural instability. Silymarin (SM) or milk thistle extract, is known to own antioxidative, anti-apoptotic, anti-inflammatory and neuroprotective effects. In the present study, we investigated the effect of intraperitoneal (i.p) administration of SM, on 6-OHDA-induced motor-impairments (catalepsy and imbalance) in the rats. Methods: Experimental model of PD was induced by unilateral infusion of 6-hydroxydopamine (6-OHDA; 8 μg/2 μl/rat) into the central region of the substantia nigra pars compacta (SNc). Catalepsy and motor coordination were assessed by using of bar test and rotarod respectively. Results: The results showed a significant (p<0.001) increase in catalepsy of 6-OHDA-lesioned rats whereas; in SM (100, 200 and 300 mg/kg, i.p for 5 days) treated hemi-parkinsonian rats catalepsy was decreased markedly (p<0.001). Furthermore, there was a significant (p<0.001) increase in motor-imbalance of 6-OHDA-lesioned rats. SM improved motor coordination significantly (p<0.001) in a dose dependent manner and increased motor balance. Conclusion: In conclusion, we found that short-term treatment with SM could improve 6-OHDA-induced catalepsy and motor imbalance in rats. We suggest that SM can be used as adjunctive therapy along with commonly used anti-parkinsonian drugs. However, further clinical trial studies should be carried out to prove this hypothesis. PMID:26819917

  4. Effect of WR-1065 on 6-hydroxydopamine-induced catalepsy and IL-6 level in rats

    PubMed Central

    Kheradmand, Afshin; Nayebi, Alireza Mohajjel; Jorjani, Masoumeh; Haddadi, Rasool

    2016-01-01

    Objective(s): Neuroinflammation and oxidative stress play a key role in pathogenesis of Parkinson’s disease (PD). In the present study we investigated the effect of reactive oxygen species (ROS) scavenger WR-1065 on catalepsy and cerebrospinal fluid (CSF) level of interleukin 6(IL-6) and striatum superoxide dismutase (SOD) activity in 6-hydroxydopamine (6-OHDA) induced experimental model of PD. Materials and Methods: Seventy two male Wistar rats were divided into 9 equal groups and 6-OHDA (8 μg/2 μl/rat) was infused unilaterally into substantia nigra pars copmacta (SNc) to induce PD. Catalepsy was measured by standard bar test, CSF level of IL-6 was assessed by enzyme-linked immunosorbent assay (ELISA) method and SOD activity measured by spectrophotometric method. In pre-treatment groups WR-1065 (20, 40 and 80 μg/2 μl/rat/day, for 3 days) was infused into the SNc before 6-OHDA administration and 21 days later, as a recovery period, behavioral and molecular assay tests were done. Results: Our results showed that pre-treatment with WR-1065 improved (P<0.001) 6-OHDA-induced catalepsy in a dose dependent manner. In 6-OHDA-lesioned animals SOD activity in SNc and CSF level of IL-6 was decreased markedly (P<0.001) when compared with non-lesioned group, while pre-treatment with WR-1065(P<0.001) restored their levels up to the normal range. Conclusion: Our study indicated that pre-treatment with WR-1065 could modulate catalepsy and IL-6 level in 6-OHDA-lesioned rats. Also WR1065 could increase SOD activity up to normal range. It can be regarded as an anti-oxidative drug in prevention or adjunctive therapy of PD. PMID:27403255

  5. In vivo L-DOPA production by genetically modified primary rat fibroblast or 9L gliosarcoma cell grafts via coexpression of GTPcyclohydrolase I with tyrosine hydroxylase.

    PubMed

    Leff, S E; Rendahl, K G; Spratt, S K; Kang, U J; Mandel, R J

    1998-06-01

    To investigate the biochemical requirements for in vivo L-DOPA production by cells genetically modified ex vivo in a rat model of Parkinson's disease (PD), rat syngeneic 9L gliosarcoma and primary Fischer dermal fibroblasts (FDFs) were transduced with retroviral vectors encoding the human tyrosine hydroxylase 2 (hTH2) and human GTP cyclohydrolase I (hGTPCHI) cDNAs. As GTPCHI is a rate-limiting enzyme in the pathway for synthesis of the essential TH cofactor, tetrahydrobiopterin (BH4), only hTH2 and GTPCHI cotransduced cultured cells produced L-DOPA in the absence of added BH4. As striatal BH4 levels in 6-hydroxydopamine (6-OHDA)-lesioned rats are minimal, the effects of cotransduction with hTH2 and hGTPCHI on L-DOPA synthesis by striatal grafts of either 9L cells or FDFs in unilateral 6-OHDA-lesioned rats were tested. Microdialysis experiments showed that those subjects that received cells cotransduced with hTH2 and hGTPCHI produced significantly higher levels of L-DOPA than animals that received either hTH2 or untransduced cells. However, animals that received transduced FDF grafts showed a progressive loss of transgene expression until expression was undetectable 5 weeks after engraftment. In FDF-engrafted animals, no differential effect of hTH2 vs hTH2 + hGTPCHI transgene expression on apomorphine-induced rotation was observed. The differences in L-DOPA production found with cells transduced with hTH2 alone and those cotransduced with hTH2 and hGTPCHI show that BH4 is critical to the restoration of the capacity for L-DOPA production and that GTPCHI expression is an effective means of supplying BH4 in this rat model of PD. PMID:9628761

  6. Monoaminergic PET imaging and histopathological correlation in unilateral and bilateral 6-hydroxydopamine lesioned rat models of Parkinson's disease: a longitudinal in-vivo study.

    PubMed

    Molinet-Dronda, Francisco; Gago, Belén; Quiroga-Varela, Ana; Juri, Carlos; Collantes, María; Delgado, Mercedes; Prieto, Elena; Ecay, Margarita; Iglesias, Elena; Marín, Concepció; Peñuelas, Iván; Obeso, José A

    2015-05-01

    Carbon-11 labeled dihydrotetrabenazine ((11)C-DTBZ) binds to the vesicular monoamine transporter 2 and has been used to assess nigro-striatal integrity in animal models and patients with Parkinson's disease. Here, we applied (11)C-DTBZ positron emission tomography (PET) to obtain longitudinally in-vivo assessment of striatal dopaminergic loss in the classic unilateral and in a novel bilateral 6-hydroxydopamine (6-OHDA) lesion rat model. Forty-four Sprague-Dawley rats were divided into 3 sub-groups: 1. 6-OHDA-induced unilateral lesion in the medial forebrain bundle, 2. bilateral lesion by injection of 6-OHDA in the third ventricle, and 3. vehicle injection in either site. (11)C-DTBZ PET studies were investigated in the same animals successively at baseline, 1, 3 and 6weeks after lesion using an anatomically standardized volumes-of-interest approach. Additionally, 12 rats had PET and Magnetic Resonance Imaging to construct a new (11)C-DTBZ PET template. Behavior was characterized by rotational, catalepsy and limb-use asymmetry tests and dopaminergic striatal denervation was validated post-mortem by immunostaining of the dopamine transporter (DAT). (11)C-DTBZ PET showed a significant decrease of striatal binding (SB) values one week after the unilateral lesion. At this point, there was a 60% reduction in SB in the affected hemisphere compared with baseline values in 6-OHDA unilaterally lesioned animals. A 46% symmetric reduction over baseline SB values was found in bilaterally lesioned rats at the first week after lesion. SB values remained constant in unilaterally lesioned rats whereas animals with bilateral lesions showed a modest (22%) increase in binding values at the 3rd and 6th weeks post-lesion. The degree of striatal dopaminergic denervation was corroborated histologically by DAT immunostaining. Statistical analysis revealed a high correlation between (11)C-DTBZ PET SB and striatal DAT immunostaining values (r=0.95, p<0.001). The data presented here indicate

  7. Modulation of Corpus Striatal Neurochemistry by Astrocytes and Vasoactive Intestinal Peptide (VIP) in Parkinsonian Rats.

    PubMed

    Yelkenli, İbrahim Halil; Ulupinar, Emel; Korkmaz, Orhan Tansel; Şener, Erol; Kuş, Gökhan; Filiz, Zeynep; Tunçel, Neşe

    2016-06-01

    The neurotoxin 6-hydroxydopamine (6-OHDA) is widely used in animal models of Parkinson's disease. In various neurodegenerative diseases, astrocytes play direct, active, and critical roles in mediating neuronal survival and functions. Vasoactive intestinal peptide (VIP) has neurotrophic actions and modulates a number of astrocytic activities. In this study, the effects of VIP on the striatal neurochemistry were investigated in parkinsonian rats. Adult Sprague-Dawley rats were divided into sham-operated, unilaterally 6-OHDA-lesioned, and lesioned + VIP-administered (25 ng/kg i.p.) groups. VIP was first injected 1 h after the intrastriatal 6-OHDA microinjection and then every 2 days throughout 15 days. Extracellular striatal concentration of glutathione (GSH), gamma-aminobutyric acid (GABA), glutamate (GLU), and lactate were measured in microdialysates by high-performance liquid chromatography (HPLC). Quantification of GABA and activity dependent neuroprotective protein (ADNP)-expressing cells were determined by glutamic acid decarboxylase (GAD)/ADNP + glial fibrillary acidic protein (GFAP) double immunohistochemistry. Our results demonstrated that a 6-OHDA lesion significantly increased the density of astrocytes in the striatum and VIP treatment slightly reduced the gliosis. Extracellular concentration of GABA, GLU, and lactate levels did not change, but GSH level significantly increased in the striatum of parkinsonian rats. VIP treatment reduced GSH level comparable to sham-operated groups, but enhanced GABA and GLU levels. Our double labeling results showed that VIP primarily acts on neurons to increase ADNP and GAD expression for protection. These results suggest that, in the 6-OHDA-induced neurodegeneration model, astrocytes were possibly activated for forefront defensiveness by modulating striatal neurochemistry. PMID:27115671

  8. Exposure to Early Life Stress Results in Epigenetic Changes in Neurotrophic Factor Gene Expression in a Parkinsonian Rat Model

    PubMed Central

    Mpofana, Thabisile; Daniels, Willie M. U.; Mabandla, Musa V.

    2016-01-01

    Early life adversity increases the risk of mental disorders later in life. Chronic early life stress may alter neurotrophic factor gene expression including those for brain derived neurotrophic factor (BDNF) and glial cell derived neurotrophic factor (GDNF) that are important in neuronal growth, survival, and maintenance. Maternal separation was used in this study to model early life stress. Following unilateral injection of a mild dose of 6-hydroxydopamine (6-OHDA), we measured corticosterone (CORT) in the blood and striatum of stressed and nonstressed rats; we also measured DNA methylation and BDNF and GDNF gene expression in the striatum using real time PCR. In the presence of stress, we found that there was increased corticosterone concentration in both blood and striatal tissue. Further to this, we found higher DNA methylation and decreased neurotrophic factor gene expression. 6-OHDA lesion increased neurotrophic factor gene expression in both stressed and nonstressed rats but this increase was higher in the nonstressed rats. Our results suggest that exposure to early postnatal stress increases corticosterone concentration which leads to increased DNA methylation. This effect results in decreased BDNF and GDNF gene expression in the striatum leading to decreased protection against subsequent insults later in life. PMID:26881180

  9. PET Imaging of Serotonin Transporters With 4-[(18)F]-ADAM in a Parkinsonian Rat Model With Porcine Neural Xenografts.

    PubMed

    Chiu, Chuang-Hsin; Li, I-Hsun; Weng, Shao-Ju; Huang, Yuahn-Sieh; Wu, Shinn-Chih; Chou, Ta-Kai; Huang, Wen-Sheng; Liao, Mei-Hsiu; Shiue, Chyng-Yann; Cheng, Cheng-Yi; Ma, Kuo-Hsing

    2016-01-01

    Parkinson's disease (PD) is a neurodegenerative disease characterized by a loss of dopaminergic neurons in the nigrostriatal pathway. Apart from effective strategies to halt the underlying neuronal degeneration, cell replacement now offers novel prospects for PD therapy. Porcine embryonic neural tissue has been considered an alternative source to human fetal grafts in neurodegenerative disorders because its use avoids major practical and ethical issues. This study was undertaken to evaluate the effects of embryonic day 27 (E27) porcine mesencephalic tissue transplantation in a PD rat model using animal positron emission tomography (PET) coupled with 4-[(18)F]-ADAM, a serotonin transporter (SERT) imaging agent. The parkinsonian rat was induced by injecting 6-hydroxydopamine into the medial forebrain bundle (MFB) of the right nigrostriatal pathway. The apomorphine-induced rotation behavioral test and 4-[(18)F]-ADAM/animal PET scanning were carried out following 6-OHDA lesioning. At the second week following 6-OHDA lesioning, the parkinsonian rat rotates substantially on apomorphine-induced contralateral turning. In addition, the mean striatal-specific uptake ratio (SUR) of 4-[(18)F]-ADAM decreased by 44%. After transplantation, the number of drug-induced rotations decreased markedly, and the mean SUR of 4-[(18)F]-ADAM and the level of SERT immunoreactivity (SERT-ir) in striatum were partially restored. The mean SUR level was restored to 71% compared to that for the contralateral intact side, which together with the abundant survival of tyrosine hydroxylase (TH) neurons accounted for functional recovery at the fourth week postgraft. In regard to the extent of donor-derived cells, we found the neurons of the xenografts from E27 transgenic pigs harboring red fluorescent protein (RFP) localized with TH-ir cells and SERT-ir in the grafted area. Thus, transplanted E27 porcine mesencephalic tissue may restore dopaminergic and serotonergic systems in the parkinsonian rat

  10. Heat shock protein 60 affects behavioral improvement in a rat model of Parkinson's disease grafted with human umbilical cord mesenchymal stem cell-derived dopaminergic-like neurons.

    PubMed

    Zhao, Can; Li, Hui; Zhao, Xian-Jing; Liu, Zheng-Xia; Zhou, Ping; Liu, Ying; Feng, Mei-Jiang

    2016-06-01

    Parkinson's disease (PD) is a neurodegenerative disorder that is caused by a loss of dopaminergic (DAergic) neurons in mesencephalic substantia nigra (SN). Human umbilical cord mesenchymal stem cells (hUC-MSCs) are capable of self-renewal and differentiation into multiple cell lineages, including DAergic neurons. Thus, hUC-MSCs could be a promising alternative to compensate for the loss of DAergic neurons in PD. In the current study, hUC-MSCs and hUC-MSCs-derived DAergic-like neurons were transplanted into the striatum and SN of a rat model of PD that is induced by 6-hydroxydopamine (6-OHDA). We evaluated their therapeutic effects on improving rotation behavior in the rat and on modulating the level of heat shock protein 60 (Hsp60) expression in the brain. After transplantation, an amelioration of rotation behavior was observed in rats that underwent cell grafting, and hUC-MSCs-derived DAergic-like neurons were superior to hUC-MSCs at inducing behavioral improvement. Western blot and immunohistochemistry analysis indicated significantly elevated levels of Hsp60 in cell-grafted rats compared to 6-OHDA-lesioned (PD) rats. These results demonstrate that hUC-MSCs-based cell transplantation is potential therapeutic treatment for PD, and hUC-MSCs-derived DAergic-like neurons appear to be favorable candidates for cell replacement therapy in PD. Finally, Hsp60 could be involved in a mechanism of behavioral recovery. PMID:26758268

  11. Effect of serotonin transporter blockade on L-DOPA-induced dyskinesia in animal models of Parkinson's disease.

    PubMed

    Fidalgo, C; Ko, W K D; Tronci, E; Li, Q; Stancampiano, R; Chuan, Q; Bezard, E; Carta, M

    2015-07-01

    Serotonin transporter blockade with selective serotonin reuptake inhibitors (SSRIs) was recently shown to counteract L-DOPA-induced dyskinesia in 6-hydroxydopamine (6-OHDA)-lesioned rats. However, this effect has never been described in Parkinson's disease (PD) patients, despite that they often receive SSRIs for the treatment of depression. In the present study, we investigated the efficacy of the SSRI citalopram against dyskinesia in two experimental models of PD, the 6-OHDA-lesioned rat and 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP)-treated macaque. First, we studied the acute and chronic effect of citalopram, given at different time points before L-DOPA, in L-DOPA-primed parkinsonian rats. Moreover, the acute effect of citalopram was also evaluated in dyskinetic MPTP-treated macaques. In L-DOPA-primed rats, a significant and long-lasting reduction of L-DOPA-induced dyskinesia (LID) was observed only when citalopram was given 30 min before L-DOPA, suggesting that the time of injection relative to L-DOPA is a key factor for the efficacy of the treatment. Interestingly, an acute challenge with the 5-HT1A/1B receptor agonist eltoprazine, given at the end of the chronic study, was equally effective in reducing LID in rats previously chronically treated with L-DOPA or L-DOPA plus citalopram, suggesting that no auto-receptor desensitization was induced by chronic citalopram treatment. In MPTP-treated macaques, citalopram produced a striking suppression of LID but at the expense of L-DOPA therapeutic efficacy, which represents a concern for possible clinical application. PMID:25907446

  12. Low-frequency stimulation of the pedunculopontine nucleus affects gait and the neurotransmitter level in the ventrolateral thalamic nucleus in 6-OHDA Parkinsonian rats.

    PubMed

    Wen, Peng; Li, Min; Xiao, Hu; Ding, Rui; Chen, Huan; Chang, Jingyu; Zhou, Ming; Yang, Yong; Wang, Jun; Zheng, Weixin; Zhang, Wangming

    2015-07-23

    The pedunculopontine nucleus (PPN) is connected to spinal, cerebellar and cerebral motor control structures and can be activated with external electrodes. Intrinsic cholinergic neuronal degeneration in the PPN is associated with postural instabilities and gait disturbances (PIGD) in advanced Parkinson's disease (PD). Clinical studies have demonstrated that PPN stimulation may improve PIGD. We investigated this claim and the underlying mechanisms using the 6-hydroxydopamine (6-OHDA) hemilesion model of PD. In this study, gait-related parameters, including the base of support (BOS), stride length, and maximum contact area, were analyzed via CatWalk gait analysis following PPN-low frequency stimulation (LFS) of rats with unilateral 6-OHDA lesions. Additionally, neurotransmitter concentrations in the ventrolateral thalamic nucleus (VL) were measured by microdialysis and liquid chromatography-mass spectrometry (LC-MS). Our data revealed that unilateral 6-OHDA lesions of the medial forebrain bundle (MFB) induced significant gait deficits. PPN-LFS significantly improved the BOS (hindlimb) and maximum contact area (impaired forelimb) scores, whereas no other gait parameters were significantly affected. Unilateral 6-OHDA MFB lesions significantly decreased acetylcholine (ACh) and moderately decreased noradrenaline (NA) concentrations in the VL. PPN-LFS mildly reversed the ACh loss in the VL in the lesioned rats but did not alter the NA levels. Taken together, our data indicate that PPN-LFS is useful for treating gait deficits of PD and that these effects are probably mediated by a rebalancing of ACh levels in the PPN-VL pathway. Thus, our findings provide possible insight into the mechanisms underlying PIGD in PD. PMID:26054938

  13. Chronic Amitriptyline Treatment Attenuates Nigrostriatal Degeneration and Significantly Alters Trophic Support in a Rat Model of Parkinsonism

    PubMed Central

    Paumier, Katrina L; Sortwell, Caryl E; Madhavan, Lalitha; Terpstra, Brian; Celano, Stephanie L; Green, Joshua J; Imus, Nastassja M; Marckini, Nathan; Daley, Brian; Steece-Collier, Kathy; Collier, Timothy J

    2015-01-01

    In addition to alleviating depression, long-term adaptive changes induced by antidepressants may regulate neural plasticity in the diseased brain, providing symptomatic and disease-modifying effects in Parkinson's disease. The present study investigated whether chronic treatment with a frequently prescribed tricyclic antidepressant was neuroprotective in a 6-hydroxydopamine (6-OHDA) rat model of parkinsonism. In lesioned animals, chronic amitriptyline (AMI; 5 mg/kg) treatment resulted in a significant sparing of tyrosine hydroxylase-immunoreactive (THir) neurons in the substantia nigra pars compacta (SNpc) compared with saline treatment. Additionally, striatal fibers were preserved and functional motor deficits were attenuated. Although 6-OHDA lesions did not induce anhedonia in our model, the dose of AMI utilized had antidepressant activity as demonstrated by reduced immobility. Recent in vitro and in vivo data provide evidence that trophic factors such as brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) may be key mediators of the therapeutic response to antidepressants. Therefore, we investigated whether AMI mediates changes in these specific trophic factors in the intact and degenerating nigrostriatal system. Chronic AMI treatment mediates an increase in nigral BDNF both before and during ongoing degeneration, suggesting it may contribute to neuroprotection observed in vivo. However, over time, AMI reduced BDNF levels in the striatum, indicating tricyclic therapy differentially regulates trophic factors within the nigrostriatal system. Combined, these results suggest that AMI treatment attenuates dopamine neuron loss and elicits significant trophic changes relevant to dopamine neuron survival. PMID:25267343

  14. Differential Dopamine Receptor Occupancy Underlies L-DOPA-Induced Dyskinesia in a Rat Model of Parkinson's Disease

    PubMed Central

    Sahin, Gurdal; Thompson, Lachlan H.; Lavisse, Sonia; Ozgur, Merve; Rbah-Vidal, Latifa; Dollé, Frédéric

    2014-01-01

    Dyskinesia is a major side effect of an otherwise effective L-DOPA treatment in Parkinson's patients. The prevailing view for the underlying presynaptic mechanism of L-DOPA-induced dyskinesia (LID) suggests that surges in dopamine (DA) via uncontrolled release from serotonergic terminals results in abnormally high level of extracellular striatal dopamine. Here we used high-sensitivity online microdialysis and PET imaging techniques to directly investigate DA release properties from serotonergic terminals both in the parkinsonian striatum and after neuronal transplantation in 6-OHDA lesioned rats. Although L-DOPA administration resulted in a drift in extracellular DA levels, we found no evidence for abnormally high striatal DA release from serotonin neurons. The extracellular concentration of DA remained at or below levels detected in the intact striatum. Instead, our results showed that an inefficient release pool of DA associated with low D2 receptor binding remained unchanged. Taken together, these findings suggest that differential DA receptor activation rather than excessive release could be the underlying mechanism explaining LID seen in this model. Our data have important implications for development of drugs targeting the serotonergic system to reduce DA release to manage dyskinesia in patients with Parkinson's disease. PMID:24614598

  15. Human adipose-derived mesenchymal stem cells improve motor functions and are neuroprotective in the 6-hydroxydopamine-rat model for Parkinson's disease when cultured in monolayer cultures but suppress hippocampal neurogenesis and hippocampal memory function when cultured in spheroids.

    PubMed

    Berg, Jürgen; Roch, Manfred; Altschüler, Jennifer; Winter, Christine; Schwerk, Anne; Kurtz, Andreas; Steiner, Barbara

    2015-02-01

    Adult human adipose-derived mesenchymal stem cells (MSC) have been reported to induce neuroprotective effects in models for Parkinson's disease (PD). However, these effects strongly depend on the most optimal application of the transplant. In the present study we compared monolayer-cultured (aMSC) and spheroid (sMSC) MSC following transplantation into the substantia nigra (SN) of 6-OHDA lesioned rats regarding effects on the local microenvironment, degeneration of dopaminergic neurons, neurogenesis in the hippocampal DG as well as motor and memory function in the 6-OHDA-rat model for PD. aMSC transplantation significantly increased tyrosine hydroxylase (TH) and brain-derived neurotrophic factor (BDNF) levels in the SN, increased the levels of the glial fibrillary acidic protein (GFAP) and improved motor functions compared to untreated and sMSC treated animals. In contrast, sMSC grafting induced an increased local microgliosis, decreased TH levels in the SN and reduced numbers of newly generated cells in the dentate gyrus (DG) without yet affecting hippocampal learning and memory function. We conclude that the neuroprotective potential of adipose-derived MSC in the rat model of PD crucially depends on the applied cellular phenotype. PMID:25120226

  16. Decomposition of abnormal free locomotor behavior in a rat model of Parkinson's disease

    PubMed Central

    Grieb, Benjamin; von Nicolai, Constantin; Engler, Gerhard; Sharott, Andrew; Papageorgiou, Ismini; Hamel, Wolfgang; Engel, Andreas K.; Moll, Christian K.

    2013-01-01

    Poverty of spontaneous movement, slowed execution and reduced amplitudes of movement (akinesia, brady- and hypokinesia) are cardinal motor manifestations of Parkinson's disease that can be modeled in experimental animals by brain lesions affecting midbrain dopaminergic neurons. Most behavioral investigations in experimental parkinsonism have employed short-term observation windows to assess motor impairments. We postulated that an analysis of longer-term free exploratory behavior could provide further insights into the complex fine structure of altered locomotor activity in parkinsonian animals. To this end, we video-monitored 23 h of free locomotor behavior and extracted several behavioral measures before and after the expression of a severe parkinsonian phenotype following bilateral 6-hydroxydopamine (6-OHDA) lesions of the rat dopaminergic substantia nigra. Unbiased stereological cell counting verified the degree of midbrain tyrosine hydroxylase positive cell loss in the substantia nigra and ventral tegmental area. In line with previous reports, overall covered distance and maximal motion speed of lesioned animals were found to be significantly reduced compared to controls. Before lesion surgery, exploratory rat behavior exhibited a bimodal distribution of maximal speed values obtained for single movement episodes, corresponding to a “first” and “second gear” of motion. 6-OHDA injections significantly reduced the incidence of second gear motion episodes and also resulted in an abnormal prolongation of these fast motion events. Likewise, the spatial spread of such episodes was increased in 6-OHDA rats. The increase in curvature of motion tracks was increased in both lesioned and control animals. We conclude that the discrimination of distinct modes of motion by statistical decomposition of longer-term spontaneous locomotion provides useful insights into the fine structure of fluctuating motor functions in a rat analog of Parkinson's disease. PMID:24348346

  17. Altered neuronal activity in the pedunculopontine nucleus: An electrophysiological study in a rat model of Parkinson's disease.

    PubMed

    Geng, Xiwen; Xie, Jinlu; Wang, Xuenan; Wang, Xiusong; Zhang, Xiao; Hou, Yabing; Lei, Chengdong; Li, Min; Qu, Qingyang; He, Tingting; Han, Hongyu; Yao, Xiaomeng; Wang, Min

    2016-05-15

    The pedunculopontine nucleus (PPN) is a new deep brain stimulation target for treating Parkinson's disease (PD). But the alterations of the PPN electrophysiological activities in PD are still debated. To investigate these potential alterations, extracellular single unit and local field potential (LFP) activities in the PPN were recorded in unilateral hemispheric 6-hydroxydopamine (6-OHDA) lesioned rats and in control rats, respectively. The spike activity results revealed two types of neurons (Type I and Type II) with distinct electrophysiological characteristics in the PPN. Both types of neurons had increased firing rate and changed firing pattern in lesioned rats when compared to control rats. Specifically, Type II neurons showed an increased firing rate when the rat state was switched from rest to locomotion. The LFP results demonstrated that lesioned rats had lower LFP power at 0.7-12Hz and higher power at 12-30Hz than did control animals in either resting or locomotor state. These findings provide a better understanding of the effects of 6-OHDA lesion on neuronal activities in the PPN and also provide a proof of the link between this structure and locomotion, which contributes to better understanding the mechanisms of the PPN functioning in the pathophysiology of PD. PMID:26924016

  18. The 6-OHDA mouse model of Parkinson's disease - Terminal striatal lesions provide a superior measure of neuronal loss and replacement than median forebrain bundle lesions.

    PubMed

    Bagga, V; Dunnett, S B; Fricker, R A

    2015-07-15

    Unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway produce side-biased motor impairments that reflect the motor deficits seen in Parkinson's disease (PD). This toxin-induced model in the rat has been used widely, to evaluate possible therapeutic strategies, but has not been well established in mice. With the advancements in mouse stem cell research we believe the requirement for a mouse model is essential for the therapeutic potential of these and other mouse-derived cells to be efficiently assessed. This aim of this study focused on developing a mouse model of PD using the 129 P2/OLA Hsd mouse strain as this is widely used in the generation of mouse embryonic stem cells. Both unilateral 6-OHDA medial forebrain bundle (MFB) and striatal lesion protocols were compared, with mice analysed for appropriate drug-induced rotational bias. Results demonstrated that lesioned mice responded to d-amphetamine with peak rotation dose at 5mg/kg and 10mg/kg for MFB and striatal lesions respectively. Apomorphine stimulation produced no significant rotational responses, at any dose, in either the MFB or striatal 6-OHDA lesioned mice. Analysis of dopamine neuron loss revealed that the MFB lesion was unreliable with little correlation between dopamine neuron loss and rotational asymmetry. Striatal lesions however were more reliable, with a strong correlation between dopamine neuron loss and rotational asymmetry. Functional recovery of d-amphetamine-induced rotational bias was shown following transplantation of E13 mouse VM tissue into the lesioned striatum; confirming the validity of this mouse model. PMID:25841616

  19. Intrastriatal GDNF gene transfer by inducible lentivirus vectors protects dopaminergic neurons in a rat model of parkinsonism.

    PubMed

    Chen, Sha-Sha; Yang, Chun; Hao, Fei; Li, Chen; Lu, Tao; Zhao, Li-Ru; Duan, Wei-Ming

    2014-11-01

    Glial cell line-derived neurotrophic factor (GDNF) has neuroprotective effects on dopaminergic (DA) neurons both in vivo and in vitro. However, substantial evidence has shown that a long-term overexpression of GDNF gene is often associated with side effects. We previously improved tetracycline (Tet)-On lentivirus system carrying human GDNF (hGDNF) gene, and demonstrated that hGDNF gene expression was tightly regulated and functional in vitro. Here we further examined the efficiency and neuroprotection of Tet-On lentivirus-mediated hGDNF gene regulation in neural progenitor cells (NPCs) and a rat model of parkinsonism. The results showed that hGDNF gene expression was tightly regulated in transduced NPCs. Doxycycline (Dox)-induced hGDNF protected DA neurons from 6-hydroxydopamine (6-OHDA)-induced toxicity in vitro. Intrastriatal injections of Tet-On lentivirus vectors resulted in dramatically increased levels of hGDNF protein in the striatum of rats with Dox-drinking water, when compared to lentivirus-injected and saline-injected rats with normal drinking water, respectively. In addition, hGDNF protected nigral DA neurons and striatal DA fibers, and attenuated d-amphetamine-induced rotational asymmetry in the 6-OHDA lesioned rats. To the best of our knowledge, this is the first report that hGDNF gene transfer by Tet-On lentivirus vectors is tightly regulated in rat brain, and Dox-induced hGDNF is functional in neuroprotection of nigral DA neurons in a rat model of parkinsonism. PMID:24997241

  20. Neuroprotective Properties of a Standardized Extract from Myracrodruon urundeuva Fr. All. (Aroeira-Do-Sertão), as Evaluated by a Parkinson's Disease Model in Rats

    PubMed Central

    Calou, Iana; Bandeira, Mary Anne; Aguiar-Galvão, Wellida; Cerqueira, Gilberto; Siqueira, Rafaelly; Neves, Kelly Rose; Brito, Gerly Anne; Viana, Glauce

    2014-01-01

    Myracrodruon urundeuva Fr. All. (Anacardiaceae) is a Brazilian medicinal species, which is common to the Northeastern Brazilian semiarid region, whose stem-bark is widely used in folk medicine. It is an endangered species, presenting as main bioactive components tannins and chalcones. In this work, we studied the neuroprotective effects of a standardized extract from cultivated M. urundeuva (SEMU), in a model of Parkinson's disease. Thus, a unilateral injection of 6-OHDA was done into the rat right stratum. The animals were submitted to stereotaxic surgery, then treated with SEMU (5, 10, 20, or 40 mg/kg, p.o.) for 2 weeks, subjected to behavioral tests, and euthanized for striata dissections and neurochemical, histological, and immunohistochemical analyses. We showed, for the first time, that SEMU reverted behavioral alterations seen in the 6-OHDA-lesioned group and partially blocked the decrease in DA and DOPAC contents. The numbers of viable neurons and TH immunopositive cells were increased by SEMU. In addition, the SEMU-treated 6-OHDA groups showed lower numbers of GFAP and OX-42 immunopositive cells. The neuroprotective action of SEMU is possibly related to the antioxidant and anti-inflammatory properties of M. urundeuva, pointing out to its potential use in the prevention or treatment of neurodegenerative conditions, such as Parkinson's disease. PMID:25061534

  1. Neuroprotective Activity of Peripherally Administered Liver Growth Factor in a Rat Model of Parkinson’s Disease

    PubMed Central

    Gonzalo-Gobernado, Rafael; Calatrava-Ferreras, Lucía; Reimers, Diana; Herranz, Antonio Sánchez; Rodríguez-Serrano, Macarena; Miranda, Cristina; Jiménez-Escrig, Adriano; Díaz-Gil, Juan José; Bazán, Eulalia

    2013-01-01

    Liver growth factor (LGF) is a hepatic mitogen purified some years ago that promotes proliferation of different cell types and the regeneration of damaged tissues, including brain tissue. Considering the possibility that LGF could be used as a therapeutic agent in Parkinson’s disease, we analyzed its potential neuroregenerative and/or neuroprotective activity when peripherally administered to unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats. For these studies, rats subjected to nigrostriatal lesions were treated intraperitoneally twice a week with LGF (5 microg/rat) for 3 weeks. Animals were sacrificed 4 weeks after the last LGF treatment. The results show that LGF stimulates sprouting of tyrosine hydroxylase-positive terminals and increases tyrosine hydroxylase and dopamine transporter expression, as well as dopamine levels in the denervated striatum of 6-OHDA-lesioned rats. In this structure, LGF activates microglia and raises tumor necrosis factor-alpha protein levels, which have been reported to have a role in neuroregeneration and neuroprotection. Besides, LGF stimulates the phosphorylation of MAPK/ERK1/2 and CREB, and regulates the expression of proteins which are critical for cell survival such as Bcl2 and Akt. Because LGF partially protects dopamine neurons from 6-OHDA neurotoxicity in the substantia nigra, and reduces motor deficits in these animals, we propose LGF as a novel factor that may be useful in the treatment of Parkinson’s disease. PMID:23861803

  2. Multicistronic lentiviral vector-mediated striatal gene transfer of aromatic L-amino acid decarboxylase, tyrosine hydroxylase, and GTP cyclohydrolase I induces sustained transgene expression, dopamine production, and functional improvement in a rat model of Parkinson's disease.

    PubMed

    Azzouz, Mimoun; Martin-Rendon, Enca; Barber, Robert D; Mitrophanous, Kyriacos A; Carter, Emma E; Rohll, Jonathan B; Kingsman, Susan M; Kingsman, Alan J; Mazarakis, Nicholas D

    2002-12-01

    Parkinson's disease (PD) is a neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra. This loss leads to complete dopamine depletion in the striatum and severe motor impairment. It has been demonstrated previously that a lentiviral vector system based on equine infectious anemia virus (EIAV) gives rise to highly efficient and sustained transduction of neurons in the rat brain. Therefore, a dopamine replacement strategy using EIAV has been investigated as a treatment in the 6-hydroxydopamine (6-OHDA) animal model of PD. A self-inactivating EIAV minimal lentiviral vector that expresses tyrosine hydroxylase (TH), aromatic amino acid dopa decarboxylase (AADC), and GTP cyclohydrolase 1 (CH1) in a single transcription unit has been generated. In cultured striatal neurons transduced with this vector, TH, AADC, and CH1 proteins can all be detected. After stereotactic delivery into the dopamine-denervated striatum of the 6-OHDA-lesioned rat, sustained expression of each enzyme and effective production of catecholamines were detected, resulting in significant reduction of apomorphine-induced motor asymmetry compared with control animals (p < 0.003). Expression of each enzyme in the striatum was observed for up to 5 months after injection. These data indicate that the delivery of three catecholaminergic synthetic enzymes by a single lentiviral vector can achieve functional improvement and thus open the potential for the use of this vector for gene therapy of late-stage PD patients. PMID:12451130

  3. Characterization of a new low-dose 6-hydroxydopamine model of Parkinson's disease in rat.

    PubMed

    Penttinen, Anna-Maija; Suleymanova, Ilida; Albert, Katrina; Anttila, Jenni; Voutilainen, Merja H; Airavaara, Mikko

    2016-04-01

    Intrastriatal administration of 6-hydroxydopamine (6-OHDA) induces partial degeneration of the nigrostriatal pathway, mimicking the pathology of Parkinson's disease (PD). Setting up the partial lesion model can be challenging because a number of experimental settings can be altered. This study compares seven experimental settings in a single study on d-amphetamine-induced rotations, tyrosine hydroxylase (TH)-positive neurites in the striatum, dopamine transporter (DAT)-positive neurites in the striatum, and TH-positive cells in the substantia nigra pars compacta (SNpc) in rats. Moreover, we validate a new algorithm for estimating the number of TH-positive cells. We show that the behavior and immunoreactivity vary greatly depending on the injection settings, and we categorize the lesions as progressive, stable, or regressive based on d-amphetamine-induced rotations. The rotation behavior correlated with the degree of the lesion, analyzed by immunohistochemistry; the largest lesions were in the progressive group, and the smallest lesions were in the regressive group. We establish a new low-dose partial 6-OHDA lesion model in which a total of 6 μg was distributed evenly to three sites in the striatum at a 10° angle. The administration of low-dose 6-OHDA produced stable and reliable rotation behavior and induced partial loss of striatal TH-positive and DAT-positive neurites and TH-positive cells in the SNpc. This model is highly suitable for neurorestoration studies in the search for new therapies for PD, and the new algorithm increases the efficacy for estimating the number of dopamine neurons. This study can be extremely useful for laboratories setting up the partial 6-OHDA model. PMID:26762168

  4. Long-term survival and integration of porcine expanded neural precursor cell grafts in a rat model of Parkinson's disease.

    PubMed

    Harrower, T P; Tyers, P; Hooks, Y; Barker, R A

    2006-01-01

    Porcine fetal neural tissue has been considered as an alternative source to human allografts for transplantation in neurodegenerative disorders by virtue of the fact that it can overcome the ethical and practical difficulties using human fetal neural tissue. However, primary porcine neural xenografts are rejected while porcine expanded neural precursor neural cells (PNPCs) seem to be less immunogenic and thus survive better [Armstrong, R.J., Harrower, T.P., Hurelbrink, C.B., McLaughin, M., Ratcliffe, E.L., Tyers, P., Richards, A., Dunnett, S.B., Rosser, A.E., Barker, R.A., 2001a. Porcine neural xenografts in the immunocompetent rat: immune response following grafting of expanded neural precursor cells. Neuroscience 106, 201-216]. In this study, we extended these observations to investigate the long-term survival of such transplants in immunosuppressed rats. Unilateral 6 OHDA lesioned rats received grafts into the dopamine denervated striatum of either primary porcine fetal neural tissue dissected from the E26 cortex or cortically derived neural stem cells which had been derived from the same source but expanded in vitro for 21 days. All cortically derived neural stem cell grafts survived up to 5 months in contrast to the poor survival of primary porcine xenografts. Histological analysis demonstrated good graft integration with fibers extending into the surrounding host tissue including white matter with synapse formation, and in addition there was evidence of host vascularization and myelinated fibers within the graft area. This study has therefore shown for the first time the reliable long-term survival of grafts derived from porcine expanded neural precursors in a rat model of PD, with maturation and integration into the host brain. This demonstrates that such xenografted cells may be able to recreate the damaged circuitry in PD although strategies for dopaminergic differentiation of the porcine neural precursor cell remain to be refined. PMID:16246328

  5. Characterization of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, in rat partial and full nigral 6-hydroxydopamine lesion models of Parkinson's disease.

    PubMed

    Hansen, Henrik H; Fabricius, Katrine; Barkholt, Pernille; Mikkelsen, Jens D; Jelsing, Jacob; Pyke, Charles; Knudsen, Lotte Bjerre; Vrang, Niels

    2016-09-01

    Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, have been demonstrated to promote neuroprotection in the rat 6-hydroxydopamine (6-OHDA) neurotoxin model of Parkinson's disease (PD), a neurodegenerative disorder characterized by progressive nigrostriatal dopaminergic neuron loss. In this report, we characterized the effect of a long-acting GLP-1 receptor agonist, liraglutide (500µg/kg/day, s.c.) in the context of a partial or advanced (full) 6-OHDA induced nigral lesion in the rat. Rats received a low (3µg, partial lesion) or high (13.5µg, full lesion) 6-OHDA dose stereotaxically injected into the right medial forebrain bundle (n=17-20 rats per experimental group). Six weeks after induction of a partial nigral dopaminergic lesion, vehicle or liraglutide was administered for four weeks. In the full lesion model, vehicle dosing or liraglutide treatment was applied for a total of six weeks starting three weeks pre-lesion, or administered for three weeks starting on the lesion day. Quantitative stereology was applied to assess the total number of midbrain tyrosine hydroxylase (TH) positive dopaminergic neurons. As compared to vehicle controls, liraglutide had no effect on the rotational responsiveness to d-amphetamine or apomorphine, respectively. In correspondence, while numbers of TH-positive nigral neurons were significantly reduced in the lesion side (partial lesion ≈55%; full lesion ≈90%) liraglutide administration had no influence dopaminergic neuronal loss in either PD model setting. In conclusion, liraglutide showed no neuroprotective effects in the context of moderate or substantial midbrain dopaminergic neuronal loss and associated functional motor deficits in the rat 6-OHDA lesion model of PD. PMID:27233809

  6. Alterations in the motor cortical and striatal glutamatergic system and D-serine levels in the bilateral 6-hydroxydopamine rat model for Parkinson's disease.

    PubMed

    El Arfani, Anissa; Albertini, Giulia; Bentea, Eduard; Demuyser, Thomas; Van Eeckhaut, Ann; Smolders, Ilse; Massie, Ann

    2015-09-01

    Parkinson's disease (PD) is hallmarked by progressive degeneration of the substantia nigra pars compacta (SNc) neurons and is associated with aberrant glutamatergic activity. However, studies on the glutamatergic system in the motor cortex and striatum, two motor loop-related areas, are lacking in the clinically relevant bilateral SNc 6-hydroxydopamine (6-OHDA) rat model, and therefore led to the rationale behind the present investigations. Using Western blotting, the expression levels of the glial glutamate transporters, GLT-1 and GLAST, as well as xCT, the specific subunit of system xc(-), and the vesicular glutamate transporters, VGLUT1 and 2 were investigated at two different time points (1 week and 2 weeks) post-lesion. In addition, the total content of glutamate was measured. Moreover, the total D-serine levels were, to the best of our knowledge, studied for the first time in these two PD-related areas in the bilateral 6-OHDA rat model. In the motor cortex, no significant changes were observed in the different glutamate transporter expression levels in the bilaterally-lesioned rats. In the striatum, GLAST expression was significantly decreased at both time points whereas VGLUT1 and 2 expressions were significantly decreased 2 weeks after bilateral 6-OHDA lesion. Interestingly, bilateral 6-OHDA SNc lesion resulted in an enhancement of the total d-serine content in both motor cortex and striatum at 1 week post-lesion suggesting its possible involvement in the pathophysiology of PD. In conclusion, this study demonstrates disturbed glutamate and D-serine regulation in the bilateral SNc-lesioned brain which could contribute to the behavioral impairments in PD. PMID:26172319

  7. Local Change in Urinary Bladder Contractility Following CNS Dopamine Denervation in the 6-OHDA Rat Model of Parkinson’s Disease

    PubMed Central

    Mitra, Reinika; Aronsson, Patrik; Winder, Michael; Tobin, Gunnar; Bergquist, Filip; Carlsson, Thomas

    2015-01-01

    Abstract Background: Urinary problems, including urinary frequency, urgency, and nocturia are some of the non-motor symptoms that correlate most with poor quality of life in Parkinson’s disease. However, the mechanism behind these symptoms is poorly understood, in particular regarding peripheral bladder pathophysiology following dopamine degeneration. Objective: In this study, we compared the contractile responsiveness of urinary bladder from the 6-OHDA unilateral rat model of Parkinson’s disease with that of normal untreated animals. Methods: The contractility of the urinary detrusor muscle was evaluated in bladder strip preparations using electrical field stimulation, and muscarinic and purinoceptor stimulations in an vitro organ bath setup. Results: Our data show that the overall contractile response following electrical field stimulation was significantly higher (43% at maximum contraction by 20–40 Hz stimulation) in the 6-OHDA-lesioned rats as compared to control animals. This increase was associated with a significant increase in the cholinergic contractile response, where the muscarinic agonist methacholine produced a 44% (at 10 −4 M concentration) higher response in the 6-OHDA-treated rats as compared to controls with a significant left-shift of the dose response. This indicates an altered sensitivity of the muscarinic receptor system following the specific central 6-OHDA-induced dopamine depletion. In addition a 36% larger contraction of strips from the 6-OHDA animals was also observed with purinoceptor activation using the agonist ATP (5×10 −3 M) during atropine treatment. Conclusions: Our data shows that it is not only the central dopamine control of the micturition reflex that is altered in Parkinson’s disease, but also the local contractile function of the urinary bladder. The current study draws attention to a mechanism of urinary dysfunction in Parkinson’s disease that has previously not been described. PMID:25697958

  8. Antidyskinetic Effect of 7-Nitroindazole and Sodium Nitroprusside Associated with Amantadine in a Rat Model of Parkinson's Disease.

    PubMed

    Bortolanza, Mariza; Bariotto-Dos-Santos, Keila D; Dos-Santos-Pereira, Maurício; da-Silva, Célia Aparecida; Del-Bel, Elaine

    2016-07-01

    Amantadine is the noncompetitive antagonist of N-methyl-D-aspartate, receptor activated by the excitatory neurotransmitter glutamate. It is the only effective medication used to alleviate dyskinesia induced by L-3,4-dihydroxyphenylalanine (L-DOPA) in Parkinson's disease patients. Unfortunately, adverse effects as abnormal involuntary movements (AIMs) known as L-DOPA-induced dyskinesia limit its clinical utility. Combined effective symptomatic treatment modalities may lessen the liability to undesirable events. Likewise drugs known to interfere with nitrergic system reduce AIMs in animal models of Parkinson's disease. We aimed to analyze an interaction between amantadine, neuronal nitric oxide synthase inhibitor (7-nitroindazole, 7NI), and nitric oxide donor (sodium nitroprusside, SNP) in 6-hydroxydopamine-(6-OHDA)-lesioned rats (microinjection in the medial forebrain bundle) presenting L-DOPA-induced dyskinesia (20 mg/kg, gavage, during 21 days). We confirm that 7NI-30 mg/kg, SNP-2/4 mg/kg and amantadine-40 mg/kg, individually reduced AIMs. Our results revealed that co-administration of sub-effective dose of amantadine (10 mg/kg) plus sub-effective dose of 7NI (20 mg/kg) potentiates the effect of reducing AIMs scores when compared to the effect of the drugs individually. No superior benefit on L-DOPA-induced AIMs was observed with the combination of amantadine and SNP. The results revealed that combination of ineffective doses of amantadine and 7NI represents a new strategy to increase antidyskinetic effect in L-DOPA-induced AIMs. It may provide additional therapeutic benefits to Parkinson's disease patients from these disabling complications at lower and thus safer and more tolerable doses than required when either drug is used alone. To close, we discuss the paradox of both nitric oxide synthase inhibitor and/or donor produced AIMs reduction by targeting nitric oxide synthase. PMID:27053252

  9. Alterations in primary motor cortex neurotransmission and gene expression in hemi-parkinsonian rats with drug-induced dyskinesia.

    PubMed

    Lindenbach, D; Conti, M M; Ostock, C Y; Dupre, K B; Bishop, C

    2015-12-01

    Treatment of Parkinson's disease (PD) with dopamine replacement relieves symptoms of poverty of movement, but often causes drug-induced dyskinesias. Accumulating clinical and pre-clinical evidence suggests that the primary motor cortex (M1) is involved in the pathophysiology of PD and that modulating cortical activity may be a therapeutic target in PD and dyskinesia. However, surprisingly little is known about how M1 neurotransmitter tone or gene expression is altered in PD, dyskinesia or associated animal models. The present study utilized the rat unilateral 6-hydroxydopamine (6-OHDA) model of PD/dyskinesia to characterize structural and functional changes taking place in M1 monoamine innervation and gene expression. 6-OHDA caused dopamine pathology in M1, although the lesion was less severe than in the striatum. Rats with 6-OHDA lesions showed a PD motor impairment and developed dyskinesia when given L-DOPA or the D1 receptor agonist, SKF81297. M1 expression of two immediate-early genes (c-Fos and ARC) was strongly enhanced by either L-DOPA or SKF81297. At the same time, expression of genes specifically involved in glutamate and GABA signaling were either modestly affected or unchanged by lesion and/or treatment. We conclude that M1 neurotransmission and signal transduction in the rat 6-OHDA model of PD/dyskinesia mirror features of human PD, supporting the utility of the model to study M1 dysfunction in PD and the elucidation of novel pathophysiological mechanisms and therapeutic targets. PMID:26363150

  10. Effect of glutamatergic systems on in vivo binding of [(125)I]beta-CIT in the brain of a rat model of Parkinson's disease.

    PubMed

    Kagawa, Shinya; Nakano, Takayuki; Inoue, Osamu; Nishimura, Tsunehiko

    2002-10-01

    The effect of MK-801, a noncompetitive NMDA receptor antagonist, on both in vivo and in vitro binding of [(125)I]beta-CIT (RTI-55) was investigated in a rat model of Parkinson's disease. The binding experiments were performed 2 weeks after unilateral intranigral microinjection of 6-hydroxydopamine (6-OHDA). In the in vitro binding study, no alterations in [(125)I]beta-CIT binding in rat brain sections were observed after addition of MK-801, 0.03 microM or 3 microM, to the incubation medium. However, in vivo [(125)I]beta-CIT binding to the dopamine transporter in both nonlesioned and 6-OHDA-lesioned striatum was significantly increased by pretreatment with MK-801. In vivo [(125)I]beta-CIT binding to the serotonin (5HT) transporter in nonlesioned cerebral cortex, hypothalamus, and thalamus was also significantly increased by MK-801. However, the degree of change in the specific binding of [(125)I]beta-CIT induced by MK-801 was smaller in the lesioned cerebral cortex. Kinetic analysis, by a simplified three-compartment model with the cerebellum as the reference region, revealed that these alterations in the in vivo [(125)I]beta-CIT binding induced by MK-801 were mainly due to changes in the rate constants of in vivo binding, the input rate constant, k(3), and the output rate constant, k(4). These results indicate that the glutamatergic system significantly affects the function of dopamine transporters in the degenerated dopaminergic neurons in Parkinson's disease. PMID:12211097

  11. A novel therapeutic approach to 6-OHDA-induced Parkinson's disease in rats via supplementation of PTD-conjugated tyrosine hydroxylase

    SciTech Connect

    Wu Shaoping; Fu Ailing; Wang Yuxia; Yu Leiping; Jia Peiyuan; Li Qian; Jin Guozhang; Sun Manji . E-mail: Sunmj@nic.bmi.ac.cn

    2006-07-21

    The present study aimed to evaluate whether the protein transduction domain (PTD)-conjugated human tyrosine hydroxylase (TH) fusion protein was effective on the 6-hydroxydopamine (6-OHDA)-induced Parkinson's disease (PD) model rats. An expression vector pET-PTD-TH harbouring the PTD-TH gene was constructed and transformed to the Escherichia coli BL21 cells for expression. The expressed recombinant PTD-TH with a molecular weight of 61 kD was successfully transduced (1 {mu}M) into the dopaminergic SH-sy5y human neuroblastoma cells in vitro and visualized by immunohistochemical assay. An in vivo experiment in rats showed that the iv administered PTD-TH protein (8 mg/kg) permeated across the blood-brain barrier, penetrated into the striatum and midbrain, and peaked at 5-8 h after the injection. The behavioral effects of PTD-TH on the apomorphine-induced rotations in the PD model rats 8 weeks after the 6-OHDA lesion showed that a single bolus of PTD-TH (8 mg/kg) iv injection caused a decrement of 60% of the contralateral turns on day 1 and 40% on days 5-17. The results imply that iv delivery of PTD-TH is therapeutically effective on the 6-OHDA-induced PD in rats, the PTD-mediated human TH treatment opening a promising therapeutic direction in treatment of PD.

  12. Noradrenaline neuron degeneration contributes to motor impairments and development of L-DOPA-induced dyskinesia in a rat model of Parkinson's disease.

    PubMed

    Shin, Eunju; Rogers, James T; Devoto, Paola; Björklund, Anders; Carta, Manolo

    2014-07-01

    Parkinson's disease (PD) is characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra. However, studies of post-mortem PD brains have shown that not only DA neurons but also the noradrenergic (NA) neurons in the locus coeruleus degenerate, and that the NA neurodegeneration may be as profound, and also precede degeneration of the midbrain DA neurons. Previous studies in animal models of PD have suggested that loss of forebrain NA will add to the development of motor symptoms in animals with lesions of the nigrostriatal DA neurons, but the results obtained in rodents have been inconclusive due to the shortcomings of the toxin, DSP-4, used to lesion the NA projections. Here, we have developed an alternative double-lesion paradigm using injections of 6-OHDA into striatum in combination with intraventricular injections of a powerful NA immunotoxin, anti-DBH-Saporin, to eliminate the NA neurons in the locus coeruleus, and associated pontine nuclei. Animals with combined DA and NA lesions were more prone to develop L-DOPA-induced dyskinesia, even at low L-DOPA doses, and they performed significantly worse in tests of reflexive and skilled paw use, the stepping and staircase tests, compared to DA-only lesioned rats. Post-mortem analysis revealed that NA depletion did not affect the degree of DA depletion, or the loss of tyrosine hydroxylase-positive innervation in the striatum. Cell loss in the substantia nigra was similar in both single and double lesioned animals, showing that the worsening effect was not due to increased loss of nigral DA neurons. The results show that damage to brainstem NA neurons, contributes to the development of motor impairments and the appearance of L-DOPA-induced dyskinesia in 6-OHDA lesioned rats, and provide support for the view that the development of motor symptoms and dyskinetic side effects in PD patients reflects the combined loss of midbrain DA neurons and NA neurons. PMID:24747357

  13. Enhanced Neuroprotective Effects of Coadministration of Tetrandrine with Glutathione in Preclinical Model of Parkinson's Disease

    PubMed Central

    Li, Xiang-Yun; Mei, Guang-Hai; Dong, Qiang; Zhang, Yu; Guo, Zhuang-Li; Su, Jing-Jing; Tang, Yu-Ping; Jin, Xue-Hong; Zhou, Hou-Guang; Huang, Yan-Yan

    2015-01-01

    Aim. In this study we examined the influence of tetrandrine (Tet) on the neuroprotective effects of glutathione (GSH) in the 6-hydroxydopamine- (6-OHDA-) lesioned rat model of Parkinson's disease (PD). Methods. Levels in the redox system, dopamine (DA) metabolism, dopaminergic neuronal survival, and apoptosis of the substantia nigra (SN) and striatum, as well as the rotational behavior of animals were examined after a 50-day administration of GSH + Tet (or GSH) and/or L-3,4-dihydroxyphenylalanine (L-dopa) to PD rats. Ethics Committee of Huashan Hospital, Fudan University approved the protocol (number SYXK2009-0082). Results. Administration of GSH or Tet alone did not show any significant effects on the factors evaluated in the PD rats. However, in the GSH + Tet group, we observed markedly decreased oxidative damage, inhibition of DA metabolism and enhanced DA synthesis, increased tyrosine hydroxylase- (TH-) immunopositive neuronal survival, and delayed apoptosis of dopaminergic neurons in the SN. Animal rotational behavior was improved in the GSH + Tet group. Additionally, coadministration of GSH + Tet appeared to offset the possible oxidative neurotoxicity induced by L-dopa. Conclusion. In this study, we demonstrated that tetrandrine allowed occurrence of the neuroprotective effect of glutathione probably due to inhibition of P-glycoprotein on 6-hydroxydopamine-lesioned rat models of Parkinson's disease, including rats undergoing long-term L-dopa treatment. PMID:26664824

  14. Enhanced Neuroprotective Effects of Coadministration of Tetrandrine with Glutathione in Preclinical Model of Parkinson's Disease.

    PubMed

    Li, Xiang-Yun; Mei, Guang-Hai; Dong, Qiang; Zhang, Yu; Guo, Zhuang-Li; Su, Jing-Jing; Tang, Yu-Ping; Jin, Xue-Hong; Zhou, Hou-Guang; Huang, Yan-Yan

    2015-01-01

    Aim. In this study we examined the influence of tetrandrine (Tet) on the neuroprotective effects of glutathione (GSH) in the 6-hydroxydopamine- (6-OHDA-) lesioned rat model of Parkinson's disease (PD). Methods. Levels in the redox system, dopamine (DA) metabolism, dopaminergic neuronal survival, and apoptosis of the substantia nigra (SN) and striatum, as well as the rotational behavior of animals were examined after a 50-day administration of GSH + Tet (or GSH) and/or L-3,4-dihydroxyphenylalanine (L-dopa) to PD rats. Ethics Committee of Huashan Hospital, Fudan University approved the protocol (number SYXK2009-0082). Results. Administration of GSH or Tet alone did not show any significant effects on the factors evaluated in the PD rats. However, in the GSH + Tet group, we observed markedly decreased oxidative damage, inhibition of DA metabolism and enhanced DA synthesis, increased tyrosine hydroxylase- (TH-) immunopositive neuronal survival, and delayed apoptosis of dopaminergic neurons in the SN. Animal rotational behavior was improved in the GSH + Tet group. Additionally, coadministration of GSH + Tet appeared to offset the possible oxidative neurotoxicity induced by L-dopa. Conclusion. In this study, we demonstrated that tetrandrine allowed occurrence of the neuroprotective effect of glutathione probably due to inhibition of P-glycoprotein on 6-hydroxydopamine-lesioned rat models of Parkinson's disease, including rats undergoing long-term L-dopa treatment. PMID:26664824

  15. Electroacupuncture Alleviates Depressive-Like Symptoms and Modulates BDNF Signaling in 6-Hydroxydopamine Rats

    PubMed Central

    Sun, Min; Wang, Ke; Yu, Yan; Su, Wen-Ting; Jiang, Xin-Xin

    2016-01-01

    Previous studies have identified the beneficial effects of electroacupuncture (EA) on motor behaviors in Parkinson's disease (PD). However, the role and potential mechanisms of EA in PD-associated depression remain unclear. In the present study, a rat model of PD with unilateral 6-hydroxydopamine (6-OHDA) lesions in the medial forebrain bundle was treated using EA for 4 weeks. We found that 100 Hz EA improved several motor phenotypes. In addition, tyrosine hydroxylase (TH) immunohistochemical analysis showed that EA had a minimal impact on the TH-positive profiles of the ipsilateral ventral tegmental area. Compared with the 6-OHDA group, long-term EA stimulation significantly increased sucrose solution consumption and decreased immobility time in the forced swim test. EA treatment did not alter dopamine, norepinephrine, and serotonin levels in the striatum and hippocampus. Noticeably, EA treatment reversed the 6-OHDA-induced abnormal expression of brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) in the midbrain and hippocampus. These results demonstrate that EA at 100-Hz possesses the ability to improve depressive-like symptoms in PD rats, which is, at least in part, due to the distinct effect of EA on the mesostriatal and mesocorticolimbic dopaminergic pathways. Moreover, BDNF seems to participate in the effect of EA in PD. PMID:27525025

  16. Activation of 5-HT₁A receptors in the medial subdivision of the central nucleus of the amygdala produces anxiolytic effects in a rat model of Parkinson's disease.

    PubMed

    Sun, Yi-Na; Wang, Tao; Wang, Yong; Han, Ling-Na; Li, Li-Bo; Zhang, Yu-Ming; Liu, Jian

    2015-08-01

    Although the medial subdivision of the central nucleus of the amygdala (CeM) and serotonin-1A (5-HT1A) receptors are involved in the regulation of anxiety, their roles in Parkinson's disease (PD)-associated anxiety are still unknown. Here we assessed the importance of CeM 5-HT1A receptors for anxiety in rats with unilateral 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle (MFB). The lesion induced anxiety-like behaviors, increased the firing rate and burst-firing pattern of CeM γ-aminobutyric acid (GABA) neurons, as well as decreased dopamine (DA) levels in the striatum, medial prefrontal cortex (mPFC), amygdala and ventral part of hippocampus (vHip). Intra-CeM injection of the selective 5-HT1A receptor agonist 8-OH-DPAT produced anxiolytic effects in the lesioned rats, and decreased the firing rate of CeM GABAergic neurons in two groups of rats. Compared to sham-operated rats, the duration of the inhibitory effect on the firing rate of GABAergic neurons was shortened in the lesioned rats. The injection increased DA levels in the mPFC and amygdala in two groups of rats and the vHip in the lesioned rats, and increased 5-HT level in the lesioned rats, whereas it decreased NA levels in the mPFC in two groups of rats and the vHip in the lesioned rats. Moreover, the mean density of 5-HT1A receptor and GABA double-labeled neurons in the CeM was reduced after the lesioning. These results suggest that activation of CeM 5-HT1A receptor produces anxiolytic effects in the 6-OHDA-lesioned rats, which involves decreased firing rate of the GABAergic neurons, and changed monoamine levels in the limbic and limbic-related brain regions. PMID:25797491

  17. Acute L: -DOPA effect on hydroxyl radical- and DOPAC-levels in striatal microdialysates of parkinsonian rats.

    PubMed

    Nowak, Przemysław; Kostrzewa, Rose Anna; Skaba, Dariusz; Kostrzewa, Richard M

    2010-04-01

    The object of the current study was to determine the effect of L: -3,4-dihydroxyphenylalanine (L: -DOPA) on the in vivo striatal microdialysate levels of the respective dopamine and serotonin metabolites 3,4-dihydroxyphenlalanine (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA) and hydroxyl radical level (HO(*); 2,3- and 2,5-dihydroxybenzoic acid, 2,3- and 2,5-DHBA) in adult rats made parkinsonian by treatment at 3 days after birth with the neurotoxin 6-hydroxydopamine (6-OHDA; 66.7 microg, base form, on each side; desipramine pretreatment, 1 h). Using HPLC/ED we found that in 6-OHDA-lesioned rats the basal striatal extraneuronal level of DOPAC was dramatically reduced and constituted only approximately 4.5% of referenced value (intact rats). Conversely, the striatal microdialysate level of 5-HIAA was elevated 2-fold in 6-OHDA-lesioned rats. Acute L: -DOPA (60 mg/kg i.p.; S-carbidopa pretreatment, 12.5 mg/kg i.p., 30 min) produced a rapid rise in the extraneuronal DOPAC in both tested groups but to a much greater extent in intact rats (P < 0.05). Levels of HO(*) (spin-trap products of salicylate, 2,3- and 2,5-DHBA) were elevated 2-fold in 6-OHDA-lesioned rats. However, L: -DOPA did not enhance HO(*) production; acute 6-OHDOPA treatment (60 mg/kg i.p.) also did not alter HO(*) production. In summary, L: -DOPA, an effective drug in ameliorating PD symptoms, did not acutely pose a risk for HO(*) generation in parkinsonian rats. We conclude that L: -DOPA is not likely to generate reactive oxygen species in humans nor is L: -DOPA likely to accelerate PD in humans. PMID:19760476

  18. Murine model for Parkinson's disease: from 6-OH dopamine lesion to behavioral test.

    PubMed

    da Conceição, Fabio S L; Ngo-Abdalla, Stacie; Houzel, Jean-Christophe; Rehen, Stevens K

    2010-01-01

    Parkinson's disease (PD) affects at least 6.5 million people worldwide, irrespective of gender, social, ethnic, economic, or geographic boundaries. Key symptoms, such as tremor, rigidity and bradikinesia, develop when about 3/4 of dopaminergic cells are lost in the substantia nigra, and fail to provide for the smooth, coordinated regulation of striatal motor circuits. Depression and hallucinations are common, and dementia eventually occurs in 20% of patients. At this time, there is no treatment to delay or stop the progression of PD. Rather, the medications currently available aim more towards the alleviation of these symptoms. New surgical strategies may reversibly switch on the functionally damaged circuits through the electrical stimulation of deep brain structures, but although deep brain stimulation is a major advance, it is not suitable for all patients. It remains therefore necessary to test new cell therapy approaches in preclinical models. Selective neurotoxic disruption of dopaminergic pathways can be reproduced by injection of 6-hydroxydopamine (6-OHDA) or MPTP (1-methyl-4-phenyl-1,2,3,6-tertahydropyridine) whereas depleting drugs and oxidative-damaging chemicals may also reproduce specific features of PD in rodents. Unlike MPTP, 6-OHDA lesions cause massive irreversible neuronal loss, and can be uni- or bilateral. The 6-OHDA lesion model is reliable, leads to robust motor deficits, and is the most widely used after 40 years of research in rats. As interactions between grafted cells and host can now be studied more thoroughly in mice rather than in rats, the model has been transposed to mice, where it has been recently characterized. In this video, we demonstrate how to lesion the left nigro-striatal pathway of anesthetized mice by slowly delivering 2.0 microL of 6-OHDA through a stereotaxically inserted micro-syringe needle. The loss of dopaminergic input occurs within days, and the functional impairments can be monitored over post-operative weeks and

  19. Protective Effect of Oral Hesperetin Against Unilateral Striatal 6-Hydroxydopamine Damage in the Rat.

    PubMed

    Kiasalari, Zahra; Khalili, Mohsen; Baluchnejadmojarad, Tourandokht; Roghani, Mehrdad

    2016-05-01

    Parkinson's disease (PD) is a neurodegenerative disorder due to loss of dopaminergic neurons in the substantia nigra pars compacta (SNC). PD finally leads to incapacitating symptoms including motor and cognitive deficits. This study was undertaken to assess protective effect of the flavanone hesperetin against striatal 6-hydroxydopamine lesion and to explore in more detail some underlying mechanisms including apoptosis, inflammation and oxidative stress. In this research study, intrastriatal 6-hydroxydopamine (6-OHDA)-lesioned rats received hesperetin (50 mg/kg/day) for 1 week. Hesperetin reduced apomorphine-induced rotational asymmetry and decreased the latency to initiate and the total time on the narrow beam task. It also attenuated striatal malondialdehyde and enhanced striatal catalase activity and GSH content, lowered striatal level of glial fibrillary acidic protein as an index of astrogliosis and increased Bcl2 with no significant change of the nuclear factor NF-kB as a marker of inflammation. Hesperetin treatment was also capable to mitigate nigral DNA fragmentation as an index of apoptosis and to prevent loss of SNC dopaminergic neurons. This study indicated the protective effect of hesperetin in an early model of PD via attenuation of apoptosis, astrogliosis marker and oxidative stress and it may be helpful as an adjuvant therapy for management of PD at its early stages. PMID:26700436

  20. Effects of 6-hydroxydopamine lesioning of the medial prefrontal cortex on social interactions in adolescent and adult rats.

    PubMed

    Li, Chun-Rong; Huang, Guang-Biao; Sui, Zhi Yan; Han, Eui-Hyeog; Chung, Young-Chul

    2010-07-30

    Bilateral depletion of dopamine (DA) in the medial prefrontal cortex (mPFC) following local infusions of 6-hydroxydopamine (6-OHDA) was reported to affect mesolimbic DA neurotransmission and augment spontaneous and amphetamine-induced locomotion. However, the effects of 6-OHDA lesioning of the mPFC of adolescent rats have never been investigated. Given that dopaminergic neurons reach the peak of maturation during adolescence, we hypothesized that 6-OHDA lesioning of the mPFC during adolescence would have greater impact on subsequent behavioral parameters than would such lesioning during adulthood. The aim of this study was to investigate the effects of 6-OHDA lesioning of the mPFC on the open-field activities and novel investigative and socially interactive behaviors of adolescent and adult rats. Using a stereotaxic apparatus, 6-OHDA (8.0 microg) was injected bilaterally into the mPFC of adolescent and adult rats. After a 1-week recovery period, rats were placed in an open-field chamber, and spontaneous locomotion and other behaviors were monitored. Next, a novel toy was place in the center and behavioral responses were observed. One day later, socially interactive behaviors were measured by placing the lesioned rats into a cage with four unfamiliar rats matched for age. The tests of locomotor activity and novel investigative behaviors revealed no significant differences between the lesioned and sham groups of adolescent or adult rats. Grooming and socially interactive behaviors were significantly lower in the adolescent and adult lesioned groups than in each sham group. Interestingly, we observed more extensive impairment in socially interactive behaviors among the adolescent lesioned rats compared to the adult lesioned rats. The present study indicates that DA depletion in the mPFC causes significantly reduced grooming and socially interactive behaviors; this phenomenon may be comparable to the negative symptoms observed in schizophrenia. Further research is

  1. Nogo-A Neutralization Improves Graft Function in a Rat Model of Parkinson's Disease.

    PubMed

    Seiler, Stefanie; Di Santo, Stefano; Widmer, Hans Rudolf

    2016-01-01

    Transplantation of fetal human ventral mesencephalic (VM) dopaminergic neurons into the striatum is a promising strategy to compensate for the characteristic dopamine deficit observed in Parkinson's disease (PD). This therapeutic approach, however, is currently limited by the high number of fetuses needed for transplantation and the poor survival and functional integration of grafted dopaminergic neurons into the host brain. Accumulating evidence indicates that contrasting inhibitory signals endowed in the central nervous system (CNS) might support neuronal regeneration. Hence, in the present study we aimed at improving survival and integration of grafted cells in the host brain by neutralizing Nogo-A, one of the most potent neurite growth inhibitors in the CNS. For that purpose, VM tissue cultures were transplanted into rats with a partial 6-hydroxydopamine (6-OHDA) lesion causing a hemi-PD model and concomitantly treated for 2 weeks with intra-ventricular infusion of neutralizing anti-Nogo-A antibodies. Motor behavior using the cylinder test was assessed prior to and after transplantation as functional outcome. At the end of the experimental period the number of dopaminergic fibers growing into the host brain, the number of surviving dopaminergic neurons in the grafts as well as graft size was examined. We found that anti-Nogo-A antibody infusion significantly improved the asymmetrical forelimb use observed after lesions as compared to controls. Importantly, a significantly three-fold higher dopaminergic fiber outgrowth from the transplants was detected in the Nogo-A antibody treated group as compared to controls. Furthermore, Nogo-A neutralization showed a tendency for increased survival of dopaminergic neurons (by two-fold) in the grafts. No significant differences were observed for graft volume and the number of dopaminergic neurons co-expressing G-protein-coupled inward rectifier potassium channel subunit two between groups. In sum, our findings support the

  2. Nogo-A Neutralization Improves Graft Function in a Rat Model of Parkinson’s Disease

    PubMed Central

    Seiler, Stefanie; Di Santo, Stefano; Widmer, Hans Rudolf

    2016-01-01

    Transplantation of fetal human ventral mesencephalic (VM) dopaminergic neurons into the striatum is a promising strategy to compensate for the characteristic dopamine deficit observed in Parkinson’s disease (PD). This therapeutic approach, however, is currently limited by the high number of fetuses needed for transplantation and the poor survival and functional integration of grafted dopaminergic neurons into the host brain. Accumulating evidence indicates that contrasting inhibitory signals endowed in the central nervous system (CNS) might support neuronal regeneration. Hence, in the present study we aimed at improving survival and integration of grafted cells in the host brain by neutralizing Nogo-A, one of the most potent neurite growth inhibitors in the CNS. For that purpose, VM tissue cultures were transplanted into rats with a partial 6-hydroxydopamine (6-OHDA) lesion causing a hemi-PD model and concomitantly treated for 2 weeks with intra-ventricular infusion of neutralizing anti-Nogo-A antibodies. Motor behavior using the cylinder test was assessed prior to and after transplantation as functional outcome. At the end of the experimental period the number of dopaminergic fibers growing into the host brain, the number of surviving dopaminergic neurons in the grafts as well as graft size was examined. We found that anti-Nogo-A antibody infusion significantly improved the asymmetrical forelimb use observed after lesions as compared to controls. Importantly, a significantly three-fold higher dopaminergic fiber outgrowth from the transplants was detected in the Nogo-A antibody treated group as compared to controls. Furthermore, Nogo-A neutralization showed a tendency for increased survival of dopaminergic neurons (by two-fold) in the grafts. No significant differences were observed for graft volume and the number of dopaminergic neurons co-expressing G-protein-coupled inward rectifier potassium channel subunit two between groups. In sum, our findings support the

  3. Levodopa replacement therapy alters enzyme activities in striatum and neuropeptide content in striatal output regions of 6-hydroxydopamine lesioned rats.

    PubMed

    Engber, T M; Susel, Z; Kuo, S; Gerfen, C R; Chase, T N

    1991-06-21

    The effects of striatal dopamine denervation and levodopa replacement therapy on neuronal populations in the rat striatum were assessed by measurement of glutamic acid decarboxylase (GAD) and choline acetyltransferase (CAT) activities in the striatum, dynorphin and substance P concentrations in the substantia nigra, and enkephalin concentration in the globus pallidus. Rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal pathway were treated for 21 days with levodopa (100 mg/kg/day, i.p., with 25 mg/kg benserazide) on either an intermittent (b.i.d.) or continuous (osmotic pump infusion) regimen and sacrificed following a three day drug washout. In saline-treated control rats, striatal GAD activity and globus pallidus enkephalin content were elevated and nigral substance P content was reduced ipsilateral to the 6-OHDA lesion. Intermittent levodopa treatment further increased GAD activity, decreased CAT activity, restored substance P to control levels, markedly increased dynorphin content, and had no effect on enkephalin. In contrast, continuous levodopa elevated globus pallidus enkephalin beyond the levels occurring with denervation, but had no effect on any of the other neurochemical measures. These results indicate that striatal neuronal populations are differentially affected by chronic levodopa therapy and by the continuous or intermittent nature of the treatment regimen. With the exception of substance P, levodopa did not reverse the effects of the 6-OHDA lesion but, rather, either exacerbated the lesion-induced changes (e.g. GAD and enkephalin) or altered neurochemical markers which had been unaffected by the lesion (e.g. CAT and dynorphin).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1717109

  4. Anti-parkinsonian effects of fluvoxamine maleate in maternally separated rats.

    PubMed

    Dallé, Ernest; Daniels, Willie M U; Mabandla, Musa V

    2016-10-01

    Exposure to early life stress has been shown to result in anxiety-like symptoms and exacerbates degeneration of dopaminergic neurons in a rat model of Parkinson's disease (PD). First line treatment for anxiety disorders includes the use of Fluvoxamine maleate (FM). In this study, we investigated whether treating anxiety-like symptoms with FM has an effect in alleviating the neurotoxic effects of 6-OHDA in a parkinsonian rat model. Early maternal separation was used to create a rat model that depicts anxiety-like symptoms. Maternally separated adult Sprague-Dawley rats were treated with FM prior to and following lesion with 6-hydroxydopamine (6-OHDA). The elevated plus-maze (EPM) and the forelimb akinesia tests were used to evaluate anxiety-like symptoms and motor impairment respectively. Blood plasma was used to measure corticosterone concentration, and striatal tissue was collected for dopamine (DA) and serotonin (5-HT) analysis. Our results show that animals exposed to early life stress displayed increased anxiety-like symptoms and elevated basal plasma corticosterone concentration which were attenuated by treatment with FM. A 6-OHDA lesion effect was evidenced by impairment in the forelimb akinesia test as well as decreased DA and 5-HT concentrations in the lesioned striatum. These effects were attenuated on DA neurons by FM treatment in the pre-lesion treated as opposed to the post-lesion treated rats. This study suggests that early treatment of anxiety-like behavior decreases the vulnerability of DA neurons to neurotoxic insults later in life thus slowing down DA degeneration in PD. PMID:27338206

  5. Neuroprotective Effects of A Standardized Flavonoid Extract of Safflower Against Neurotoxin-Induced Cellular and Animal Models of Parkinson's Disease.

    PubMed

    Ren, Rutong; Shi, Chunyan; Cao, Jing; Sun, Yi; Zhao, Xin; Guo, Yongfei; Wang, Chen; Lei, Hui; Jiang, Hanjie; Ablat, Nuramatjan; Xu, Jiamin; Li, Wan; Ma, Yingcong; Qi, Xianrong; Ye, Min; Pu, Xiaoping; Han, Hongbin

    2016-01-01

    Safflower has long been used to treat cerebrovascular diseases in China. We previously reported that kaempferol derivatives of safflower can bind DJ-1, a protein associated with Parkinson's disease (PD), and flavonoid extract of safflower exhibited neuroprotective effects in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of PD. In this study, a standardized safflower flavonoid extract (SAFE) was isolated from safflower and mainly contained flavonoids. Two marker compounds of SAFE, kaempferol 3-O-rutinoside and anhydrosafflor yellow B, were proven to suppress microtubule destabilization and decreased cell area, respectively. We confirmed that SAFE in dripping pill form could improve behavioural performances in a 6-hydroxydopamine (6-OHDA)-induced rat model of PD, partially via the suppression of α-synuclein overexpression or aggregation, as well as the suppression of reactive astrogliosis. Using an MRI tracer-based method, we found that 6-OHDA could change extracellular space (ECS) diffusion parameters, including a decrease in tortuosity and the rate constant of clearance and an increase in the elimination half-life of the tracer in the 6-OHDA-lesioned substantia nigra. SAFE treatment could partially inhibit the changes in ECS diffusion parameters, which might provide some information about neuronal loss and astrocyte activation. Consequently, our results indicate that SAFE is a potential therapeutic herbal product for treatment of PD. PMID:26906725

  6. Neuroprotective Effects of A Standardized Flavonoid Extract of Safflower Against Neurotoxin-Induced Cellular and Animal Models of Parkinson’s Disease

    PubMed Central

    Ren, Rutong; Shi, Chunyan; Cao, Jing; Sun, Yi; Zhao, Xin; Guo, Yongfei; Wang, Chen; Lei, Hui; Jiang, Hanjie; Ablat, Nuramatjan; Xu, Jiamin; Li, Wan; Ma, Yingcong; Qi, Xianrong; Ye, Min; Pu, Xiaoping; Han, Hongbin

    2016-01-01

    Safflower has long been used to treat cerebrovascular diseases in China. We previously reported that kaempferol derivatives of safflower can bind DJ-1, a protein associated with Parkinson’s disease (PD), and flavonoid extract of safflower exhibited neuroprotective effects in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of PD. In this study, a standardized safflower flavonoid extract (SAFE) was isolated from safflower and mainly contained flavonoids. Two marker compounds of SAFE, kaempferol 3-O-rutinoside and anhydrosafflor yellow B, were proven to suppress microtubule destabilization and decreased cell area, respectively. We confirmed that SAFE in dripping pill form could improve behavioural performances in a 6-hydroxydopamine (6-OHDA)-induced rat model of PD, partially via the suppression of α-synuclein overexpression or aggregation, as well as the suppression of reactive astrogliosis. Using an MRI tracer-based method, we found that 6-OHDA could change extracellular space (ECS) diffusion parameters, including a decrease in tortuosity and the rate constant of clearance and an increase in the elimination half-life of the tracer in the 6-OHDA-lesioned substantia nigra. SAFE treatment could partially inhibit the changes in ECS diffusion parameters, which might provide some information about neuronal loss and astrocyte activation. Consequently, our results indicate that SAFE is a potential therapeutic herbal product for treatment of PD. PMID:26906725

  7. Daphnane Diterpenes from Daphne genkwa Activate Nurr1 and Have a Neuroprotective Effect in an Animal Model of Parkinson's Disease.

    PubMed

    Han, Baek-Soo; Kim, Kyoung-Shim; Kim, Yu Jin; Jung, Hoe-Yune; Kang, Young-Mi; Lee, Kyu-Suk; Sohn, Mi-Jin; Kim, Chun-Hyung; Kim, Kwang-Soo; Kim, Won-Gon

    2016-06-24

    Nurr1 is an orphan nuclear receptor that is essential for the differentiation and maintenance of dopaminergic neurons in the brain, and it is a therapeutic target for Parkinson's disease (PD). During the screening for Nurr1 activators from natural sources using cell-based assay systems, a methanol extract of the combined stems and roots of Daphne genkwa was found to activate the transcriptional function of Nurr1 at a concentration of 3 μg/mL. The active components were isolated and identified as genkwanine N (1) and yuanhuacin (2). Both compounds 1 and 2 significantly enhanced the function of Nurr1 at 0.3 μM. Nurr1-specific siRNA abolished the activity of 1 and 2, strongly suggesting that transcriptional activation by 1 and 2 occurred through the modulation of Nurr1 function. Additionally, treatment with 1 and 2 inhibited 6-hydroxydopamine (6-OHDA)-induced neuronal cell death and lipopolysaccharide (LPS)-induced neuroinflammation. Moreover, in a 6-OHDA-lesioned rat model of PD, intraperitoneal administration of 2 (0.5 mg/kg/day) for 2 weeks significantly improved behavioral deficits and reduced tyrosine hydroxylase (TH)-positive dopaminergic neuron death induced by 6-OHDA injection and had a beneficial effect on the inflammatory response in the brain. Accordingly, compounds 1 and 2, the first reported Nurr1 activators of natural origin, are potential lead compounds for the treatment of PD. PMID:27228307

  8. Trans-blood brain barrier delivery of dopamine-loaded nanoparticles reverses functional deficits in parkinsonian rats.

    PubMed

    Pahuja, Richa; Seth, Kavita; Shukla, Anshi; Shukla, Rajendra Kumar; Bhatnagar, Priyanka; Chauhan, Lalit Kumar Singh; Saxena, Prem Narain; Arun, Jharna; Chaudhari, Bhushan Pradosh; Patel, Devendra Kumar; Singh, Sheelendra Pratap; Shukla, Rakesh; Khanna, Vinay Kumar; Kumar, Pradeep; Chaturvedi, Rajnish Kumar; Gupta, Kailash Chand

    2015-05-26

    Sustained and safe delivery of dopamine across the blood brain barrier (BBB) is a major hurdle for successful therapy in Parkinson's disease (PD), a neurodegenerative disorder. Therefore, in the present study we designed neurotransmitter dopamine-loaded PLGA nanoparticles (DA NPs) to deliver dopamine to the brain. These nanoparticles slowly and constantly released dopamine, showed reduced clearance of dopamine in plasma, reduced quinone adduct formation, and decreased dopamine autoxidation. DA NPs were internalized in dopaminergic SH-SY5Y cells and dopaminergic neurons in the substantia nigra and striatum, regions affected in PD. Treatment with DA NPs did not cause reduction in cell viability and morphological deterioration in SH-SY5Y, as compared to bulk dopamine-treated cells, which showed reduced viability. Herein, we report that these NPs were able to cross the BBB and capillary endothelium in the striatum and substantia nigra in a 6-hydroxydopamine (6-OHDA)-induced rat model of PD. Systemic intravenous administration of DA NPs caused significantly increased levels of dopamine and its metabolites and reduced dopamine-D2 receptor supersensitivity in the striatum of parkinsonian rats. Further, DA NPs significantly recovered neurobehavioral abnormalities in 6-OHDA-induced parkinsonian rats. Dopamine delivered through NPs did not cause additional generation of ROS, dopaminergic neuron degeneration, and ultrastructural changes in the striatum and substantia nigra as compared to 6-OHDA-lesioned rats. Interestingly, dopamine delivery through nanoformulation neither caused alterations in the heart rate and blood pressure nor showed any abrupt pathological change in the brain and other peripheral organs. These results suggest that NPs delivered dopamine into the brain, reduced dopamine autoxidation-mediated toxicity, and ultimately reversed neurochemical and neurobehavioral deficits in parkinsonian rats. PMID:25825926

  9. Chronic L-DOPA treatment attenuates behavioral and biochemical deficits induced by unilateral lactacystin administration into the rat substantia nigra.

    PubMed

    Konieczny, Jolanta; Czarnecka, Anna; Lenda, Tomasz; Kamińska, Kinga; Lorenc-Koci, Elżbieta

    2014-03-15

    The aim of the study was to determine whether the dopamine (DA) precursor l-DOPA attenuates parkinsonian-like symptoms produced by the ubiquitin-proteasome system inhibitor lactacystin. Wistar rats were injected unilaterally with lactacystin (2.5 μg/2 μl) or 6-OHDA (8 μg/2 μl) into the substantia nigra (SN) pars compacta. Four weeks after the lesion, the animals were treated chronically with l-DOPA (25 or 50 mg/kg) for two weeks. During l-DOPA treatment, the lactacystin-treated rats were tested for catalepsy and forelimb asymmetry. Rotational behavior was evaluated after apomorphine (0.25 mg/kg) and l-DOPA in both PD models. After completion of experiments, the animals were killed and the levels of DA and its metabolites in the striatum and SN were assayed. We found that acute l-DOPA administration effectively decreased catalepsy and increased the use of the compromised forelimb in the cylinder test. However, the lactacystin group did not respond to apomorphine or acute l-DOPA administration in the rotational test. Repeated l-DOPA treatment produced contralateral rotations in both PD models, but the number of rotations was much greater in the 6-OHDA-lesioned rats. Both toxins markedly (>90%) reduced the levels of DA and its metabolites in the striatum and SN, while l-DOPA diminished these decreases, especially in the SN. By demonstrating the efficacy of l-DOPA in several behavioral tests, our study confirms the usefulness of the lactacystin lesion as a model of PD. However, marked differences in the rotational response to apomorphine and l-DOPA suggest different mechanisms of neurodegeneration evoked by lactacystin and 6-OHDA. PMID:24361083

  10. Intrastriatal injection of botulinum neurotoxin-A is not cytotoxic in rat brain - A histological and stereological analysis.

    PubMed

    Mehlan, Juliane; Brosig, Hans; Schmitt, Oliver; Mix, Eilhard; Wree, Andreas; Hawlitschka, Alexander

    2016-01-01

    Parkinson's disease (PD) is caused by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta, resulting in a deficiency of dopamine in the striatum and an increased release of acetylcholine by tonically active interneurons. Botulinum neurotoxin-A (BoNT-A) is well known for blocking transmitter release by cholinergic presynaptic terminals. Treating striatal hypercholinism by local application of BoNT-A could be a possible new local therapy option of PD. In previous studies of our group, we analyzed the effect of BoNT-A injection into the CPu of 6-OHDA lesioned hemiparkinsonian rats. Our studies showed that BoNT-A application in hemiparkinson rat model is capable of abolishing apomorphine induced rotations for approximately 3 months. Regularly occurring axonal swellings in the BoNT-A infiltrated striata were also discovered, which we named BoNT-A induced varicosities (BiVs). Résumé: Here we investigated the long-term effect of the injection of 1ng BoNT-A into the right CPu of naive Wistar rats on the number of ChAT-ir interneurons as well as on the numeric density and the volumetric size of the BiVs in the CPu. Significant differences in the number of ChAT-ir neurons between the right BoNT-A treated CPu and the left untreated CPu were not detected up to 12 month post BoNT-A injection. The numeric density of BiVs in the treated CPu reached a maximum 3 months after BoNT-A treatment and decreased afterwards, whereas the volume of single BiVs increased steadily throughout the whole time course of the experiment. PMID:26562665

  11. Palmitoyl Serotonin Inhibits L-dopa-induced Abnormal Involuntary Movements in the Mouse Parkinson Model.

    PubMed

    Park, Hye-Yeon; Ryu, Young-Kyoung; Go, Jun; Son, Eunjung; Kim, Kyoung-Shim; Kim, Mee Ree

    2016-08-01

    L-3,4-dihydroxyphenylalanine (L-DOPA) is the most common treatment for patients with Parkinson's disease (PD). However, long term use of L-DOPA for PD therapy lead to abnormal involuntary movements (AIMs) known as dyskinesia. Fatty acid amide hydrolase (FAAH) is enriched protein in basal ganglia, and inhibition of the protein reduces dyskinetic behavior of mice. Palmitoyl serotonin (PA-5HT) is a hybrid molecule patterned after arachidonoyl serotonin, antagonist of FAAH. However, the effect of PA-5HT on L-DOPA-induced dyskinesia (LID) in PD have not yet been elucidated. To investigate whether PA-5HT relieve LID in PD and decrease hyperactivation of dopamine D1 receptors, we used the 6-hydroxydopomine (6-OHDA)-lesioned mouse model of PD and treated the L-DOPA (20 mg/kg) for 10 days with PA-5HT (0.3 mg/kg/day). The number of wall contacts with the forelimb in the cylinder test was significantly decreased by 6-OHDA lesion in mice and the pharmacotherapeutic effect of L-DOPA was also revealed in PA-5HT-treated mice. Moreover, in AIMs test, PA-5HT-treated mice showed significant reduction of locomotive, axial, limb, and orofacial AIMs score compared to the vehicle-treated mice. LID-induced hyper-phosphorylation of ERK1/2 and overexpression of FosB/ΔFosB was markedly decreased in 6-OHDA-lesioned striatum of PA-5HT-treated mice, indicating that PA-5HT decreased the dopamine D1 receptor-hyperactivation induced by chronic treatment of L-DOPA in dopamine-denervated striatum. These results suggest that PA-5HT effectively attenuates the development of LID and enhance of ERK1/2 phosphorylation and FosB/ΔFosB expression in the hemi-parkinsonian mouse model. PA-5HT may have beneficial effect on the LID in PD. PMID:27574484

  12. Palmitoyl Serotonin Inhibits L-dopa-induced Abnormal Involuntary Movements in the Mouse Parkinson Model

    PubMed Central

    Park, Hye-Yeon; Ryu, Young-Kyoung; Go, Jun; Son, Eunjung

    2016-01-01

    L-3,4-dihydroxyphenylalanine (L-DOPA) is the most common treatment for patients with Parkinson's disease (PD). However, long term use of L-DOPA for PD therapy lead to abnormal involuntary movements (AIMs) known as dyskinesia. Fatty acid amide hydrolase (FAAH) is enriched protein in basal ganglia, and inhibition of the protein reduces dyskinetic behavior of mice. Palmitoyl serotonin (PA-5HT) is a hybrid molecule patterned after arachidonoyl serotonin, antagonist of FAAH. However, the effect of PA-5HT on L-DOPA-induced dyskinesia (LID) in PD have not yet been elucidated. To investigate whether PA-5HT relieve LID in PD and decrease hyperactivation of dopamine D1 receptors, we used the 6-hydroxydopomine (6-OHDA)-lesioned mouse model of PD and treated the L-DOPA (20 mg/kg) for 10 days with PA-5HT (0.3 mg/kg/day). The number of wall contacts with the forelimb in the cylinder test was significantly decreased by 6-OHDA lesion in mice and the pharmacotherapeutic effect of L-DOPA was also revealed in PA-5HT-treated mice. Moreover, in AIMs test, PA-5HT-treated mice showed significant reduction of locomotive, axial, limb, and orofacial AIMs score compared to the vehicle-treated mice. LID-induced hyper-phosphorylation of ERK1/2 and overexpression of FosB/ΔFosB was markedly decreased in 6-OHDA-lesioned striatum of PA-5HT-treated mice, indicating that PA-5HT decreased the dopamine D1 receptor-hyperactivation induced by chronic treatment of L-DOPA in dopamine-denervated striatum. These results suggest that PA-5HT effectively attenuates the development of LID and enhance of ERK1/2 phosphorylation and FosB/ΔFosB expression in the hemi-parkinsonian mouse model. PA-5HT may have beneficial effect on the LID in PD. PMID:27574484

  13. Dopamine agonists increase perseverative instrumental responses but do not restore habit formation in a rat model of Parkinsonism.

    PubMed

    Faure, A; Leblanc-Veyrac, P; El Massioui, N

    2010-06-30

    Dopamine (DA) deafferentation of the dorsolateral striatum has been shown to prevent habit development, leaving instrumental behavior under action-outcome control that is persistently sensitive to modification of the motivational value of the reward. The present experiment further explored the basis of this dysfunction by examining the ability of intrastriatal DA agonist injections (D1 SKF 38393 or D2/D3 Quinpirole) during overtraining of a signaled instrumental task to restore habit formation in rats subjected to bilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal dopaminergic pathway. Overtraining was followed by a test of goal sensitivity by satiety-specific devaluation of the reward. The results confirmed the impaired shift in performance from action to habit in control lesioned rats. However, lesioned rats repeatedly injected with quinpirole D2/D3 agonist showed an increase in non-rewarded instrumental responses (intertrials periods) during overtraining, suggesting the development of perseverative behavior. Following the procedure of devaluation, quinpirole D2/D3 agonist treatment, and to a lesser extent SKF 38393 D1 agonist, caused the persistence of sensitivity to reward devaluation, indicating clear goal-directed behavior despite extended training. This absence of restoration of habit formation by DA agonist treatment is discussed in the light of DA agonist effects in Parkinson patients. PMID:20362642

  14. Naringin treatment induces neuroprotective effects in a mouse model of Parkinson's disease in vivo, but not enough to restore the lesioned dopaminergic system.

    PubMed

    Kim, Heung Deok; Jeong, Kyoung Hoon; Jung, Un Ju; Kim, Sang Ryong

    2016-02-01

    We recently reported that treatment with naringin, a major flavonoid found in grapefruit and citrus fruits, attenuated neurodegeneration in a rat model of Parkinson's disease (PD) in vivo. In order to investigate whether its effects are universally applied to a different model of PD and whether its treatment induces restorative effects on the lesioned nigrostriatal dopaminergic (DA) projection, we observed the effects of pre-treatment or post-treatment with naringin in a mouse model of PD. For neuroprotective effects, 6-hydroxydopamine (6-OHDA) was unilaterally injected into the striatum of mouse brains for a neurotoxin model of PD in the presence or absence of naringin by daily intraperitoneal injection. Our results showed that naringin protected the nigrostriatal DA projection from 6-OHDA-induced neurotoxicity. Moreover, similar to the effects in rat brains, this treatment induced the activation of mammalian target of rapamycin complex 1 (mTORC1), which is well known as an important survival factor for DA neurons, and inhibited microglial activation in the substantia nigra (SN) of mouse brains treated with 6-OHDA. However, there was no significant change of DA phenotypes in the SN and striatum post-treated with naringin compared with 6-OHDA-lesioned mice, despite the treatment being continued for 12 weeks. These results suggest that post-treatment with naringin alone may not be enough to restore the nigrostriatal DA projection in a mouse model of PD. However, our results apparently suggest that naringin is a beneficial natural product to prevent DA degeneration, which is involved in PD. PMID:26878791

  15. Hypericum Perforatum Hydroalcoholic Extract Mitigates Motor Dysfunction and is Neuroprotective in Intrastriatal 6-Hydroxydopamine Rat Model of Parkinson's Disease.

    PubMed

    Kiasalari, Zahra; Baluchnejadmojarad, Tourandokht; Roghani, Mehrdad

    2016-05-01

    Parkinson's disease is the second most common neurodegenerative disorder with selective and progressive decline of nigral dopaminergic neurons. Hypericum perforatum L. (H. perforatum, St. John's wort) has been traditionally used for management of different disorders, especially mild-to-moderate depression. This study was conducted to evaluate the effect of H. perforatum extract against unilateral striatal 6-hydroxydopamine (6-OHDA) toxicity and to unmask some involved mechanisms. Intrastriatal 6-OHDA-lesioned rats were treated with H. perforatum hydroalcoholic extract at a dose of 200 mg/kg/day started 1 week pre-surgery for 1 week post-surgery. The extract attenuated apomorphine-induced rotational behavior, decreased the latency to initiate and the total time on the narrow beam task, lowered striatal level of malondialdehyde and enhanced striatal catalase activity and reduced glutathione content, normalized striatal expression of glial fibrillary acidic protein, tumor necrosis factor α with no significant effect on mitogen-activated protein kinase, lowered nigral DNA fragmentation, and prevented damage of nigral dopaminergic neurons with a higher striatal tyrosine hydroxylase immunoreactivity. These findings reveal the beneficial effect of H. perforatum via attenuation of DNA fragmentation, astrogliosis, inflammation, and oxidative stress. PMID:26119304

  16. The anti-dyskinetic effect of dopamine receptor blockade is enhanced in parkinsonian rats following dopamine neuron transplantation.

    PubMed

    Shin, Eunju; Lisci, Carlo; Tronci, Elisabetta; Fidalgo, Camino; Stancampiano, Roberto; Björklund, Anders; Carta, Manolo

    2014-02-01

    Graft-induced dyskinesia (GID) is a serious complication induced by dopamine (DA) cell transplantation in parkinsonian patients. We have recently shown that DA D2 receptor blockade produces striking blockade of dyskinesia induced by amphetamine in grafted 6-OHDA-lesioned rats, a model of GID. This study was designed to investigate whether blockade of DA D1 receptors could produce similar outcome, and to see whether the effect of these treatments in grafted rats was specific for dyskinesia induced by amphetamine, or could also influence L-DOPA-induced dyskinesia (LID). L-DOPA-primed rats received transplants of fetal DA neurons into the DA-denervated striatum. Beginning at 20weeks after transplantation rats were subjected to pharmacological treatments with either L-DOPA (6mg/kg) or amphetamine (1.5mg/kg) alone, or in combination with the D1 receptor antagonist SCH23390, the D2 receptor antagonist eticlopride, and the 5-HT1A agonist/D2 receptor antagonist buspirone. Grafted rats developed severe GID, while LID was reduced. Both eticlopride and SCH23390 produced near-complete suppression of GID already at very low doses (0.015 and 0.1mg/kg, respectively). Buspirone induced similar suppression at a dose as low as 0.3mg/kg, which is far lower than the dose known to affect LID in non-grafted dyskinetic rats. In agreement with our previous results, the effect of buspirone was independent from 5-HT1A receptor activation, as it was not counteracted by the selective 5-HT1A antagonist WAY100635, but likely due to D2 receptor blockade. Most interestingly, the same doses of eticlopride, SCH23390 and buspirone were found to suppress LID in grafted but not in control dyskinetic rats. Taken together, these data demonstrate that the DA cell grafts strikingly exacerbate the effect of DA D1 and D2 receptor blockade against both GID and LID, and suggest that the anti-GID effect of buspirone seen in patients may also be due to blockade of DA D2 receptors. PMID:24135006

  17. Effects of L-Dopa on circadian rhythms of 6-OHDA striatal lesioned rats: a radiotelemetric study.

    PubMed

    Boulamery, Audrey; Simon, Nicolas; Vidal, Johanna; Bruguerolle, Bernard

    2010-01-01

    Temporal variation in the motor function of Parkinson's disease (PD) patients suggests the potential importance of a chronobiological and chronopharmacological approach in its clinical management. We previously documented the effects of striatal injection of 6-OHDA (as an animal model of PD) on the circadian rhythms of temperature (T), heart rate (HR), and locomotor activity (A). The present work assessed the possible influence of L-Dopa on these same rhythms in the 6-OHDA animal model of PD. The study began after a four-week recovery period following surgical implantation of telemetric devices to monitor the study variables and/or anaesthesia. The study was divided into an initial one-week control period (W1) for baseline measurement of T, HR, and A rhythms. Thereafter, stereotaxic 6-OHDA lesioning was done. and a second monitoring for two weeks followed (W2, W3). Rats were then randomly divided into two groups: eight control rats received, via a mini-osmotic pump implanted subcutaneously, the excipient saline; the other eight rats received L-Dopa (100 mg/kg SC/day). After a seven-day period (W4), the pumps were removed and the T, HR, and A rhythms were monitored for two weeks (W5 and W6). To control for 6-OHDA striatal dopamine-induced depletion, 12 other rats were injected by identical methods (eight rats with 6-OHDA and four controls with saline) and sacrificed at W1, W3, and W5 for dopamine striatal content determination. To verify the delivery of levodopa from the osmotic pumps, plasma levels of levodopa and its main metabolites 3-OMD, DOPAC, and HVA were determined on separate group of rats receiving the drug under the same experimental conditions (osmotic pumps delivering continuously 10 microl/h for seven days, 100 mg/kg/subcutaneously). Our results agree with previously reported rhythmic changes induced by 6-OHDA--loss of circadian rhythmicity or changes in the main parameters of the registered rhythms. When circadian rhythmicity was abolished, L

  18. Comparative Analysis of the Effects of Neurotrophic Factors CDNF and GDNF in a Nonhuman Primate Model of Parkinson's Disease.

    PubMed

    Garea-Rodríguez, Enrique; Eesmaa, Ave; Lindholm, Päivi; Schlumbohm, Christina; König, Jessica; Meller, Birgit; Krieglstein, Kerstin; Helms, Gunther; Saarma, Mart; Fuchs, Eberhard

    2016-01-01

    Cerebral dopamine neurotrophic factor (CDNF) belongs to a newly discovered family of evolutionarily conserved neurotrophic factors. We demonstrate for the first time a therapeutic effect of CDNF in a unilateral 6-hydroxydopamine (6-OHDA) lesion model of Parkinson's disease in marmoset monkeys. Furthermore, we tested the impact of high chronic doses of human recombinant CDNF on unlesioned monkeys and analyzed the amino acid sequence of marmoset CDNF. The severity of 6-OHDA lesions and treatment effects were monitored in vivo using 123I-FP-CIT (DaTSCAN) SPECT. Quantitative analysis of 123I-FP-CIT SPECT showed a significant increase of dopamine transporter binding activity in lesioned animals treated with CDNF. Glial cell line-derived neurotrophic factor (GDNF), a well-characterized and potent neurotrophic factor for dopamine neurons, served as a control in a parallel comparison with CDNF. By contrast with CDNF, only single animals responded to the treatment with GDNF, but no statistical difference was observed in the GDNF group. However, increased numbers of tyrosine hydroxylase immunoreactive neurons, observed within the lesioned caudate nucleus of GDNF-treated animals, indicate a strong bioactive potential of GDNF. PMID:26901822

  19. Acupuncture inhibits oxidative stress and rotational behavior in 6-hydroxydopamine lesioned rat.

    PubMed

    Yu, Yong-Peng; Ju, Wei-Ping; Li, Zhen-Guang; Wang, Dao-Zhen; Wang, Yuan-Chen; Xie, An-Mu

    2010-06-01

    Increasing evidence suggests the beneficial effects of acupuncture on Parkinson's disease (PD). Although clinical evidence for the acupuncture anti-Parkinson's disease effect has been demonstrated, the precise mechanism still remains elusive. It has been suggested a relationship between PD and reactive oxygen species (ROS) can result in neurodegeneration. The aim of this study was to evaluate the status of oxidative stress, as well as the antioxidant enzyme response, and the role of acupuncture stimulation at GB34 (Yanglingquan), LR3 (Taichong), ST36 (Zusanli) and SP10 (Xuehai) acupoints on regulating oxidative stress in the nigrostriatal system in the 6-hydroxydopamine (6-OHDA) lesioned rat. Two weeks after unilateral injection of 6-OHDA into the left medial forebrain bundle (MFB), an apomorphine induced rotational behavior test was performed. The levels of enzymatic, viz., superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and nonenzymatic, viz., reduced glutathione (GSH), and the levels of malondialdehyde (MDA) in the nigrostriatal system were measured to assess the oxidative stress status. Brain MDA levels significantly increased, while GSH levels were decreased in impaired groups with 6-OHDA injection only, accompanied by a marked reduction in the level of SOD and GSH-Px. The levels of oxidative stress related parameters except CAT, as well as the rotational asymmetry, were reversed by acupuncture stimulation. These results showed that acupuncture treatment displayed antioxidative and/or neuroprotective properties in the 6-OHDA lesioned rat and these protective properties might be mediated, at least in part, by involving regulation of the antioxidant defense system. PMID:20399757

  20. Graft-mediated functional recovery on a skilled forelimb use paradigm in a rodent model of Parkinson's disease is dependent on reward contingency.

    PubMed

    Cordeiro, Karina Kohn; Jiang, Wei; Papazoglou, Anna; Tenório, Sérgio Bernardo; Döbrössy, Máté; Nikkhah, Guido

    2010-10-15

    The Staircase test measures lateralised deficits in skilled paw reaching in rodents, and there is a long-standing discrepancy in the literature on whether the paradigm is sensitive to graft-mediated functional recovery in the rodent model of Parkinson's disease. The aim of the current study was to evaluate the critical influence of test conditions like pellet density on dopamine-dependent graft-mediated functional recovery. Rats were pre-trained on the Staircase test with a configuration of 8 pellets in each of the 6 wells bilaterally prior to receiving unilateral 6-OHDA lesions of the medial forebrain bundle. Later, the lesioned animals received E14 VM grafts into the striatum, and were tested on the Staircase test under one of two test configurations: bilaterally, either with 10 (HIGH) or with 2 (LOW) pellets per well. Subsequent sessions included unilateral forced-choice testing under the same pellet configuration, and second bilateral and forced-choice sessions with the pellet density configurations switched around between the groups (Cross-over). Animals were also tested on the Corridor and the Cylinder test, and subjected to drug-induced rotation. Graft-mediated functional recovery was observed in the pellets taken criteria only under the HIGH pellet configuration during the bilateral and the forced choice condition. When tested under the LOW configuration, the graft provided no measurable benefit. The presence of VM grafts reduced lateralised motor deficits in the Cylinder test, the adjacent version of the Corridor test, and drug-induced rotation. Our results confirm that VM transplants can partially restore skilled forelimb sensorimotor deficits under specific testing configuration. PMID:20394782

  1. The metabotropic glutamate receptor 4-positive allosteric modulator VU0364770 produces efficacy alone and in combination with L-DOPA or an adenosine 2A antagonist in preclinical rodent models of Parkinson's disease.

    PubMed

    Jones, Carrie K; Bubser, Michael; Thompson, Analisa D; Dickerson, Jonathan W; Turle-Lorenzo, Nathalie; Amalric, Marianne; Blobaum, Anna L; Bridges, Thomas M; Morrison, Ryan D; Jadhav, Satyawan; Engers, Darren W; Italiano, Kimberly; Bode, Jacob; Daniels, J Scott; Lindsley, Craig W; Hopkins, Corey R; Conn, P Jeffrey; Niswender, Colleen M

    2012-02-01

    Parkinson's disease (PD) is a debilitating neurodegenerative disorder associated with severe motor impairments caused by the loss of dopaminergic innervation of the striatum. Previous studies have demonstrated that positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGlu₄), including N-phenyl-7-(hydroxyimino) cyclopropa[b]chromen-1a-carboxamide, can produce antiparkinsonian-like effects in preclinical models of PD. However, these early mGlu₄ PAMsexhibited unsuitable physiochemical properties for systemic dosing, requiring intracerebroventricular administration and limiting their broader utility as in vivo tools to further understand the role of mGlu₄ in the modulation of basal ganglia function relevant to PD. In the present study, we describe the pharmacologic characterization of a systemically active mGlu₄ PAM, N-(3-chlorophenyl)picolinamide (VU0364770), in several rodent PD models. VU0364770 showed efficacy alone or when administered in combination with L-DOPA or an adenosine 2A (A2A) receptor antagonist currently in clinical development (preladenant). When administered alone, VU0364770 exhibited efficacy in reversing haloperidol-induced catalepsy, forelimb asymmetry-induced by unilateral 6-hydroxydopamine (6-OHDA) lesions of the median forebrain bundle, and attentional deficits induced by bilateral 6-OHDA nigrostriatal lesions in rats. In addition, VU0364770 enhanced the efficacy of preladenant to reverse haloperidol-induced catalepsy when given in combination. The effects of VU0364770 to reverse forelimb asymmetry were also potentiated when the compound was coadministered with an inactive dose of L-DOPA, suggesting that mGlu₄ PAMs may provide L-DOPA-sparing activity. The present findings provide exciting support for the potential role of selective mGlu₄ PAMs as a novel approach for the symptomatic treatment of PD and a possible augmentation strategy with either L-DOPA or A2A antagonists. PMID:22088953

  2. Chronic L-DOPA administration increases the firing rate but does not reverse enhanced slow frequency oscillatory activity and synchronization in substantia nigra pars reticulata neurons from 6-hydroxydopamine-lesioned rats.

    PubMed

    Aristieta, A; Ruiz-Ortega, J A; Miguelez, C; Morera-Herreras, T; Ugedo, L

    2016-05-01

    The pathophysiology of Parkinson's disease (PD) and of L-DOPA-induced dyskinesia (LID) is associated with dysfunctional neuronal activity in several nuclei of the basal ganglia. Moreover, high levels of oscillatory activity and synchronization have also been described in both intra- and inter-basal ganglia nuclei and the cerebral cortex. However, the relevance of these alterations in the motor symptomatology related to Parkinsonism and LID is not fully understood. Recently, we have shown that subthalamic neuronal activity correlates with axial abnormal movements and that a subthalamic nucleus (STN) lesion partially reduces LID severity as well as the expression of some striatal molecular modifications. The aim of the present study was to assess, through single-unit extracellular recording techniques under urethane anaesthesia, neuronal activity of the substantia nigra pars reticulata (SNr) and its relationship with LID and STN hyperactivity together with oscillatory and synchronization between these nuclei and the cerebral cortex in 6-OHDA-lesioned and dyskinetic rats. Twenty-four hours after the last injection of L-DOPA the firing rate and the inhibitory response to an acute challenge of L-DOPA of SNr neurons from dyskinetic animals were increased with respect to those found in intact and 6-OHDA-lesioned rats. Moreover, there was a significant correlation between the mean firing rate of SNr neurons and the severity of the abnormal movements (limb and orolingual subtypes). There was also a significant correlation between the firing activity of SNr and STN neurons recorded from dyskinetic rats. In addition, low frequency band oscillatory activity and synchronization both within the SNr or STN and with the cerebral cortex were enhanced in 6-OHDA-lesioned animals and not or slightly affected by chronic treatment with L-DOPA. Altogether, these results indicate that neuronal SNr firing activity is relevant in dyskinesia and may be driven by STN hyperactivity. Conversely

  3. Transcription factor Six2 mediates the protection of GDNF on 6-OHDA lesioned dopaminergic neurons by regulating Smurf1 expression

    PubMed Central

    Gao, J; Kang, X-y; Sun, S; Li, L; Zhang, B-l; Li, Y-q; Gao, D-s

    2016-01-01

    Glial cell line-derived neurotrophic factor (GDNF) has strong neuroprotective and neurorestorative effects on dopaminergic (DA) neurons in the substantia nigra (SN); however, the underlying molecular mechanisms remain to be fully elucidated. In this study, we found that the expression level of transcription factor Six2 was increased in damaged DA neurons after GDNF rescue in vivo and in vitro. Knockdown of Six2 resulted in decreased cell viability and increased the apoptosis of damaged DA neurons after GDNF treatment in vitro. In contrast, Six2 overexpression increased cell viability and decreased cell apoptosis. Furthermore, genome-wide chromatin immunoprecipitation sequencing (ChIP-seq) indicated that Six2 directly bound to the promoter CAGCTG sequence of smad ubiquitylation regulatory factor 1 (Smurf1). ChIP-quantitative polymerase chain reaction (qPCR) analysis showed that Smurf1 expression was significantly upregulated after GDNF rescue. Moreover, knockdown of Six2 decreased Smurf1 expression, whereas overexpression of Six2 increased Smurf1 expression in damaged DA neurons after GDNF rescue. Meanwhile, knockdown and overexpression of Smurf1 increased and decreased p53 expression, respectively. Taken together, our results from in vitro and in vivo analysis indicate that Six2 mediates the protective effects of GDNF on damaged DA neurons by regulating Smurf1 expression, which could be useful in identifying potential drug targets for injured DA neurons. PMID:27148690

  4. Comparative Analysis of the Effects of Neurotrophic Factors CDNF and GDNF in a Nonhuman Primate Model of Parkinson’s Disease

    PubMed Central

    Garea-Rodríguez, Enrique; Eesmaa, Ave; Lindholm, Päivi; Schlumbohm, Christina; König, Jessica; Meller, Birgit; Krieglstein, Kerstin; Helms, Gunther; Saarma, Mart; Fuchs, Eberhard

    2016-01-01

    Cerebral dopamine neurotrophic factor (CDNF) belongs to a newly discovered family of evolutionarily conserved neurotrophic factors. We demonstrate for the first time a therapeutic effect of CDNF in a unilateral 6-hydroxydopamine (6-OHDA) lesion model of Parkinson’s disease in marmoset monkeys. Furthermore, we tested the impact of high chronic doses of human recombinant CDNF on unlesioned monkeys and analyzed the amino acid sequence of marmoset CDNF. The severity of 6-OHDA lesions and treatment effects were monitored in vivo using 123I-FP-CIT (DaTSCAN) SPECT. Quantitative analysis of 123I-FP-CIT SPECT showed a significant increase of dopamine transporter binding activity in lesioned animals treated with CDNF. Glial cell line-derived neurotrophic factor (GDNF), a well-characterized and potent neurotrophic factor for dopamine neurons, served as a control in a parallel comparison with CDNF. By contrast with CDNF, only single animals responded to the treatment with GDNF, but no statistical difference was observed in the GDNF group. However, increased numbers of tyrosine hydroxylase immunoreactive neurons, observed within the lesioned caudate nucleus of GDNF-treated animals, indicate a strong bioactive potential of GDNF. PMID:26901822

  5. Long-term treatment with L-DOPA or pramipexole affects adult neurogenesis and corresponding non-motor behavior in a mouse model of Parkinson's disease.

    PubMed

    Chiu, W-H; Depboylu, C; Hermanns, G; Maurer, L; Windolph, A; Oertel, W H; Ries, V; Höglinger, G U

    2015-08-01

    Non-motor symptoms such as hyposmia and depression are often observed in Parkinson's disease (PD) and can precede the onset of motor symptoms for years. The underlying pathological alterations in the brain are not fully understood so far. Dysregulation of adult neurogenesis in the dentate gyrus of the hippocampus and the olfactory bulb has been recently suggested to be implicated in non-motor symptoms of PD. However, there is so far no direct evidence to support the relationship of non-motor symptoms and the modulation of adult neurogenesis following dopamine depletion and/or dopamine replacement. In this study, we investigated the long-term effects of l-DOPA and pramipexole, a dopamine agonist, in a mouse model of bilateral intranigral 6-OHDA lesion, in order to assess the impact of adult neurogenesis on non-motor behavior. We found that l-DOPA and pramipexole can normalize decreased neurogenesis in the hippocampal dentate gyrus and the periglomerular layer of the olfactory bulb caused by a 6-OHDA lesion. Interestingly, pramipexole showed an antidepressant and anxiolytic effect in the forced swim test and social interaction test. However, there was no significant change in learning and memory function after dopamine depletion and dopamine replacement, respectively. PMID:25839898

  6. HYPERACTIVITY AND HYPOACTIVITY PRODUCED BY LESIONS TO THE MESOLIMBIC DOPAMINE SYSTEM

    EPA Science Inventory

    Spontaneous locomotor activity and the locomotor response to amphetamine and apomorphine were studied in rats subjected to either radiofrequency(RF), 6-hydroxydopamine (6-OHDA) of both RF and 6-OHDA lesions of the mesolimbic dopamine (DA) system. Large 6-OHDA lesions of the ventr...

  7. Relationship of dopamine to serotonin in the neonatal 6-OHDA rat model of Lesch-Nyhan syndrome.

    PubMed

    Allen, S M; Davis, W M

    1999-09-01

    Rats were treated as neonates with either 6-hydroxydopamine (6-OHDA) 100 micrograms or vehicle intracisternally. Upon maturation, animals receiving 6-OHDA were assigned to four groups, with two of the four groups receiving intraventricular 5,7-dihydroxytryptamine (5,7-DHT) 75 micrograms bilaterally. At 94 days of age, animals were injected with either SKF-38393 (3.0 mg/kg, intraperitoneally (i.p.)), a dopamine D1 agonist, or m-chlorophenylpiperazine (m-CPP) (3.0 mg/kg, i.p.), a 5-HT2C agonist, in an attempt to evoke behaviors such as stereotypical chewing, head-nodding, self-biting and self-mutilation. Both SKF-38393 and m-CPP induced the target behaviors in animals receiving 6-OHDA alone. Animals receiving additional 5,7-DHT treatment did not show any of the target behaviors in response to SKF-38393, but exhibited a much higher sensitivity to m-CPP. Pre-treatment with SCH-23390 in animals receiving 6-OHDA alone was effective in preventing SKF-38393-induced target behaviors, but not those induced by m-CPP. Pre-treatment with mianserin partially antagonized the effects of both SKF-38393 and m-CPP in these same animals. In groups receiving both neonatal 6-OHDA and adult 5,7-DHT, mianserin was effective in reducing m-CPP-induced behaviors, while SCH-23390 was largely ineffective. These data provide evidence of a serial relationship between the D1 and 5-HT2C receptor systems in the neostriatum of animals receiving neonatal 6-OHDA lesions. PMID:10780253

  8. Deuterium-substituted L-DOPA displays increased behavioral potency and dopamine output in an animal model of Parkinson's disease: comparison with the effects produced by L-DOPA and an MAO-B inhibitor.

    PubMed

    Malmlöf, Torun; Feltmann, Kristin; Konradsson-Geuken, Åsa; Schneider, Frank; Alken, Rudolf-Giesbert; Svensson, Torgny H; Schilström, Björn

    2015-02-01

    The most effective treatment of Parkinson's disease (PD) L-DOPA is associated with major side effects, in particular L-DOPA-induced dyskinesia, which motivates development of new treatment strategies. We have previously shown that chronic treatment with a substantially lower dose of deuterium-substituted L-DOPA (D3-L-DOPA), compared with L-DOPA, produced equal anti-parkinsonian effect and reduced dyskinesia in 6-OHDA-lesioned rats. The advantageous effects of D3-L-DOPA are in all probability related to a reduced metabolism of deuterium dopamine by the enzyme monoamine oxidase (MAO). Therefore, a comparative neurochemical analysis was here performed studying the effects of D3-L-DOPA and L-DOPA on dopamine output and metabolism in 6-OHDA-lesioned animals using in vivo microdialysis. The effects produced by D3-L-DOPA and L-DOPA alone were additionally compared with those elicited when the drugs were combined with the MAO-B inhibitor selegiline, used in PD treatment. The different treatment combinations were first evaluated for motor activation; here the increased potency of D3-L-DOPA, as compared to that of L-DOPA, was confirmed and shown to be of equal magnitude as the effect produced by the combination of selegiline/L-DOPA. The extracellular levels of dopamine were also increased following both D3-L-DOPA and selegiline/L-DOPA administration compared with L-DOPA administration. The enhanced behavioral and neurochemical effects produced by D3-L-DOPA and the combination of selegiline/L-DOPA are attributed to decreased metabolism of released dopamine by MAO-B. The similar effect produced by D3-L-DOPA and selegiline/L-DOPA, respectively, is of considerable clinical interest since D3-L-DOPA, previously shown to exhibit a wider therapeutic window, in addition may reduce the need for adjuvant MAO-B inhibitor treatment. PMID:24906468

  9. Two-step grafting significantly enhances the survival of foetal dopaminergic transplants and induces graft-derived vascularisation in a 6-OHDA model of Parkinson's disease.

    PubMed

    Büchele, Fabian; Döbrössy, Máté; Hackl, Christina; Jiang, Wei; Papazoglou, Anna; Nikkhah, Guido

    2014-08-01

    Following transplantation of foetal primary dopamine (DA)-rich tissue for neurorestaurative treatment of Parkinson's disease (PD), only 5-10% of the functionally relevant DAergic cells survive both in experimental models and in clinical studies. The current work tested how a two-step grafting protocol could have a positive impact on graft survival. DAergic tissue is divided in two portions and grafted in two separate sessions into the same target area within a defined time interval. We hypothesized that the first graft creates a "DAergic" microenvironment or "nest" similar to the perinatal substantia nigra that stimulates and protects the second graft. 6-OHDA-lesioned rats were sequentially transplanted with wild-type (GFP-, first graft) and transgenic (GFP+, second graft) DAergic cells in time interims of 2, 5 or 9days. Each group was further divided into two sub-groups receiving either 200k (low cell number groups: 2dL, 5dL, 9dL) or 400k cells (high cell number groups: 2dH, 5dH, 9dH) as first graft. During the second transplantation, all groups received the same amount of 200k GFP+ cells. Controls received either low or high cell numbers in one single session (standard protocol). Drug-induced rotations, at 2 and 6weeks after grafting, showed significant improvement compared to the baseline lesion levels without significant differences between the groups. Rats were sacrificed 8weeks after transplantation for post-mortem histological assessment. Both two-step groups with the time interval of 2days (2dL and 2dH) showed a significantly higher survival of DAergic cells compared to their respective standard control group (2dL, +137%; 2dH, +47%). Interposing longer intervals of 5 or 9days resulted in the loss of statistical significance, neutralising the beneficial two-step grafting effect. Furthermore, the transplants in the 2dL and 2dH groups had higher graft volume and DA-fibre-density values compared to all other two-step groups. They also showed intense growth of

  10. Rat Endovascular Perforation Model

    PubMed Central

    Sehba, Fatima A.

    2014-01-01

    Experimental animal models of aneurysmal subarachnoid hemorrhage (SAH) have provided a wealth of information on the mechanisms of brain injury. The Rat endovascular perforation model (EVP) replicates the early pathophysiology of SAH and hence is frequently used to study early brain injury following SAH. This paper presents a brief review of historical development of the EVP model, details the technique used to create SAH and considerations necessary to overcome technical challenges. PMID:25213427

  11. Intraventricular injection of 6-hydroxydopamine results in an increased number of tyrosine hydroxylase immune-positive cells in the rat cortex.

    PubMed

    Wachter, B; Caradonna, S; Gittinger, K; Schläger, A; Küppers, E

    2014-11-01

    Previously we have demonstrated that intraventricular injection of 6-hydroxydopamine (6-OHDA) results in increased proliferation and de-differentiation of rat cortical astrocytes into progenitor-like cells 4 days after lesion (Wachter et al., 2010). To find out if these cells express tyrosine hydroxylase (TH), the rate-limiting enzyme in the catecholamine synthesis pathway, we performed immunohistochemistry in the rat cortex following intraventricular injection of 6-OHDA. Four days after injection we demonstrated a strong emergence of TH-positive (TH(+)) somata in the cortices of 6-OHDA-lesioned animals. The number of TH(+) cells in the cortex of 6-OHDA-lesioned animals was 15 times higher than in sham-operated animals, where virtually no TH(+) somata occurred. Combining TH immunohistochemistry with classical Nissl stain yielded complete congruency, and ∼45% of the TH(+) cells co-expressed calretinin, which indicates an interneuron affiliation. There was no co-staining of TH with other interneuron markers or with glial markers such as glial fibrillary acidic protein (GFAP) or the neural stem/progenitor marker Nestin, nor could we find co-localization with the proliferation marker Ki67. However, we found a co-localization of TH with glial progenitor cell markers (Sox2 and S100β) and with polysialylated-neural cell adhesion molecule (PSA-NCAM), which has been shown to be expressed in immature, but not recently generated cortical neurons. Taken together, this study seems to confirm our previous findings with respect to a 6-OHDA-induced expression of neuronal precursor markers in cells of the rat cortex, although the TH(+) cells found in this study are not identical with the potentially de-differentiated astrocytes described recently (Wachter et al., 2010). The detection of cortical cells expressing the catecholaminergic key enzyme TH might indicate a possible compensatory role of these cells in a dopamine-(DA)-depleted system. Future studies are needed to determine

  12. Effect of exercise on dopamine neuron survival in prenatally stressed rats.

    PubMed

    Mabandla, Musa V; Kellaway, Lauriston A; Daniels, William M U; Russell, Vivienne A

    2009-12-01

    Prenatal stress has been associated with increased vulnerability to psychiatric disturbances including schizophrenia, depression, attention-deficit hyperactivity disorder and autism. Elevated maternal circulating stress hormones alter development of neural circuits in the fetal brain and cause long-term changes in behaviour. The aim of the present study was to investigate whether mild prenatal stress increases the vulnerability of dopamine neurons in adulthood. A low dose of 6-hydroxydopamine (6-OHDA, 5 microg/4 microl saline) was unilaterally infused into the medial forebrain bundle of nerve fibres in the rat brain in order to create a partial lesion of dopamine neurons which was sufficient to cause subtle behavioural deficits associated with early onset of Parkinson's disease without complete destruction of dopamine neurons. Voluntary exercise appeared to have a neuroprotective effect resulting in an improvement in motor control and decreased asymmetry in the use of left and right forelimbs to explore a novel environment as well as decreased asymmetry of tyrosine hydroxylase-positive cells in the substantia nigra pars compacta and decreased dopamine cell loss in 6-OHDA-lesioned rats. Prenatal stress appeared to enhance the toxic effect of 6-OHDA possibly by reducing the compensatory adaptations to exercise. PMID:19844780

  13. Animal models of Parkinson's disease: a source of novel treatments and clues to the cause of the disease

    PubMed Central

    Duty, Susan; Jenner, Peter

    2011-01-01

    Animal models of Parkinson's disease (PD) have proved highly effective in the discovery of novel treatments for motor symptoms of PD and in the search for clues to the underlying cause of the illness. Models based on specific pathogenic mechanisms may subsequently lead to the development of neuroprotective agents for PD that stop or slow disease progression. The array of available rodent models is large and ranges from acute pharmacological models, such as the reserpine- or haloperidol-treated rats that display one or more parkinsonian signs, to models exhibiting destruction of the dopaminergic nigro-striatal pathway, such as the classical 6-hydroxydopamine (6-OHDA) rat and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse models. All of these have provided test beds in which new molecules for treating the motor symptoms of PD can be assessed. In addition, the emergence of abnormal involuntary movements (AIMs) with repeated treatment of 6-OHDA-lesioned rats with L-DOPA has allowed for examination of the mechanisms responsible for treatment-related dyskinesia in PD, and the detection of molecules able to prevent or reverse their appearance. Other toxin-based models of nigro-striatal tract degeneration include the systemic administration of the pesticides rotenone and paraquat, but whilst providing clues to disease pathogenesis, these are not so commonly used for drug development. The MPTP-treated primate model of PD, which closely mimics the clinical features of PD and in which all currently used anti-parkinsonian medications have been shown to be effective, is undoubtedly the most clinically-relevant of all available models. The MPTP-treated primate develops clear dyskinesia when repeatedly exposed to L-DOPA, and these parkinsonian animals have shown responses to novel dopaminergic agents that are highly predictive of their effect in man. Whether non-dopaminergic drugs show the same degree of predictability of response is a matter of debate. As our

  14. Inhibition of Glycogen Synthase Kinase-3β (GSK-3β) as potent therapeutic strategy to ameliorates L-dopa-induced dyskinesia in 6-OHDA parkinsonian rats

    PubMed Central

    Xie, Cheng-long; Lin, Jing-Ya; Wang, Mei-Hua; Zhang, Yu; Zhang, Su-fang; Wang, Xi-Jin; Liu, Zhen-Guo

    2016-01-01

    Levodopa (L-dopa) is the dominating therapy drug for exogenous dopaminergic substitution and can alleviate most of the manifestations of Parkinson’s disease (PD), but long-term therapy is associated with the emergence of L-dopa-induced dyskinesia (LID). Evidence points towards an involvement of Glycogen Synthase Kinase-3β (GSK-3β) in development of LID. In the present study, we found that animals rendered dyskinetic by L-dopa treatment, administration of TDZD8 (2mg/kg) obviously prevented the severity of AIM score, as well as improvement in motor function (P < 0.05). Moreover, the TDZD8-induced reduction in dyskinetic behavior correlated with a reduction in molecular correlates of LID. TDZD8 reduced the phosphorylation levels of tau, DARPP32, ERK and PKA protein, which represent molecular markers of LID, as well as reduced L-dopa-induced FosB mRNA and PPEB mRNA levels in the lesioned striatum. In addition, we found that TDZD8 antidyskinetic properties were overcome by D1 receptor, as pretreatment with SKF38393 (5 mg/kg, 10 mg/kg, reapectively), a D1 receptor agonist, blocked TDZD8 antidyskinetic actions. This study supported the hypothesis that GSK-3β played an important role in the development and expression of LID. Inhibition of GSK-3β with TDZD8 reduced the development of ALO AIM score and associated molecular changes in 6-OHDA-lesioned rats. PMID:26997328

  15. Distinct temporal spike and local field potential activities in the thalamic parafascicular nucleus of parkinsonian rats during rest and limb movement.

    PubMed

    Wang, Min; Qu, Qingyang; He, Tingting; Li, Min; Song, Zhimin; Chen, Feiyu; Zhang, Xiao; Xie, Jinlu; Geng, Xiwen; Yang, Maoquan; Wang, Xiusong; Lei, Chengdong; Hou, Yabing

    2016-08-25

    Several studies have suggested that the thalamic centromedian-parafascicular (CM/PF or the PF in rodents) is implicated in the pathophysiology of Parkinson's disease (PD). However, inconsistent changes in the neuronal firing rate and pattern have been reported in parkinsonian animals. To investigate the impact of a dopaminergic cell lesion on PF extracellular discharge in behaving rats, the PF neural activities in the spike and local field potential (LFP) were recorded in unilaterally 6-hydroxydopamine- (6-OHDA) lesioned and neurologically intact control rats during rest and limb movement. During rest, the two PF neuronal subtypes was less spontaneously active, with no difference in the spike firing rates between the control and lesioned rats; only the lesioned rats reshaped their spike firing pattern. Furthermore, the simultaneously recorded LFP in the lesioned rats exhibited a significant increase in power at 12-35 and 35-70Hz and a decrease in power at 0.7-12Hz. During the execution of a voluntary movement, two subtypes of PF neurons were identified by a rapid increase in the discharge activity in both the control and lesioned rats. However, dopamine lesioning was associated with a decrease in neuronal spiking fire rate and reshaping in the firing pattern in the PF. The simultaneously recorded LFP activity exhibited a significant increase in power at 12-35Hz and a decrease in power at 0.7-12Hz compared with the control rats. These findings indicate that 6-OHDA induces modifications in PF spike and LFP activities in rats during rest and movement and suggest that PF dysfunction may be an important contributor to the pathophysiology of parkinsonian motor impairment. PMID:27238892

  16. Effects of GDF5 overexpression on embryonic rat dopaminergic neurones in vitro and in vivo.

    PubMed

    O'Sullivan, David B; Harrison, Patrick T; Sullivan, Aideen M

    2010-05-01

    Transplantation of embryonic dopaminergic neurones has shown promise for the treatment of Parkinson's disease (PD), but this approach is limited by the poor survival of the transplanted cells. Exogenous dopaminergic neurotrophic factors such as growth/differentiation factor 5 (GDF5) have been found to enhance the survival of transplanted dopaminergic neurones. However, this approach is limited by the rapid degradation of such factors in vivo; thus, methods for long-term delivery of these factors are under investigation. The present study shows, using optimised lipid-mediated transfection procedures, that overexpression of GDF5 significantly improves the survival of dopaminergic neurones in cultures of embryonic day (E) 13 rat ventral mesencephalon (VM) and protects them against 6-hydroxydopamine (6-OHDA)-induced toxicity. In another experiment, E13 VM cells were transfected with GDF5 after 1 day in vitro (DIV), then transplanted into 6-OHDA-lesioned adult rat striata after 2 DIV. The survival of these E13 VM dopaminergic neurones after transfection and transplantation was as least as high as that of freshly dissected E14 VM dopaminergic neurones, demonstrating that transfection was not detrimental to these cells. Furthermore, GDF5-overexpressing E13 VM transplants significantly reduced amphetamine-induced rotational asymmetry in the lesioned rats. This study shows that lipid-mediated transfection in vitro prior to transplantation is a valid approach for the introduction of neurotrophic proteins such as GDF5, as well as lending further support to the potential use of GDF5 in neuroprotective therapy for PD. PMID:20349094

  17. Modeling nicotine addiction in rats.

    PubMed

    Caille, Stephanie; Clemens, Kelly; Stinus, Luis; Cador, Martine

    2012-01-01

    Among the human population, 15% of drug users develop a pathological drug addiction. This figure increases substantially with nicotine, whereby more than 30% of those who try smoking develop a nicotine addiction. Drug addiction is characterized by compulsive drug-seeking and drug-taking behaviors (craving), and loss of control over intake despite impairment in health, social, and occupational functions. This behavior can be accurately modeled in the rat using an intravenous self-administration (IVSA) paradigm. Initial attempts at establishing nicotine self-administration had been problematic, yet in recent times increasingly reliable models of nicotine self-administration have been developed. The present article reviews different characteristics of the nicotine IVSA model that has been developed to examine nicotine reinforcing and motivational properties in rats. PMID:22231818

  18. Role of nucleus of the solitary tract noradrenergic neurons in post-stress cardiovascular and hormonal control in male rats

    PubMed Central

    Bundzikova-Osacka, Jana; Ghosal, Sriparna; Packard, Benjamin A.; Ulrich-Lai, Yvonne M.; Herman, James P.

    2015-01-01

    Chronic stress causes hypothalamo-pituitary-adrenal (HPA) axis hyperactivity and cardiovascular dyshomeostasis. Noradrenergic neurons in the nucleus of the solitary tract (NTS) are considered to play a role in these changes. Here, we tested the hypothesis that NTS noradrenergic A2 neurons are required for cardiovascular and HPA axis responses to both acute and chronic stress. Adult male rats received bilateral microinjection into the NTS of 6-hydroxydopamine (6-OHDA) to lesion A2 neurons [cardiovascular study, n= 5; HPA study, n= 5], or vehicle [cardiovascular study, n= 6; HPA study, n= 4]. Rats were exposed to acute restraint stress followed by 14 days of chronic variable stress (CVS). On the last day of testing, rats were placed in a novel elevated plus maze (EPM) to test post-CVS stress responses. Lesions of NTS A2 neurons reduced the tachycardic response to acute restraint, confirming that A2 neurons promote sympathetic activation following acute stress. In addition, CVS increased the ratio of low frequency to high frequency power for heart rate variability, indicative of sympathovagal imbalance, and this effect was significantly attenuated by 6-OHDA lesion. Lesions of NTS A2 neurons reduced acute restraint-induced corticosterone secretion, but did not affect the corticosterone response to the EPM, indicating that A2 neurons promote acute HPA axis responses, but are not involved in CVS-mediated HPA axis sensitization. Collectively, these data indicate that A2 neurons promote both cardiovascular and HPA axis responses to acute stress. Moreover, A2 catecholaminergic neurons may contribute to the potentially deleterious enhancement of sympathetic drive following chronic stress. PMID:25765732

  19. Advances on genetic rat models of epilepsy

    PubMed Central

    Serikawa, Tadao; Mashimo, Tomoji; Kuramoto, Takashi; Voigt, Birger; Ohno, Yukihiro; Sasa, Masashi

    2014-01-01

    Considering the suitability of laboratory rats in epilepsy research, we and other groups have been developing genetic models of epilepsy in this species. After epileptic rats or seizure-susceptible rats were sporadically found in outbred stocks, the epileptic traits were usually genetically-fixed by selective breeding. So far, the absence seizure models GAERS and WAG/Rij, audiogenic seizure models GEPR-3 and GEPR-9, generalized tonic-clonic seizure models IER, NER and WER, and Canavan-disease related epileptic models TRM and SER have been established. Dissection of the genetic bases including causative genes in these epileptic rat models would be a significant step toward understanding epileptogenesis. N-ethyl-N-nitrosourea (ENU) mutagenesis provides a systematic approach which allowed us to develop two novel epileptic rat models: heat-induced seizure susceptible (Hiss) rats with an Scn1a missense mutation and autosomal dominant lateral temporal epilepsy (ADLTE) model rats with an Lgi1 missense mutation. In addition, we have established episodic ataxia type 1 (EA1) model rats with a Kcna1 missense mutation derived from the ENU-induced rat mutant stock, and identified a Cacna1a missense mutation in a N-Methyl-N-nitrosourea (MNU)-induced mutant rat strain GRY, resulting in the discovery of episodic ataxia type 2 (EA2) model rats. Thus, epileptic rat models have been established on the two paths: ‘phenotype to gene’ and ‘gene to phenotype’. In the near future, development of novel epileptic rat models will be extensively promoted by the use of sophisticated genome editing technologies. PMID:25312505

  20. Advances on genetic rat models of epilepsy.

    PubMed

    Serikawa, Tadao; Mashimo, Tomoji; Kuramoro, Takashi; Voigt, Birger; Ohno, Yukihiro; Sasa, Masashi

    2015-01-01

    Considering the suitability of laboratory rats in epilepsy research, we and other groups have been developing genetic models of epilepsy in this species. After epileptic rats or seizure-susceptible rats were sporadically found in outbred stocks, the epileptic traits were usually genetically-fixed by selective breeding. So far, the absence seizure models GAERS and WAG/Rij, audiogenic seizure models GEPR-3 and GEPR-9, generalized tonic-clonic seizure models IER, NER and WER, and Canavan-disease related epileptic models TRM and SER have been established. Dissection of the genetic bases including causative genes in these epileptic rat models would be a significant step toward understanding epileptogenesis. N-ethyl-N-nitrosourea (ENU) mutagenesis provides a systematic approach which allowed us to develop two novel epileptic rat models: heat-induced seizure susceptible (Hiss) rats with an Scn1a missense mutation and autosomal dominant lateral temporal epilepsy (ADLTE) model rats with an Lgi1 missense mutation. In addition, we have established episodic ataxia type 1 (EA1) model rats with a Kcna1 missense mutation derived from the ENU-induced rat mutant stock, and identified a Cacna1a missense mutation in a N-Methyl-N-nitrosourea (MNU)-induced mutant rat strain GRY, resulting in the discovery of episodic ataxia type 2 (EA2) model rats. Thus, epileptic rat models have been established on the two paths: 'phenotype to gene' and 'gene to phenotype'. In the near future, development of novel epileptic rat models will be extensively promoted by the use of sophisticated genome editing technologies. PMID:25312505

  1. Rho kinase inhibition by fasudil in the striatal 6-hydroxydopamine lesion mouse model of Parkinson disease.

    PubMed

    Tatenhorst, Lars; Tönges, Lars; Saal, Kim-Ann; Koch, Jan C; Szegő, Éva M; Bähr, Mathias; Lingor, Paul

    2014-08-01

    Chronic degeneration of nigrostriatal projections, followed by nigral dopaminergic cell death, is a key feature of Parkinson disease (PD). This study examines the neuroprotective potential of the rho kinase inhibitor fasudil in the 6-hydroxydopamine (6-OHDA) mouse model of PD in vivo. C57Bl/6 mice were lesioned by striatal stereotactic injections with 4 μg of 6-OHDA and treated with fasudil 30 or 100 mg/kg body weight via drinking water. Motor behavior was tested biweekly; histologic and biochemical analyses were performed at 4 and 12 weeks after lesion. Motor behavior was severely impaired after 6-OHDA lesion and was not improved by fasudil treatment. Fasudil 100 mg/kg did not significantly increase the number of dopaminergic cells in the substantia nigra after 12 weeks versus lesion controls. Interestingly, however, high-performance liquid chromatography analysis of dopamine metabolites revealed that striatal levels of 3,4-dihydroxyphenylacetic acid were significantly increased after 12 weeks, suggesting a regenerative response. In contrast to recent findings in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin model, fasudil effects seem limited in this severe 6-OHDA model of PD. Nevertheless, high therapeutic concentrations of fasudil are suggestive of a proregenerative potential for dopaminergic neurons, making further evaluations of rho kinase inhibition as a proregenerative therapeutic strategy in PD promising. PMID:25003236

  2. The network of causal interactions for beta oscillations in the pedunculopontine nucleus, primary motor cortex, and subthalamic nucleus of walking parkinsonian rats.

    PubMed

    Li, Min; Zhou, Ming; Wen, Peng; Wang, Qiang; Yang, Yong; Xiao, Hu; Xie, Zhengyuan; Li, Xing; Wang, Ning; Wang, Jinyan; Luo, Fei; Chang, Jingyu; Zhang, Wangming

    2016-08-01

    Oscillatory activity has been well-studied in many structures within cortico-basal ganglia circuits, but it is not well understood within the pedunculopontine nucleus (PPN), which was recently introduced as a potential target for the treatment of gait and postural impairments in advanced stages of Parkinson's disease (PD). To investigate oscillatory activity in the PPN and its relationship with oscillatory activity in cortico-basal ganglia circuits, we simultaneously recorded local field potentials in the PPN, primary motor cortex (M1), and subthalamic nucleus (STN) of 6-hydroxydopamine (6-OHDA)-induced hemiparkinsonian rats during resting and walking. After analysis of power spectral density, coherence, and partial Granger causality, three major findings emerged: 1) after 6-OHDA lesions, beta band oscillations were enhanced in all three regions during walking; 2) the direction of information flow for beta oscillations among the three structures was STN→M1, STN→PPN, and PPN→M1; 3) after the treatment of levodopa, beta activity in the three regions was reduced significantly and the flow of beta band was also abrogated. Our results suggest that beta activity in the PPN is transmitted from the basal ganglia and probably comes from the STN, and the STN plays a dominant role in the network of causal interactions for beta activity. Thus, the STN may be a potential source of aberrant beta band oscillations in PD. Levodopa can inhibit beta activity in the PPN of parkinsonian rats but cannot relieve parkinsonian patients' axial symptoms clinically. Therefore, beta oscillations may not be the major cause of axial symptoms. PMID:27163550

  3. PBPK MODELING OF DELTAMETHRIN IN RATS

    EPA Science Inventory

    The pyrethroid pesticide deltamethrin is cleared nearly twice as rapidly in human liver microsomes compared to rat liver microsomes. A species difference such as this could influence the toxic potency of deltamethrin between rats and humans. PBPK modeling is a tool that can be ut...

  4. Gravitational Biology: The Rat Model

    NASA Technical Reports Server (NTRS)

    1997-01-01

    In this session, Session JP3, the discussion focuses on the following topics: Morphology of brain, pituitary and thyroid in the rats exposed to altered gravity; Biochemical Properties of B Adrenoceptors After Spaceflight (LMS-STS78) or Hindlimb Suspension in Rats; Influence of Hypergravity on the Development of Monoaminergic Systems in the Rat Spinal Cord; A Vestibular Evoked Potentials (VsEPs) Study of the Function of the Otolith Organs in Different Head Orientations with respect to Earth Gravity Vector in the Rat; Quantitative Observations on the Structure of Selected Proprioceptive Components in Adult Rats that Underwent About Half of their Fetal Development in Space; Effects of a Nine-Day Shuttle Mission on the Development of the Neonatal Rat Nervous System, A Behavioral Study; Muscle Atrophy Associated to Microgravity in Rat, Basic Data For Countermeasures; Simulated Weightlessness by Unloading in the Rat, Results of a Time Course Study of Biochemical Events Occurring During Unloading and Lack of Effect of a rhBNP-2 Treatment on Bone Formation and Bone Mineral Content in Unloading Rats; and Cytological Mechanism of the Osteogenesis Under Microgravity Conditions.

  5. Traumatic arteriogenic erectile dysfunction: a rat model.

    PubMed

    El-Sakka, A; Yen, T S; Lin, C S; Lue, T F

    2001-06-01

    We developed a rat model of traumatic arteriogenic erectile dysfunction (ED) for the study of vasculogenic ED. Bilateral ligation of the internal iliac artery was performed on 30 three-month old male Sprague-Dawley rats as an experimental group. The control group consisted of 12 rats which underwent dissection of the internal iliac artery without ligation. Before their euthanization at 3 days, 7 days, and 1 month (10 rats in the experimental group and four rats in the control group at each time point), erectile function was assessed by electrostimulation of the cavernous nerves. Penile tissues were collected for nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase staining, trichrome staining, electron microscopy and RT-PCR for transforming growth factor beta (TGF-beta1), insulin like growth factor-I (IGF-I) and fibroblast growth factors (FGF) mRNA expression. Electrostimulation of the cavernous nerves revealed a highly significant declining of the intracavernous pressure after 3 and 7 days. No significant recovery of erectile function was noted at 1 month. Histology showed degeneration of the dorsal nerve fibers in all experimental rats. There was little decrease in the bulk of intracavernous smooth muscle in the experimental rats euthanazed 7 and 30 days. NADPH diaphorase staining revealed a significant decrease in nitric oxide synthase (NOS) containing nerve fibers in the dorsal and intracavernosal nerves in all rats in the experimental group. Electron microscopy showed a variety of changes such as collapse of sinusoids, increased cell debris, fibroblast and myofibroblast loss, intracellular deposition of fat and collagen and fatty degeneration. RT-PCR revealed up-regulation of TGF-beta1 after 3 days but not after 7 days or 1 month. There is no significant difference in IGF-I or FGF expression between the experimental and control group. Bilateral ligation of internal iliac arteries produces a reliable animal model for traumatic arteriogenic ED. Further

  6. Enhanced visual responses in the superior colliculus and subthalamic nucleus in an animal model of Parkinson's disease.

    PubMed

    Rolland, M; Carcenac, C; Overton, P G; Savasta, M; Coizet, V

    2013-11-12

    Striatal dopaminergic denervation leads to a change in afferent activity within the basal ganglia. Coupled with the effect of local dopaminergic denervation in the subthalamic nucleus, this is likely to affect the responsiveness of subthalamic neurons to their hyperdirect inputs in Parkinson's disease. Therefore, in this report, we investigated subthalamic nucleus responses to visual stimuli relayed by one such input - the superior colliculus - in 6-hydroxydopamine (6-OHDA)-lesioned rats. We used a protocol where the superior colliculus was selectively unlocked from the inhibitory effect of anesthesia with an injection of bicuculline, attenuating GABAergic inhibition in the colliculus, which arises predominantly from the substantia nigra pars reticulata. We found that visual responses in the superior colliculus were facilitated by partial or total lesions of dopaminergic neurons in the substantia nigra pars compacta, once the colliculus was disinhibited by bicuculline. Responses were faster, larger in amplitude and lasted longer compared to those in control rats. In the subthalamic nucleus, visual responses were also increased in amplitude and magnitude in partial or total lesioned groups. A classic hypothesis in Parkinson's disease suggests that following dopaminergic denervation, the discharge of cells in the substantia nigra pars reticulata increases, thereby intensifying the inhibitory influence that this structure exerts on its targets in the thalamus and brainstem. Our results suggest that neuroadaptations may have taken place within the superior colliculus in order to maintain normal function in the face of increased inhibitory tone coming from the substantia nigra pars reticulata, which once reduced, gave rise to facilitated responding. This facilitated responding in the superior colliculus then appears to lead to facilitated responding in the subthalamic nucleus. PMID:23916713

  7. Consensus Modeling of Oral Rat Acute Toxicity

    EPA Science Inventory

    An acute toxicity dataset (oral rat LD50) with about 7400 compounds was compiled from the ChemIDplus database. This dataset was divided into a modeling set and a prediction set. The compounds in the prediction set were selected so that they were present in the modeling set used...

  8. The rat choledochojejunostomy model for microsurgical training

    PubMed Central

    Lee, Jun Suh

    2016-01-01

    Purpose The feasibility of a rat choledochojejunostomy (CJ) training model was investigated, as an introductory model to microsurgery for general surgeons. Methods Roux-en-Y CJ was performed on 20 rats. Interrupted 10-0 prolene sutures were used to perform CJ. The animals were observed for 7 days and sacrificed and examined. Results The rats were divided into 2 groups of 10 based on surgical order. The CJ time showed a significant decrease from 36.2 ± 5.6 minutes in group 1 to 29.4 ± 5.7 minutes in group 2 (P = 0.015). The bile leakage rate was 40% in group 1 and 10% in group 2. The survival time was 5.4 ± 2.2 days in group 1 and 7 days in group 2 (P = 0.049). Conclusion The rat CJ training model is a feasible introductory model for general surgeons with no previous experience in microsurgery. PMID:27186568

  9. Small molecule TrkB agonist deoxygedunin protects nigrostriatal dopaminergic neurons from 6-OHDA and MPTP induced neurotoxicity in rodents.

    PubMed

    Nie, Shuke; Xu, Yan; Chen, Guiqin; Ma, Kai; Han, Chao; Guo, Zhenli; Zhang, Zhentao; Ye, Keqiang; Cao, Xuebing

    2015-12-01

    Dopaminergic neurons loss in the substantia nigra (SN) and dopamine (DA) content loss in the striatum correlate well with disease severity in Parkinson's disease (PD). Brain-derived neurotrophic factor (BDNF) is a member of neurotrophin family and is necessary for the survival and development of DA neurons in the SN. Deficits in BDNF/TrkB receptors signaling contribute to the dysfunction of PD. Deoxygedunin, a derivative of gedunin produced from Indian neem tree, binds TrkB receptor and activates TrkB and its downstream signaling cascades in a BDNF-independent manner, and possesses neuroprotective effects in vitro and in vivo. In this study, we tested the neuroprotective effects of deoxygedunin in 6-hydroxydopamine (6-OHDA)-lesioned rat model and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice model of Parkinson's disease. Rats were treated with deoxygedunin 5 mg/kg (i.p.) for one month started two weeks before 6-OHDA lesion (pre-treatment), or for two weeks right after lesion (post-treatment), with isovolumetric vehicle as control and normal. Mice were given deoxygedunin 5 mg/kg (i.p.) for 2 weeks and administrated with MPTP twice at the dose of 20 mg/kg (i.p.) on day 7. The results revealed that pretreatment with deoxygedunin improved PD models' behavioral performance and reduced dopaminergic neurons loss in SN, associated with the activation of TrkB receptors and its two major signaling cascades involving mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K). Thus, our current study indicates that deoxygedunin, as a small molecule TrkB agonist, displays prominent neuroprotective properties, providing a novel therapeutic strategy for treating Parkinson's disease. PMID:26282118

  10. On the rat model of human osteopenias and osteoporoses

    NASA Technical Reports Server (NTRS)

    Frost, Harold M.; Jee, Webster S. S.

    1992-01-01

    The idea that rats cannot model human osteopenias errs. The same mechanisms control gains in bone mass (longitudinal bone growth and modeling drifts) and losses (BMU-based remodeling), in young and aged rats and humans. Furthermore, they respond similarly in rats and man to mechanical influences, hormones, drugs and other agents.

  11. Rat Model of Parkes Weber Syndrome.

    PubMed

    Bojakowski, Krzysztof; Janusz, Gabriela; Grabowska, Iwona; Zegrocka-Stendel, Oliwia; Surowiecka-Pastewka, Agnieszka; Kowalewska, Magdalena; Maciejko, Dorota; Koziak, Katarzyna

    2015-01-01

    The Parkes Weber syndrome is a congenital vascular malformation, characterized by varicose veins, arterio-venous fistulas and overgrown limbs. No broadly accepted animal model of Parkes Weber syndrome has been described. We created side-to-side arterio-venous fistula between common femoral vessels with proximal non-absorbable ligature on common femoral vein limiting the enlargement of the vein diameter in Wistar rats. Contralateral limb was sham operated. Invasive blood pressure measurements in both iliac and inferior cava veins were performed in rats 30 days after fistula creation. Tight circumference and femoral bone length were measured. Histopathology and morphology of soleus muscle, extensor digitorum longus muscle, and the common femoral vessel were analyzed. 30 days following arterio-venous fistula creation, a statistically significant elevation of blood pressure in common iliac vein and limb overgrowth was observed. Limb enlargement was caused by muscle overgrowth, varicose veins formation and bone elongation. Arterio-venous fistula with proximal outflow limitation led to significant increase of femoral vein circumference and venous wall thickness. Our study indicates that the described rat model mimics major clinical features characteristic for the human Parkes Weber syndrome: presence of arterio-venous fistula, venous hypertension and dilatation, varicose veins formation, and the limb hypertrophy. We reveal that limb overgrowth is caused by bone elongation, muscle hypertrophy, and venous dilatation. The newly established model will permit detailed studies on the mechanisms underlying the disease and on the efficacy of novel therapeutic strategies for the Parkes Weber syndrome treatment. PMID:26217941

  12. Rat Model of Parkes Weber Syndrome

    PubMed Central

    Bojakowski, Krzysztof; Janusz, Gabriela; Grabowska, Iwona; Zegrocka-Stendel, Oliwia; Surowiecka-Pastewka, Agnieszka; Kowalewska, Magdalena; Maciejko, Dorota; Koziak, Katarzyna

    2015-01-01

    The Parkes Weber syndrome is a congenital vascular malformation, characterized by varicose veins, arterio-venous fistulas and overgrown limbs. No broadly accepted animal model of Parkes Weber syndrome has been described. We created side-to-side arterio-venous fistula between common femoral vessels with proximal non-absorbable ligature on common femoral vein limiting the enlargement of the vein diameter in Wistar rats. Contralateral limb was sham operated. Invasive blood pressure measurements in both iliac and inferior cava veins were performed in rats 30 days after fistula creation. Tight circumference and femoral bone length were measured. Histopathology and morphology of soleus muscle, extensor digitorum longus muscle, and the common femoral vessel were analyzed. 30 days following arterio-venous fistula creation, a statistically significant elevation of blood pressure in common iliac vein and limb overgrowth was observed. Limb enlargement was caused by muscle overgrowth, varicose veins formation and bone elongation. Arterio-venous fistula with proximal outflow limitation led to significant increase of femoral vein circumference and venous wall thickness. Our study indicates that the described rat model mimics major clinical features characteristic for the human Parkes Weber syndrome: presence of arterio-venous fistula, venous hypertension and dilatation, varicose veins formation, and the limb hypertrophy. We reveal that limb overgrowth is caused by bone elongation, muscle hypertrophy, and venous dilatation. The newly established model will permit detailed studies on the mechanisms underlying the disease and on the efficacy of novel therapeutic strategies for the Parkes Weber syndrome treatment. PMID:26217941

  13. Ideal Experimental Rat Models for Liver Diseases.

    PubMed

    Lee, Sang Woo; Kim, Sung Hoon; Min, Seon Ok; Kim, Kyung Sik

    2011-05-01

    There are many limitations for conducting liver disease research in human beings due to the high cost and potential ethical issues. For this reason, conducting a study that is difficult to perform in humans using appropriate animal models, can be beneficial in ascertaining the pathological physiology, and in developing new treatment modalities. However, it is difficult to determine the appropriate animal model which is suitable for research purposes, since every patient has different and diverse clinical symptoms, adverse reactions, and complications due to the pathological physiology. Also, it is not easy to reproduce identically various clinical situations in animal models. Recently, the Guide for the Care and Use of Laboratory Animals has tightened up the regulations, and therefore it is advisable to select the appropriate animals and decide upon the appropriate quantities through scientific and systemic considerations before conducting animal testing. Therefore, in this review article the authors examined various white rat animal testing models and determined the appropriate usable rat model, and the pros and cons of its application in liver disease research. The authors believe that this review will be beneficial in selecting proper laboratory animals for research purposes. PMID:26421020

  14. A mouse model of non-motor symptoms in Parkinson's disease: focus on pharmacological interventions targeting affective dysfunctions

    PubMed Central

    Bonito-Oliva, Alessandra; Masini, Débora; Fisone, Gilberto

    2014-01-01

    Non-motor symptoms, including psychiatric disorders, are increasingly recognized as a major challenge in the treatment of Parkinson's disease (PD). These ailments, which often appear in the early stage of the disease, affect a large number of patients and are only partly resolved by conventional antiparkinsonian medications, such as L-DOPA. Here, we investigated non-motor symptoms of PD in a mouse model based on bilateral injection of the toxin 6-hydroxydopamine (6-OHDA) in the dorsal striatum. This model presented only subtle gait modifications, which did not affect horizontal motor activity in the open-field test. Bilateral 6-OHDA lesion also impaired olfactory discrimination, in line with the anosmia typically observed in early stage parkinsonism. The effect of 6-OHDA was then examined for mood-related dysfunctions. Lesioned mice showed increased immobility in the forced swim test and tail suspension test, two behavioral paradigms of depression. Moreover, the lesion exerted anxiogenic effects, as shown by reduced time spent in the open arms, in the elevated plus maze test, and by increased thigmotaxis in the open-field test. L-DOPA did not modify depressive- and anxiety-like behaviors, which were instead counteracted by the dopamine D2/D3 receptor agonist, pramipexole. Reboxetine, a noradrenaline reuptake inhibitor, was also able to revert the depressive and anxiogenic effects produced by the lesion with 6-OHDA. Interestingly, pre-treatment with desipramine prior to injection of 6-OHDA, which is commonly used to preserve noradrenaline neurons, did not modify the effect of the lesion on depressive- and anxiety-like behaviors. Thus, in the present model, mood-related conditions are independent of the reduction of noradrenaline caused by 6-OHDA. Based on these findings we propose that the anti-depressive and anxiolytic action of reboxetine is mediated by promoting dopamine transmission through blockade of dopamine uptake from residual noradrenergic terminals. PMID

  15. Rat injury model of docetaxel extravasation

    PubMed Central

    ZHU, JING-JING; FU, JIAN-FEI; YANG, JIAO; HU, BING; ZHANG, HUI; YU, JIAN-HUA

    2014-01-01

    Docetaxel is a novel type of chemotherapy drug that actively treats a number of malignant tumors. The aim of the present study was to explore the severity and natural course of tissue damage induced by docetaxel extravasation and to confirm the vesicant potential of docetaxel. Rats were selected for the establishment of the ulcer model. Different volumes and concentrations were explored to induce the skin ulcer and to confirm the optimum rational injection model. The natural course of tissue injury and pathological changes produced by docetaxel extravasation were observed by comparing to vinorelbine extravasation. A 0.4 ml volume and a 6 mg/ml concentration were the optimum rational injection model for the induction of the skin ulcer. The docetaxel extravasation induced local tissue necrosis, followed by granuloma formation and hyperpigmentation or scar formation. The severity of the injury depended on the concentration of the extravasation used in the rat model. The injury occurred on the first day following extravasation and lasted 4–6 weeks. The damage from docetaxel was weaker than vinorelbine in association with the depth and extension of necrosis. In conclusion, docetaxel extravasation can induce tissue necrosis. However, the severity of necrosis was weaker than that of vinorelbine. Docetaxel has superficial vesicant properties. PMID:25054005

  16. Rat Carotid Artery Balloon Injury Model

    PubMed Central

    Tulis, David Anthony

    2010-01-01

    i. Summary Numerous and diverse experimental animal models have been used over the years to examine reactions to various forms of blood vessel disease and/or injury across species and in multiple vascular beds in a cumulative effort to relate these findings to the human condition. In this context, the rat carotid artery balloon injury model is highly characterized and commonly used for investigating gross morphological, cellular, biochemical, and molecular components of the response to experimentally-induced arterial injury. The mechanical damage caused by the balloon catheter completely removes the intimal endothelial lining and creates a distending mural injury in the operated vessel. This elicits a reproducible remodeling response characterized by vascular smooth muscle cell (SMC) mitogenesis and migration (via phenotypic switching), SMC apoptosis, partial vascular endothelial cell regeneration, enhanced matrix synthesis, and establishment of an invasive neointima in time-dependent fashion. This multi-factorial process allows for investigation of these many important pathophysiological processes and can serve as a valuable “proof-of-concept” tool to verify and substantiate in vitro results; however, inherent anatomical and adaptive constraints of this in vivo model ration comparison to the diseased human system (see Note 1). In this chapter, brief overview of the materials needed and the methodologies commonly employed for successful routine performance of this important experimental animal model will be provided. Individual sub-sections will cover animal care and handling, pre- and post-operative procedures, and the surgery proper. Protocols for histopathology and morphometry and procedures for data management and interpretation pertinent to the rat carotid artery balloon injury model will be discussed in Chapter __ of this series. Notes will conclude with important caveats, limitations, and considerations for practical use of this technique. PMID:18287662

  17. A Rat Excised Larynx Model of Vocal Fold Scar

    ERIC Educational Resources Information Center

    Welham, Nathan V.; Montequin, Douglas W.; Tateya, Ichiro; Tateya, Tomoko; Choi, Seong Hee; Bless, Diane M.

    2009-01-01

    Purpose: To develop and evaluate a rat excised larynx model for the measurement of acoustic, aerodynamic, and vocal fold vibratory changes resulting from vocal fold scar. Method: Twenty-four 4-month-old male Sprague-Dawley rats were assigned to 1 of 4 experimental groups: chronic vocal fold scar, chronic vocal fold scar treated with 100-ng basic…

  18. Buspirone requires the intact nigrostriatal pathway to reduce the activity of the subthalamic nucleus via 5-HT1A receptors.

    PubMed

    Sagarduy, A; Llorente, J; Miguelez, C; Morera-Herreras, T; Ruiz-Ortega, J A; Ugedo, L

    2016-03-01

    The most effective treatment for Parkinson's disease (PD), l-DOPA, induces dyskinesia after prolonged use. We have previously shown that in 6-hydroxydopamine (6-OHDA) lesioned rats rendered dyskinetic by prolonged l-DOPA administration, lesion of the subthalamic nucleus (STN) reduces not only dyskinesias but also buspirone antidyskinetic effect. This study examined the effect of buspirone on STN neuron activity. Cell-attached recordings in parasagittal slices from naïve rats showed that whilst serotonin excited the majority of STN neurons, buspirone showed an inhibitory main effect but only in 27% of the studied cells which was prevented by the 5-HT1A receptor selective antagonist WAY-100635. Conversely, single-unit extracellular recordings were performed in vivo on STN neurons from four different groups, i.e., control, chronically treated with l-DOPA, 6-OHDA lesioned and lesioned treated with l-DOPA (dyskinetic) rats. In control animals, systemic-buspirone administration decreased the firing rate in a dose-dependent manner in every cell studied. This effect, prevented by WAY-100635, was absent in 6-OHDA lesioned rats and was not modified by prolonged l-DOPA administration. Altogether, buspirone in vivo reduces consistently the firing rate of the STN neurons through 5-HT1A receptors whereas ex vivo buspirone seems to affect only a small population of STN neurons. Furthermore, the lack of effect of buspirone in 6-OHDA lesioned rats, suggests the requirement of not only the activation of 5-HT1A receptors but also an intact nigrostriatal pathway for buspirone to inhibit the STN activity. PMID:26687972

  19. Cardiopulmonary bypass model in the rat: a new minimal invasive model with a low flow volume†

    PubMed Central

    Lebreton, Guillaume; Tamion, Fabienne; Bessou, Jean-Paul; Doguet, Fabien

    2012-01-01

    Numerous cardiopulmonary bypass (CPB) models in the rat have already been described, but these models often have an important mortality and differ a lot from human clinical conditions thus making them hardly usable. The CPB model in the rat we describe allows a femoro-femoral support CPB with a low priming volume, minimal surgical approach and excellent peroperative survival. This CPB model in the rat allows evaluating extracorporeal circulation effects. PMID:22345055

  20. Animal models of neurological deficits: how relevant is the rat?

    PubMed

    Cenci, M Angela; Whishaw, Ian Q; Schallert, Timothy

    2002-07-01

    Animal models of neurological deficits are essential for the assessment of new therapeutic options. It has been suggested that rats are not as appropriate as primates for the symptomatic modelling of disease, but a large body of data argues against this view. Comparative analyses of movements in rats and primates show homology of many motor patterns across species. Advances have been made in identifying rat equivalents of akinesia, tremor, postural deficits and dyskinesia, which are relevant to Parkinson's disease. Rat models of hemiplegia, neglect and tactile extinction are useful in assessing the outcome of ischaemic or traumatic brain injury, and in monitoring the effects of therapeutic interventions. Studies in rodents that emphasize careful behavioural analysis should continue to be developed as effective and inexpensive models that complement studies in primates. PMID:12094213

  1. Modeling Alzheimer's disease with non-transgenic rat models

    PubMed Central

    2013-01-01

    Alzheimer's disease (AD), for which there is no cure, is the most common form of dementia in the elderly. Despite tremendous efforts by the scientific community, the AD drug development pipeline remains extremely limited. Animal models of disease are a cornerstone of any drug development program and should be as relevant as possible to the disease, recapitulating the disease phenotype with high fidelity, to meaningfully contribute to the development of a successful therapeutic agent. Over the past two decades, transgenic models of AD based on the known genetic origins of familial AD have significantly contributed to our understanding of the molecular mechanisms involved in the onset and progression of the disease. These models were extensively used in AD drug development. The numerous reported failures of new treatments for AD in clinical trials indicate that the use of genetic models of AD may not represent the complete picture of AD in humans and that other types of animal models relevant to the sporadic form of the disease, which represents 95% of AD cases, should be developed. In this review, we will discuss the evolution of non-transgenic rat models of AD and how these models may open new avenues for drug development. PMID:23634826

  2. The Carbohydrate Sensitive Rat as a Model of Obesity

    PubMed Central

    Nadkarni, Nachiket A.; Chaumontet, Catherine; Azzout-Marniche, Dalila; Piedcoq, Julien; Fromentin, Gilles; Tomé, Daniel; Even, Patrick C.

    2013-01-01

    Background Sensitivity to obesity is highly variable in humans, and rats fed a high fat diet (HFD) are used as a model of this inhomogeneity. Energy expenditure components (basal metabolism, thermic effect of feeding, activity) and variations in substrate partitioning are possible factors underlying the variability. Unfortunately, in rats as in humans, results have often been inconclusive and measurements usually made after obesity onset, obscuring if metabolism was a cause or consequence. Additionally, the role of high carbohydrate diet (HCD) has seldom been studied. Methodology/Findings Rats (n=24) were fed for 3 weeks on HCD and then 3 weeks on HFD. Body composition was tracked by MRI and compared to energy expenditure components measured prior to obesity. Results: 1) under HFD, as expected, by adiposity rats were variable enough to be separable into relatively fat resistant (FR) and sensitive (FS) groups, 2) under HCD, and again by adiposity, rats were also variable enough to be separable into carbohydrate resistant (CR) and sensitive (CS) groups, the normal body weight of CS rats hiding viscerally-biased fat accumulation, 3) HCD adiposity sensitivity was not related to that under HFD, and both HCD and HFD adiposity sensitivities were not related to energy expenditure components (BMR, TEF, activity cost), and 4) only carbohydrate to fat partitioning in response to an HCD test meal was related to HCD-induced adiposity. Conclusions/Significance The rat model of human obesity is based on substantial variance in adiposity gains under HFD (FR/FS model). Here, since we also found this phenomenon under HCD, where it was also linked to an identifiable metabolic difference, we should consider the existence of another model: the carbohydrate resistant (CR) or sensitive (CS) rat. This new model is potentially complementary to the FR/FS model due to relatively greater visceral fat accumulation on a low fat high carbohydrate diet. PMID:23935869

  3. Effect of curcumin on diabetic rat model of cerebral ischemia.

    PubMed

    Miao, Mingsan; Cheng, Bolin; Li, Min

    2015-01-01

    To investigate the effect of curcumin on cerebral ischemia in diabetic rats the effects and features. intravenous injection alloxan diabetes model, to give alloxan first seven days the tail measured blood glucose value, the election successful model rats were fed with large, medium and small doses of curcumin suspension, Shenqijiangtang suspension and the same volume of saline, administered once daily. The first 10 days after administration 2h (fasting 12h) rat tail vein blood glucose values measured in the first 20 days after administration of 2h (fasting 12h), do cerebral ischemia surgery; rapid carotid artery blood after 30min rats were decapitated, blood serum, blood glucose and glycated serum protein levels; take part of the brain homogenates plus nine times the amount of normal saline, made 10 percent of brain homogenates. Another part of the brain tissue, in the light microscope observation of pathological tissue. Compared with model group, large, medium and small doses of curcumin can significantly lower blood sugar and glycated serum protein levels, significantly reduced brain homogenates lactic acid content and lactate dehydrogenase activity; large, medium-dose curcumin can significantly increase brain homogenates Na(+)-K(+)-ATP activity, dose curcumin can significantly improve brain homogenates Ca(+)-Mg(+)- ATP activity. Curcumin can reduce blood sugar in diabetic rat model of cerebral ischemia and improve brain energy metabolism, improve their brain tissue resistance to ischemia and hypoxia, cerebral ischemia in diabetic rats have a good drop the role of sugar and protect brain tissue. PMID:25631517

  4. Ciclamilast Ameliorates Adjuvant-Induced Arthritis in a Rat Model

    PubMed Central

    Zhang, Zhi-cheng; Zhang, Shui-juan; Jin, Bo; Wu, Yujin; Yang, Xin-fu; Yu, Bing; Xie, Qiang-min

    2015-01-01

    We assessed the effect of a novel and selective phosphodiesterase 4 (PDE4) inhibitor, ciclamilast, on chronic inflammation in adjuvant-induced arthritis (AIA), a rat model of rheumatoid arthritis (RA), and acute inflammation in the rat and mouse model of carrageenan-induced paw edema and peritonitis. Our results showed that daily oral administration of ciclamilast at 1, 3, and 10 mg/kg dose-dependently inhibited the increase in hind paw volume of rats with AIA. The inhibition of paw edema was associated with inhibition of both the production of cytokines such as TNF-α, IL-1β, and IL-6 and cell infiltration assessed in subcutaneous paw tissue. Moreover, there was significantly less tissue destruction in the ciclamilast-treated rats compared to the vehicle-treated rats, as assessed by radiographic analysis and histopathological evaluation. In the two acute inflammation models, ciclamilast inhibited carrageenan-induced paw edema in rats and inflammatory cell migration into the peritoneal cavity in mice in a dose-dependent manner. These results not only suggest that ciclamilast, as a disease-modifying antirheumatic drug (DMARD), can attenuate RA but also provide proof of principle that a PDE4 inhibitor may be useful for the treatment of arthritis. PMID:26000303

  5. ANIMAL MODELS OF DYSTONIA: LESSONS FROM A MUTANT RAT

    PubMed Central

    LeDoux, Mark S.

    2010-01-01

    Dystonia is a motor sign characterized by involuntary muscle contractions which produce abnormal postures. Genetic factors contribute significantly to primary dystonia. In comparison, secondary dystonia can be caused by a wide variety of metabolic, structural, infectious, toxic and inflammatory insults to the nervous system. Although classically ascribed to dysfunction of the basal ganglia, studies of diverse animal models have pointed out that dystonia is a network disorder with important contributions from abnormal olivocerebellar signaling. In particular, work with the dystonic (dt) rat has engendered dramatic paradigm shifts in dystonia research. The dt rat manifests generalized dystonia caused by deficiency of the neuronally-restricted protein caytaxin. Electrophysiological and biochemical studies have shown that defects at the climbing fiber-Purkinje cell synapse in the dt rat lead to abnormal bursting firing patterns in the cerebellar nuclei, which increases linearly with postnatal age. In a general sense, the dt rat has shown the scientific and clinical communities that dystonia can arise from dysfunctional cerebellar cortex. Furthermore, work with the dt rat has provided evidence that dystonia (1) is a neurodevelopmental network disorder and (2) can be driven by abnormal cerebellar output. In large part, work with other animal models has expanded upon studies in the dt rat and shown that primary dystonia is a multi-nodal network disorder associated with defective sensorimotor integration. In addition, experiments in genetically-engineered models have been used to examine the underlying cellular pathologies that drive primary dystonia. PMID:21081162

  6. Novel rat model for neurocysticercosis using Taenia solium.

    PubMed

    Verastegui, Manuela R; Mejia, Alan; Clark, Taryn; Gavidia, Cesar M; Mamani, Javier; Ccopa, Fredy; Angulo, Noelia; Chile, Nancy; Carmen, Rogger; Medina, Roxana; García, Hector H; Rodriguez, Silvia; Ortega, Ynes; Gilman, Robert H

    2015-08-01

    Neurocysticercosis is caused by Taenia solium infecting the central nervous system and is the leading cause of acquired epilepsy and convulsive conditions worldwide. Research into the pathophysiology of the disease and appropriate treatment is hindered by lack of cost-effective and physiologically similar animal models. We generated a novel rat neurocysticercosis model using intracranial infection with activated T. solium oncospheres. Holtzman rats were infected in two separate groups: the first group was inoculated extraparenchymally and the second intraparenchymally, with different doses of activated oncospheres. The groups were evaluated at three different ages. Histologic examination of the tissue surrounding T. solium cysticerci was performed. Results indicate that generally infected rats developed cysticerci in the brain tissue after 4 months, and the cysticerci were observed in the parenchymal, ventricle, or submeningeal brain tissue. The route of infection did not have a statistically significant effect on the proportion of rats that developed cysticerci, and there was no dependence on infection dose. However, rat age was crucial to the success of the infection. Epilepsy was observed in 9% of rats with neurocysticercosis. In histologic examination, a layer of collagen tissue, inflammatory infiltrate cells, perivascular infiltrate, angiogenesis, spongy change, and mass effect were observed in the tissue surrounding the cysts. This study presents a suitable animal model for the study of human neurocysticercosis. PMID:26216286

  7. Novel Rat Model for Neurocysticercosis Using Taenia solium

    PubMed Central

    Verastegui, Manuela R.; Mejia, Alan; Clark, Taryn; Gavidia, Cesar M.; Mamani, Javier; Ccopa, Fredy; Angulo, Noelia; Chile, Nancy; Carmen, Rogger; Medina, Roxana; García, Hector H.; Rodriguez, Silvia; Ortega, Ynes; Gilman, Robert H.

    2016-01-01

    Neurocysticercosis is caused by Taenia solium infecting the central nervous system and is the leading cause of acquired epilepsy and convulsive conditions worldwide. Research into the pathophysiology of the disease and appropriate treatment is hindered by lack of cost-effective and physiologically similar animal models. We generated a novel rat neurocysticercosis model using intracranial infection with activated T. solium oncospheres. Holtzman rats were infected in two separate groups: the first group was inoculated extraparenchymally and the second intraparenchymally, with different doses of activated oncospheres. The groups were evaluated at three different ages. Histologic examination of the tissue surrounding T. solium cysticerci was performed. Results indicate that generally infected rats developed cysticerci in the brain tissue after 4 months, and the cysticerci were observed in the parenchymal, ventricle, or submeningeal brain tissue. The route of infection did not have a statistically significant effect on the proportion of rats that developed cysticerci, and there was no dependence on infection dose. However, rat age was crucial to the success of the infection. Epilepsy was observed in 9% of rats with neurocysticercosis. In histologic examination, a layer of collagen tissue, inflammatory infiltrate cells, perivascular infiltrate, angiogenesis, spongy change, and mass effect were observed in the tissue surrounding the cysts. This study presents a suitable animal model for the study of human neurocysticercosis. PMID:26216286

  8. Surgical Intervention to Rescue Hirschsprung Disease in a Rat Model

    PubMed Central

    Stamp, Lincon A; Obermayr, Florian; Pontell, Louise; Young, Heather M; Xie, Dan; Croaker, David H; Song, Zan-Min; Furness, John B

    2015-01-01

    Background/Aims Rats with a spontaneous null mutation in endothelin receptor type B or Ednrb (sl/sl; spotting lethal) lack enteric neurons in the distal bowel and usually die within the first week after birth. This early postnatal lethality limits their use for examining the potential of cell therapy to treat Hirschsprung disease, and for studies of the influence of EDNRB on the mature CNS and vascular systems. Methods We have developed a surgical intervention to prolong the life of the spotting lethal sl/sl rat, in which we perform a colostomy on postnatal (P) day 4–6 rats to avoid the fatal obstruction caused by the lack of colonic enteric neurons. Results The stomas remained patent and functional and the rats matured normally following surgery. Weight gains were comparable between control and Hirschsprung phenotype (sl/sl) rats, which were followed until 4 weeks after surgery (5 weeks old). We confirmed the absence of enteric neurons in the distal colon of rats whose lives were saved by the surgical intervention. Conclusions This study provides a novel approach for studying EDNRB signalling in multiple organ systems in mature rats, including an animal model to study the efficacy of cell therapy to treat Hirschsprung disease. PMID:26424040

  9. Fat Preference: a novel model of eating behavior in rats.

    PubMed

    Kasper, James M; Johnson, Sarah B; Hommel, Jonathan D

    2014-01-01

    Obesity is a growing problem in the United States of America, with more than a third of the population classified as obese. One factor contributing to this multifactorial disorder is the consumption of a high fat diet, a behavior that has been shown to increase both caloric intake and body fat content. However, the elements regulating preference for high fat food over other foods remain understudied. To overcome this deficit, a model to quickly and easily test changes in the preference for dietary fat was developed. The Fat Preference model presents rats with a series of choices between foods with differing fat content. Like humans, rats have a natural bias toward consuming high fat food, making the rat model ideal for translational studies. Changes in preference can be ascribed to the effect of either genetic differences or pharmacological interventions. This model allows for the exploration of determinates of fat preference and screening pharmacotherapeutic agents that influence acquisition of obesity. PMID:24998978

  10. A novel rat model for chemotherapy-induced alopecia

    PubMed Central

    Wikramanayake, T. C.; Amini, S.; Simon, J.; Mauro, L. M.; Elgart, G.; Schachner, L. A.; Jimenez, J. J.

    2011-01-01

    Summary Background More than half of all people diagnosed with cancer receive chemotherapy, and approximately 65% of these develop chemotherapy-induced alopecia (CIA), a side-effect that can have considerable negative psychological repercussions. Currently, there are very few animal models available to study the mechanism and prevention of CIA. Aim To develop a clinically relevant adult rat model for CIA. Methods We first tested whether neonatal pigmented Long–Evans (LE) rats developed alopecia in response to the chemotherapeutic agents etoposide and cyclophosphamide. We then determined whether the rats developed CIA as adults. In the latter experiment, rat dorsal hair was clipped during the early telogen stage to synchronize the hair cycle. and starting 15 days later, the rats were treated with etoposide for 3 days. Results Neonatal LE pups developed CIA in response to etoposide and cyclophosphamide, similar to other murine models for CIA. Clipping of the hair shaft during early telogen resulted in synchronized anagen induction and subsequent alopecia after etoposide treatment in the clipped areas only. Hair follicles in the clipped areas had the typical chemotherapy-induced follicular dystrophy (dystrophic catagen). When the hair in the pigmented alopecic areas regrew, it had normal pigmentation. Conclusions A novel, pigmented adult rat model has been established for CIA. By hair shaft clipping during early telogen, synchronized anagen entry was induced that resulted in alopecia in response to chemotherapy. This is the first clinically relevant adult rat model for CIA and will be a useful tool to test agents for the prevention and treatment of CIA. PMID:22409523

  11. The isolated working heart model in infarcted rat hearts.

    PubMed

    Itter, G; Jung, W; Schoelkens, B A; Linz, W

    2005-04-01

    Congestive heart failure (CHF) is one of the most common causes of death in western countries. The aim of this study was to establish and validate the working heart model in rat hearts with CHF. In the rat model the animals show parameters and symptoms that can be extrapolated to the clinical situation of patients with end-stage heart failure. The focus of attention was the evaluation of cardiodynamics (e.g.contractility) in the isolated 'working heart' model. The geometric properties of the left ventricle were measured by planimetry (stereology). Formulae available in the past for determining certain parameters in the working heart model (e.g.external heart work) have to be fitted to the circumstances of the infarcted rat hearts with its different organ properties.CHF was induced in Wistar Kyoto (WKY/NHsd) and spontaneously hypertensive rats (SHR/NHsd) by creating a permanent (8 week) occlusion of the left coronary artery, 2 mm distal to the origin from the aorta, by a modified technique (Itter et al. 2004). This resulted in a large infarction of the free left ventricular wall. We were able to establish and adapt a new and predictive working heart model in spontaneously hypertensive rat hearts with myocardial infarction (MI) 8-12 weeks after coronary artery ligation. At this stage the WKY rat did not show any symptoms of CHF. The SHR rat represented characteristic parameters and symptoms that could be extrapolated to the clinical situation of patients with end-stage heart failure (NYHA III-IV). Upon inspection, severe clinical symptoms of CHF such as dyspnoea, subcutaneous oedema, palebluish limbs and impaired motion were prominent. On necropsy the SHR showed lung oedema, hydrothorax, large dilated left and right ventricular chambers and hypertrophy of the septum. In the working heart model the infarcted animals showed reduced heart power, diminished contractility and enhanced heart work, much more so in the SHR/NHsd than in the Wistar Kyoto rat (WKY/NHsd). The

  12. Detection of visual signals by rats: A computational model

    EPA Science Inventory

    We applied a neural network model of classical conditioning proposed by Schmajuk, Lam, and Gray (1996) to visual signal detection and discrimination tasks designed to assess sustained attention in rats (Bushnell, 1999). The model describes the animals’ expectation of receiving fo...

  13. Modeling Hypercalciuria in the Genetic Hypercalciuric Stone-Forming Rat

    PubMed Central

    Frick, Kevin K.; Krieger, Nancy S.; Bushinsky, David A.

    2015-01-01

    Purpose of Review In this review we discuss how the Genetic Hypercalciuric Stone-Forming (GHS) rats, which closely model idiopathic hypercalciuria and stone formation in humans, provide insights into the pathophysiology and consequences of clinical hypercalciuria. Recent Findings Hypercalciuria in the GHS rats is due to a systemic dysregulation of calcium transport, as manifest by increased intestinal calcium absorption, increased bone resorption and decreased renal tubule calcium reabsorption. Increased levels of vitamin D receptor in intestine, bone and kidney appear to mediate these changes. The excess receptors are biologically active and increase tissue sensitivity to exogenous vitamin D. Bones of GHS rats have decreased bone mineral density (BMD) as compared with Sprague Dawley rats, and exogenous 1,25(OH)2D3 exacerbates the loss of BMD. Thiazide diuretics improve the BMD in GHS rats. Summary Studying GHS rats allows direct investigation of the effects of alterations in diet and utilization of pharmacologic therapy on hypercalciuria, urine supersaturation, stone formation and bone quality in ways that are not possible in humans. PMID:26050120

  14. Physiologically based pharmacokinetic modeling of deltamethrin: Development of a rat and human diffusion-limited model

    EPA Science Inventory

    Mirfazaelian et al. (2006) developed a physiologically based pharmacokinetic (PBPK) model for the pyrethroid pesticide deltamethrin in the rat. This model describes gastrointestinal tract absorption as a saturable process mediated by phase III efflux transporters which pump delta...

  15. Dopamine Depletion In Either The Dorsomedial Or Dorsolateral Striatum Impairs Egocentric Cincinnati Water Maze Performance While Sparing Allocentric Morris Water Maze Learning

    PubMed Central

    Braun, Amanda A.; Amos-Kroohs, Robyn M.; Guetierez, Arnold; Lundgren, Kerstin H.; Seroogy, Kim B.; Skelton, Matthew R.; Vorhees, Charles V.; Williams, Michael T.

    2014-01-01

    Both egocentric route-based learning and spatial learning, as assessed by the Cincinnati water maze (CWM) and Morris water maze (MWM), respectively, are impaired following an 80% dopamine (DA) loss in the neostriatum after 6-hydroxydopamine (6-OHDA) administration in rats. The dorsolateral striatum (DLS) and the dorsomedial striatum (DMS) are implicated in different navigational learning types, namely the DLS is implicated in egocentric learning while the DMS is implicated in spatial learning. This experiment tested whether selective DA loss through 6-OHDA lesions in the DMS or DLS would impair one or both types of navigation. Both DLS and DMS DA loss significantly impaired route-based CWM learning, without affecting spatial or cued MWM performance. DLS 6-OHDA lesions produced a 75% DA loss in this region, with no changes in other monoamine levels in the DLS or DMS. DMS 6-OHDA lesions produced a 62% DA loss in this region, without affecting other monoamine levels in the DMS or DLS. The results indicate a role for DA in DLS and DMS regions in route-based egocentric but not spatial learning and memory. Spatial learning deficits may require more pervasive monoamine reductions within each region before deficits are exhibited. This is the first study to implicate DLS and DMS DA in route-based egocentric navigation. PMID:25451306

  16. Dopamine depletion in either the dorsomedial or dorsolateral striatum impairs egocentric Cincinnati water maze performance while sparing allocentric Morris water maze learning.

    PubMed

    Braun, Amanda A; Amos-Kroohs, Robyn M; Gutierrez, Arnold; Lundgren, Kerstin H; Seroogy, Kim B; Skelton, Matthew R; Vorhees, Charles V; Williams, Michael T

    2015-02-01

    Both egocentric route-based learning and spatial learning, as assessed by the Cincinnati water maze (CWM) and Morris water maze (MWM), respectively, are impaired following an 80% dopamine (DA) loss in the neostriatum after 6-hydroxydopamine (6-OHDA) administration in rats. The dorsolateral striatum (DLS) and the dorsomedial striatum (DMS) are implicated in different navigational learning types, namely the DLS is implicated in egocentric learning while the DMS is implicated in spatial learning. This experiment tested whether selective DA loss through 6-OHDA lesions in the DMS or DLS would impair one or both types of navigation. Both DLS and DMS DA loss significantly impaired route-based CWM learning, without affecting spatial or cued MWM performance. DLS 6-OHDA lesions produced a 75% DA loss in this region, with no changes in other monoamine levels in the DLS or DMS. DMS 6-OHDA lesions produced a 62% DA loss in this region, without affecting other monoamine levels in the DMS or DLS. The results indicate a role for DA in DLS and DMS regions in route-based egocentric but not spatial learning and memory. Spatial learning deficits may require more pervasive monoamine reductions within each region before deficits are exhibited. This is the first study to implicate DLS and DMS DA in route-based egocentric navigation. PMID:25451306

  17. A novel rat contact lens model for Fusarium keratitis

    PubMed Central

    Abou Shousha, Mohamed; Santos, Andrea Rachelle C.; Oechsler, Rafael A.; Iovieno, Alfonso; Maestre-Mesa, Jorge; Ruggeri, Marco; Echegaray, Jose J.; Dubovy, Sander R.; Perez, Victor L.; Miller, Darlene; Alfonso, Eduardo C.

    2013-01-01

    Purpose The aim of this study was to develop and characterize a new contact lens–associated fungal keratitis rat model and to assess the ability of non-invasive spectral-domain optical coherence tomography (SD-OCT) to detect pathological changes in vivo in fungal keratitis. Methods We used SD-OCT to image and measure the cornea of Sprague Dawley rats. Fusarium infection was initiated in the rat eye by fitting Fusarium solani–soaked contact lenses on the experimental eye, while the control animals received contact lenses soaked in sterile saline. The fungal infection was monitored with periodic slit-lamp examination and in vivo SD-OCT imaging of the rat eye, and confirmed by histology, counting of viable fungi in the infected rat cornea, and PCR with specific primers for Fusarium sp. Results We imaged and measured the rat cornea with SD-OCT. Custom-made contact lenses were developed based on the OCT measurements. Incubation of contact lenses in a F. solani suspension resulted in biofilm formation. We induced contact lens–associated Fusarium keratitis by fitting the rat eyes for 4 h with the Fusarium-contaminated contact lenses. The SD-OCT images of the cornea correlated well with the slit-lamp and histopathological results and clearly defined clinical signs of infection, namely, increased corneal thickening, loss of epithelial continuity, hyper-reflective areas representing infiltrates, and endothelial plaques characteristic of fungal infection. Moreover, in three cases, SD-OCT detected the infection without any clear findings on slit-lamp examination. Infection was confirmed with histological fungal staining, PCR, and microbiological culture positivity. Conclusions We developed a highly reproducible rat contact lens model and successfully induced contact lens–associated Fusarium keratitis in this model. The clinical presentation of contact lens–associated Fusarium keratitis in the rat model is similar to the human condition. SD-OCT is a valuable tool that

  18. Bacterial translocation in the rat model of lectin induced diarrhoea.

    PubMed

    Shoda, R; Mahalanabis, D; Wahed, M A; Albert, M J

    1995-03-01

    Red kidney beans were fed to weanling Long-Evans rats to cause diarrhoea (mean (SD) faecal wet weight: 2.66 (0.73) g/day in six rats fed beans v 1.12 (0.47) g/day in six control rats, p < 0.01) and increased faecal energy loss (4.87 (0.41) v 2.14 (0.23) kcal/day, p < 0.01). In addition, the rats fed beans had heavier small intestines (80.6 (4.6) v 51.9 (8.4) g/kg body weight, p < 0.01), heavier mesenteric lymph nodes (0.72 (0.27) v 0.08 (0.08) g/kg body weight, p < 0.05), and translocation of indigenous intestinal bacteria, Citrobacter Spp and Escherichia coli, to the mesenteric lymph nodes. (Translocation positive, that is, > 100 colonies per g of nodal tissue: 75% v 0%, p < 0.005.) These data suggest that diarrhoea induced by red kidney beans is a suitable model for studies of an important cause of persistent diarrhoea--that is, systemic complications. This rat model of lectin induced diarrhoea with translocation of intraluminal enteric bacteria into mesenteric lymph nodes should be useful in understanding the well known septicaemic complications associated with prolonged diarrhoea in infants and small children and in studies on factors that may modify or prevent bacterial translocation. PMID:7698696

  19. Calcium Balance in A Rat Space Flight Model

    NASA Technical Reports Server (NTRS)

    Arnaud, Sara B.; Navidi, M.; Holton, Emily M. (Technical Monitor)

    1997-01-01

    One of the main characteristics of calcium (Ca) metabolism during space flight and the human bed rest model for microgravity is negative Ca balance, attributed, to an increase in urinary Ca excretion and depressed intestinal Ca absorption. No differences or less positive Ca balances are reported after skeletal unloading in similar studies in weaning or juvenile rats. To determine Ca balances and evaluate the Ca endocrine system in mature rats exposed to a space flight model which unloaded the hind limbs by tail suspension, we modified the cage to quantify dietary, fecal and urinary Ca. Five 2-5 d balance periods in 8 loaded (C) and 8 unloaded (S) rats were compared during a 4 week study in 6 month old 490 g male rats. The first period revealed negative balances of -16+/-3 and -14+/-5 mg/d which reflected adaptation to the cages, the change in diet from Purina to AIN 76 and weight loss in both C and S. Average Ca balances in rats fed 0.1% Ca and 0.3% phosphorus (Pi) diets, remained negative in S and were less than C after 6 -10 d (-2.9 vs 0.12 mg/d, p<.05) but not thereafter. In spite of eating 10% more food than C, initial weight loss, restored in C, was never recovered in S. Fecal excretion exceeded dietary intake by -3.7% in S and reflected absorption and retention of 8.4% dietary Ca in C. Urinary Ca was the same fraction of dietary intake in S and C (9.0 vs 8.6%, NS). Serum Ca, Pi, parathyroid hormone and 1,25-dihydroxyvitamin D were the same in both groups after 28 days. In contrast to the human, a major determinant of negative Ca balance in the mature rat exposed to a space flight model appears to be losses from gastrointestinal Ca secretion, rather than urinary Ca excretion.

  20. PHARMACOKINETIC/PHARMACODYNAMIC MODELING OF PERMETHRIN IN THE RAT

    EPA Science Inventory

    A physiologically-based pharmacokinetic (PBPK) model was used to describe pharmacokinetics of permethrin and calibrated using experimental data on the concentration time-course of cis- and trans-permethrin in rat blood and brain tissues following oral administration...

  1. [Effects of buyang huan wu decoction on rat hyperlipemia model].

    PubMed

    Bian, H; Zhou, J

    1995-11-01

    Buyang Huan Wu Decoction can obviously lower the blood-lipid in rat hyperlipemia model, as well as drop the cholesterol in the aortic wall. Moreover, the decoction can drop the rising specific viscosity of blood and plasma, raise SOD and lower LPO in the blood. PMID:8737474

  2. The mathematical whisker: A review of numerical models of the rat׳s vibrissa biomechanics.

    PubMed

    Lucianna, Facundo Adrián; Albarracín, Ana Lía; Vrech, Sonia Mariel; Farfán, Fernando Daniel; Felice, Carmelo José

    2016-07-01

    The vibrissal system of the rat refers to specialized hairs the animal uses for tactile sensory perception. Rats actively move their whiskers in a characteristic way called "whisking". Interaction with the environment produces elastic deformation of the whiskers, generating mechanical signals in the whisker-follicle complex. Advances in our understanding of the vibrissal complex biomechanics is of interest not only for the biological research field, but also for biomimetic approaches. The recent development of whisker numerical models has contributed to comprehending its sophisticated movements and its interactions with the follicle. The great diversity of behavioral patterns and complexities of the whisker-follicle ensemble encouraged the creation of many different biomechanical models. This review analyzes most of the whisker biomechanical models that have been developed so far. This review was written so as to render it accessible to readers coming from different research areas. PMID:27260019

  3. Generation and characterization of rat liver stem cell lines and their engraftment in a rat model of liver failure

    PubMed Central

    Kuijk, Ewart W.; Rasmussen, Shauna; Blokzijl, Francis; Huch, Meritxell; Gehart, Helmuth; Toonen, Pim; Begthel, Harry; Clevers, Hans; Geurts, Aron M.; Cuppen, Edwin

    2016-01-01

    The rat is an important model for liver regeneration. However, there is no in vitro culture system that can capture the massive proliferation that can be observed after partial hepatectomy in rats. We here describe the generation of rat liver stem cell lines. Rat liver stem cells, which grow as cystic organoids, were characterized by high expression of the stem cell marker Lgr5, by the expression of liver progenitor and duct markers, and by low expression of hepatocyte markers, oval cell markers, and stellate cell markers. Prolonged cultures of rat liver organoids depended on high levels of WNT-signalling and the inhibition of BMP-signaling. Upon transplantation of clonal lines to a Fah−/− Il2rg−/− rat model of liver failure, the rat liver stem cells engrafted into the host liver where they differentiated into areas with FAH and Albumin positive hepatocytes. Rat liver stem cell lines hold potential as consistent reliable cell sources for pharmacological, toxicological or metabolic studies. In addition, rat liver stem cell lines may contribute to the development of regenerative medicine in liver disease. To our knowledge, the here described liver stem cell lines represent the first organoid culture system in the rat. PMID:26915950

  4. A new rat model for studies of hypokinesia and antiorthostasis

    NASA Technical Reports Server (NTRS)

    Musacchia, X. J.; Deavers, D. R.

    1982-01-01

    A new rat model (suspension and immobilization) is described for induction of hypokinesia and orthostatic manipulations. Hypokinetic responses were comparable to those in prolonged bed rest and weightlessness in humans, body or limb casted and small cage restrained animals. Responses to antiorthostasis (15 to 20 deg head down tilt) in rats were similar to those in neutral bouyancy tests in humans and animals and to those in prolonged bed rest in humans. During seven days of hypokinesia there was an atrophy of the gastrocnemius and increased excretion of urinary nitrogeneous end products. The antiorthostatic (AOH) 15 to 20 deg head down tilt resulted in diuresis, natriuresis and kaliuresis. No comparable responses were observed in orthostatic hypokinetic (OH) rats. Readaptation from AOH and OH occurred during one week recovery in metabolic cage conditions.

  5. Comparison of starvation and elastase models of emphysema in the rat

    SciTech Connect

    Harkema, J.R.; Mauderly, J.L.; Gregory, R.E.; Pickrell, J.A.

    1984-01-01

    Starvation and elastase-induced changes in rat lung structure, biochemistry, and function were compared as models of human pulmonary emphysema. Ten-week-old male rats were instilled intratracheally with either porcine pancreatic elastase in saline (E) or with saline alone. A group of the saline-instilled rats were fed one third of their normal food intake until a 45% loss of body weight occurred (S). The remaining saline-instilled rats served as control animals (C). Post-treatment evaluations included in vivo respiratory function, lung histopathologic and morphometric analyses, lung tissue proteinolytic activity, and lung collagen. The E rats had in vivo respiratory function changes more similar to human emphysema than those of S rats. All lung volume subdivisions were decreased in S rats and increased in E rats. The volume-pressure curve of S rats was shifted to the right of the C curve, whereas that of E rats was shifted to the left. Forced expiratory flow rates of E rats were decreased at all lung volumes, but those of S rats were not. Both E and S rats had larger terminal air spaces and less alveolar surface area than did C rats. The S rats had more collagen per gram lung and higher proteinolytic activity than did C or E rats. These results show that, although starvation induces some changes characteristic of human emphysema, elastase-treatment provides a model more similar to the human disease. 44 references, 5 figures, 4 tables.

  6. Rat model of Achilles tendon disorder. A pilot study.

    PubMed

    Messner, K; Wei, Y; Andersson, B; Gillquist, J; Räsänen, T

    1999-01-01

    Three-month-old male rats were subjected 3 times weekly for 1 h to eccentric exercise of one triceps surae muscle (30 stimulations/min) under general anesthesia in order to induce Achilles tendon disorder corresponding to paratenonitis and tendinosis in man. Net muscle work during the sessions ranged between 0.67 and 4.37 mJ (mean 1.72, SD 0.77). After 9 and 13 sessions, respectively, 2 rats started to show gait alterations during the functional test which was performed 2-3 times weekly. These rats were killed after additional sessions which showed a worsening of the limp. The other trained rats and controls did not limp and were killed after 7-11 weeks. Histologic evaluation of the Achilles tendons from the exercised limb showed in the majority of the cases hypervascularization, increased number of nerve filaments and increased immunoreactivity for substance P and calcitonin gene-related peptide. The tendons from the nonstimulated limb looked normal. The distribution of collagen types I and II appeared normal in the tendon and its insertion to the calcaneus. Inflammation of the epi- and paratenon could be provoked in the rat, but tendon changes corresponding to chronic tendinosis did not develop within 11 weeks with the used training regime. The clinical relevance of this model for chronic tendon disease needs to be evaluated further. PMID:10460971

  7. Experimental model of heterotopic ossification in Wistar rats

    PubMed Central

    Zotz, T.G.G.; de Paula, J.B.; Moser, A.D.L.

    2012-01-01

    Heterotopic ossification (HO) is a metaplastic biological process in which there is newly formed bone in soft tissues adjacent to large joints, resulting in joint mobility deficit. In order to determine which treatment techniques are more appropriate for such condition, experimental models of induced heterotopic bone formation have been proposed using heterologous demineralized bone matrix implants and bone morphogenetic protein and other tissues. The objective of the present experimental study was to identify a reliable protocol to induce HO in Wistar rats, based on autologous bone marrow (BM) implantation, comparing 3 different BM volumes and based on literature evidence of this HO induction model in larger laboratory animals. Twelve male Wistar albino rats weighing 350/390 g were used. The animals were anesthetized for blood sampling before HO induction in order to quantify serum alkaline phosphatase (ALP). HO was induced by BM implantation in both quadriceps muscles of these animals, experimental group (EG). Thirty-five days after the induction, another blood sample was collected for ALP determination. The results showed a weight gain in the EG and no significant difference in ALP levels when comparing the periods before and after induction. Qualitative histological analysis confirmed the occurrence of heterotopic ossification in all 12 EG rats. In conclusion, the HO induction model was effective when 0.35 mL autologous BM was applied to the quadriceps of Wistar rats. PMID:22473322

  8. Hyperactivity and hypoactivity produced by lesions to the mesolimbic dopamine system.

    PubMed

    Koob, G F; Stinus, L; Le Moal, M

    1981-11-01

    Spontaneous locomotor activity and the locomotor response to amphetamine and apomorphine were studied in rats subjected to either radiofrequency (RF), 6-hydroxydopamine (6-OHDA) or both RF and 6-OHDA lesions of the mesolimbic dopamine (DA) system. Large 6-OHDA lesions of the ventral tegmental area (VTA) or of the nucleus accumbens (N.Acc.) produced hypo-activity in the open field, a complete blockade of the locomotor stimulating effects of D-amphetamine and a profound supersensitive response to apomorphine as measured by a significant increase in locomotor activity as compared to sham-operated animals. In contrast, smaller 6-OHDA lesions of the VTA produced significant increases in spontaneous daytime and nocturnal activity with the biggest effect occurring at the lowest dose. RF lesions to the VTA produced even greater hyperactivity which was blocked by the addition of a 6-OHDA lesion to the N.Acc. The rats with RF lesions to VTA alone that were spontaneously hyperactive remained hyperactive after injection of amphetamine, whereas apomorphine produced a significant decrease in this hyperactivity. In contrast, the rats with the combined RF lesion and N.Acc. 6-OHDA lesion showed a blockade of the locomotor stimulating effects of D-amphetamine and a potentiated response to apomorphine identical to that observed with a N.Acc. lesion alone. All lesion groups revealed massive depletion of DA in the N.Acc. and anterior striatum with significantly greater depletions in those groups showing hypoactivity and hypo-responsiveness to amphetamine. All groups except the N.Acc. 6-OHDA alone group showed significant depletions of DA in the posterior striatum. Thus, limited destruction of the mesolimbic DA system can produce hyperactivity, but more extensive destruction of this system in the region of the N.Acc. and anterior striatum can reverse this hyperactivity and produce a hypo-responsiveness to the locomotor stimulating effects of amphetamine. These results suggest an

  9. Pentamidine-induced dysglycaemia: experimental models in the rat.

    PubMed

    Assan, R; Assan, D; Delaby, J; Debussche, X; Toublanc, M

    1993-01-01

    In order to analyse further the pathophysiology of pentamidine effects on blood glucose regulation, the following experimental models were established in rats: impairment of the renal function, bile duct ligation, inhibition of the P450 cytochrome enzyme system. In otherwise intact rats, 7.5 mg/day pentamidine was well tolerated whereas doses of 15 mg/day induced severe, relapsing and eventually lethal hypoglycaemia within a few days. Induction of a renal insufficiency of graded severity by treatment with gentamycin, subtotal nephrectomy and total bilateral nephrectomy resulted in repetitive, severe (sometimes lethal) hypoglycaemia, alternating with hyperglycaemia, glucosuria and ketonuria in pentamidine-treated rats (7.5 mg/d). No long-standing insulin-dependent diabetes was observed. In the dysglycemic animals, plasma insulin levels were inappropriate to the concomitant glycaemia; no stimulation was obtained by i.v. glucose. Glucagon levels were higher than normal, suppressible by i.v. glucose, responsive to IV arginine and to hypoglycaemia. Dysglycemic events were more frequent and marked in the rats with the most severe renal functional derangement. They were more frequent in the rats treated with pentamidine mesylate than in those treated with the isethionate salt. Control uremic rats (free of pentamidine) remained euglycaemic. The islets of Langerhans displayed severe vascular congestion and degranulation and necrosis of the B cells, while the non B cells (and particularly the A cells) were intact. Exocrine pancreatitis was occasionally observed in the most severely uremic rats. In contrast with uremic rats, neither surgical ligation of choledocus, nor treatment by P450 cytochrome inhibitors (particularly ketoconazole) precipitated dysglycaemia in the pentamidine-treated rats. These experimental data: 1) strengthen the concept of inappropriate insulin release from pentamidine-lesioned islet B cells due to pentamidine accumulation; 2) indicate a predominant

  10. The rat as an animal model of Alzheimer’s disease

    PubMed Central

    Benedikz, Eirikur; Kloskowska, Ewa; Winblad, Bengt

    2009-01-01

    As a disease model, the laboratory rat has contributed enormously to neuroscience research over the years. It has also been a popular animal model for Alzheimer’s disease but its popularity has diminished during the last decade, as techniques for genetic manipulation in rats have lagged behind that of mice. In recent years, the rat has been making a comeback as an Alzheimer’s disease model and the appearance of increasing numbers of transgenic rats will be a welcome and valuable complement to the existing mouse models. This review summarizes the contributions and current status of the rat as an animal model of Alzheimer’s disease. PMID:19432812

  11. Emphysema model in rats treated intratracheally with elastase

    SciTech Connect

    Yokoyama, E.; Nambu, Z.; Uchiyama, I.; Kyono, H.

    1987-04-01

    Pulmonary functions, morphology, and morphometry were examined in rats at 3, 7, and 10 weeks after a single intratracheal administration of 6.5 units of porcine pancreatic elastase in order to obtain a model of pulmonary emphysema which would be suitable for studying the responses of emphysematous lungs to atmospheric pollutants. Functional residual capacity and residual volume of the elastase-treated rats increased at all the times studied, but their total lung capacity increased only at 7 and 10 weeks compared with those of the saline-treated control rats. The increase in static lung compliance and the decrease in peak flow and maximum flow at 50% of total lung capacity during forced expiration were also observed in all except the 3-week elastase animals. The elastase-treated lungs showed morphological changes characteristic of emphysematous lesions. The increase in mean linear intercept length and the decrease in total alveolar surface area were demonstrated by these elastase-treated lungs. Based on these results, they conclude that an adequate and suitable model of pulmonary emphysemia could be obtained in rats 7-10 weeks after treatment with the present dose of elastase.

  12. Validation of the rat model of cryptogenic infantile spasms

    PubMed Central

    Chachua, Tamar; Yum, Mi-Sun; Velíšková, Jana; Velíšek, Libor

    2011-01-01

    Purpose To determine whether a new model of cryptogenic infantile spasms consisting of prenatal priming with betamethasone and postnatal trigger of spasms by N-methyl-D-aspartic acid responds to chronic ACTH treatment, and has similar EEG signature, efficacy of treatments, and behavioral impairments as human infantile spasms. Methods Rats prenatally primed with betamethasone on gestational day 15 were used. Spasms were triggered with N-methyl-D-aspartic acid between postnatal days (P) 10-15 in a single session or in multiple sessions in one subject. The expression of spasms was compared to prenatally saline-injected controls. Effects of relevant treatments (ACTH, vigabatrin, methylprednisolone, rapamycin) were determined in betamethasone-primed rats. In the rats after spasms, behavioral evaluation was performed in the open field and and elevated plus maze on P20-22. Key Findings NMDA at P10-15 (the rat “infant” period) triggers the spasms significantly earlier and in greater numbers in the prenatal betamethasone-exposed brain compared to controls. Similar to human condition, the spasms occur in clusters. Repeated trigger of spasms is associated with ictal EEG electrodecrements and interictal large-amplitude waves, a possible rat variant of hypsarrhythmia. Chronic ACTH treatment in a randomized experiment, and chronic pretreatment with methylprednisolone significantly suppress number of spasms similar to human condition. Pretreatment with vigabatrin, but not rapamycin, suppressed the spasms. Significant behavioral changes occurred following multiple bouts of spasms. Significance The model of infantile spasms has remarkable similarities with the human condition in semiology, EEG, pharmacological response, and long-term outcome. Thus, the model can be used for search of novel and more effective treatments for infantile spasms. PMID:21854372

  13. Particulate matter inhalation exacerbates cardiopulmonary injury in a rat model of isoproterenol-induced cardiomyopathy

    EPA Science Inventory

    Ambient particulate matter (PM) exposure is linked to cardiovascular events and death, especially among individuals with heart disease. A model of toxic cardiomyopathy was developed in Spontaneously Hypertensive Heart Failure (SHHF) rats to explore potential mechanisms. Rats were...

  14. Electroacupuncture Produces the Sustained Motor Improvement in 6-Hydroxydopamine-Lesioned Mice

    PubMed Central

    Deng, Jiahui; Sun, Min; Jia, Jun; Wang, Xiaomin

    2016-01-01

    Clinical and research evidence has shown that electroacupuncture (EA) promotes recovery of motor function in patients with Parkinson’s disease (PD). However, the “efficacy span” of EA treatment, especially the long-term effect of EA that is thought to last after the cessation of EA treatment, has not been investigated. The present study thus investigated and compared the effect of EA during and after chronic EA application on motor activity and dopamine lesions in a 6-hydroxydopamine (6-OHDA)-lesioned mouse model of PD. Chronic EA treatment (30 min a day, 6 days a week for 2 or 4 weeks) significantly attenuated motor deficiency and reduced dopamine neuron degeneration. Remarkably, EA showed a long-lasting effect after the cessation of EA stimulation. At 2 and 4 weeks after the termination of EA, EA continued to improve motor function in 6-OHDA-lesioned mice. Consistent with sustained behavioral effects, EA induced an enduring increase in the dopamine turnover ratio in the striatum 2 weeks after the cessation of EA treatment. Here we demonstrated that the therapeutic effect of EA outlasted the duration of EA application. During a relatively long period of time after the completion of EA treatment, EA is able to continue to improve motor function and enhance dopamine availability in 6-OHDA-lesioned PD mice. PMID:26894437

  15. Establishment of reproducible osteosarcoma rat model using orthotopic implantation technique.

    PubMed

    Yu, Zhe; Sun, Honghui; Fan, Qingyu; Long, Hua; Yang, Tongtao; Ma, Bao'an

    2009-05-01

    In experimental musculoskeletal oncology, there remains a need for animal models that can be used to assess the efficacy of new and innovative treatment methodologies for bone tumors. Rat plays a very important role in the bone field especially in the evaluation of metabolic bone diseases. The objective of this study was to develop a rat osteosarcoma model for evaluation of new surgical and molecular methods of treatment for extremity sarcoma. One hundred male SD rats weighing 125.45+/-8.19 g were divided into 5 groups and anesthetized intraperitoneally with 10% chloral hydrate. Orthotopic implantation models of rat osteosarcoma were performed by injecting directly into the SD rat femur with a needle for inoculation with SD tumor cells. In the first step of the experiment, 2x10(5) to 1x10(6) UMR106 cells in 50 microl were injected intraosseously into median or distal part of the femoral shaft and the tumor take rate was determined. The second stage consisted of determining tumor volume, correlating findings from ultrasound with findings from necropsia and determining time of survival. In the third stage, the orthotopically implanted tumors and lung nodules were resected entirely, sectioned, and then counter stained with hematoxylin and eosin for histopathologic evaluation. The tumor take rate was 100% for implants with 8x10(5) tumor cells or more, which was much less than the amount required for subcutaneous implantation, with a high lung metastasis rate of 93.0%. Ultrasound and necropsia findings matched closely (r=0.942; p<0.01), which demonstrated that Doppler ultrasonography is a convenient and reliable technique for measuring cancer at any stage. Tumor growth curve showed that orthotopically implanted tumors expanded vigorously with time-lapse, especially in the first 3 weeks. The median time of survival was 38 days and surgical mortality was 0%. The UMR106 cell line has strong carcinogenic capability and high lung metastasis frequency. The present rat

  16. A New Rat Model for Orthotopic Abdominal Wall Allotransplantation

    PubMed Central

    Lao, William W.; Wang, Yen-Ling; Ramirez, Alejandro E.; Cheng, Hui-Yun

    2014-01-01

    Background: Abdominal wall, one of the most commonly transplanted composite tissues, is less researched and lacking animal models. Its clinical necessities were emphasized in multiple case series to reconstruct large abdominal defects. Previous animal models have only studied components of the abdominal wall transplant. We describe findings from a new model that more likely reflect clinical transplantation. Methods: Full-thickness hemiabdominal wall flap was procured from Brown Norway (BN) rats and transplanted to an orthotopic defect on Lewis rats. Three groups were studied: group 1: Lewis to Lewis syngeneic; group 2: BN to Lewis control; and group 3: BN to Lewis with postoperative cyclosporine. Vascular imaging and cross vessel section were performed along with full-thickness abdominal wall. Immune cell profiling with flow cytometry at different time points was studied in all groups. Results: Syngeneic group had no rejection. Control group consistently showed rejection around postoperative day 6. With cyclosporine treatment, however, transplant and recipient tissue integration was observed. Flow cytometry revealed that innate immunity is responsible for the initial inflammatory events following abdominal wall engraftment. Adaptive immunity cells, specifically interferon-γ-producing T helper (Th) 1 and interleukin-17-producing Th17 cells, dramatically and positively correlate with rejection progression of abdominal wall transplants. Conclusions: Technical, histological, and immunological aspects of a new rat model are described. These results give clues to what occurs in human abdominal wall transplantation. In addition, Th1, a proinflammatory cell, was found to be a potential biomarker for allograft rejection. PMID:25289329

  17. Fat Preference: A Novel Model of Eating Behavior in Rats

    PubMed Central

    Kasper, James M; Johnson, Sarah B; Hommel, Jonathan D

    2016-01-01

    Obesity is a growing problem in the United States of America, with more than a third of the population classified as obese. One factor contributing to this multifactorial disorder is the consumption of a high-fat diet, a behavior that has been shown to increase both caloric intake and body fat content. However, the elements regulating preference for high-fat food over other foods remain understudied. To overcome this deficit, a model to quickly and easily test changes in the preference for dietary fat was developed. The Fat Preference model presents rats with a series of choices between foods with differing fat content. Like humans, rats have a natural bias toward consuming high-fat food, making the rat model ideal for translational studies. Changes in preference can be ascribed to the effect of either genetic differences or pharmacological interventions. This model allows for the exploration of determinates of fat preference and screening pharmacotherapeutic agents that influence acquisition of obesity. PMID:24998978

  18. Creation of Consistent Burn Wounds: A Rat Model

    PubMed Central

    Cai, Elijah Zhengyang; Ang, Chuan Han; Raju, Ashvin; Tan, Kong Bing; Hing, Eileen Chor Hoong; Loo, Yihua; Wong, Yong Chiat; Lee, Hanjing; Lim, Jane; Moochhala, Shabbir M; Hauser, Charlotte AE

    2014-01-01

    Background Burn infliction techniques are poorly described in rat models. An accurate study can only be achieved with wounds that are uniform in size and depth. We describe a simple reproducible method for creating consistent burn wounds in rats. Methods Ten male Sprague-Dawley rats were anesthetized and dorsum shaved. A 100 g cylindrical stainless-steel rod (1 cm diameter) was heated to 100℃ in boiling water. Temperature was monitored using a thermocouple. We performed two consecutive toe-pinch tests on different limbs to assess the depth of sedation. Burn infliction was limited to the loin. The skin was pulled upwards, away from the underlying viscera, creating a flat surface. The rod rested on its own weight for 5, 10, and 20 seconds at three different sites on each rat. Wounds were evaluated for size, morphology and depth. Results Average wound size was 0.9957 cm2 (standard deviation [SD] 0.1845) (n=30). Wounds created with duration of 5 seconds were pale, with an indistinct margin of erythema. Wounds of 10 and 20 seconds were well-defined, uniformly brown with a rim of erythema. Average depths of tissue damage were 1.30 mm (SD 0.424), 2.35 mm (SD 0.071), and 2.60 mm (SD 0.283) for duration of 5, 10, 20 seconds respectively. Burn duration of 5 seconds resulted in full-thickness damage. Burn duration of 10 seconds and 20 seconds resulted in full-thickness damage, involving subjacent skeletal muscle. Conclusions This is a simple reproducible method for creating burn wounds consistent in size and depth in a rat burn model. PMID:25075351

  19. Numerical modeling of odorant uptake in the rat nasal cavity.

    PubMed

    Yang, Geoffrey C; Scherer, Peter W; Zhao, Kai; Mozell, Maxwell M

    2007-03-01

    An anatomically accurate 3-dimensional numerical model of the right rat nasal cavity was developed and used to compute low, medium, and high flow rate inspiratory and expiratory mucosal odorant uptake (imposed patterning) for 3 odorants with different mucus solubilities. The computed surface mass flux distributions were compared with anatomic receptor gene expression zones identified in the literature. In general, simulations predicted that odorants that were highly soluble in mucus were absorbed dorsally and medially, corresponding roughly to receptors from one of the gene expression zones. Insoluble odorants tended to be absorbed more peripherally in the rat olfactory region corresponding to the other 2 zones. These findings also agreed in general with the electroolfactogram measurements and the voltage-sensitive dye measurements reported in the literature. This numerical approach is the first to predict detailed odorant flux information across the olfactory mucosa in the rat nasal cavity during inspiratory and expiratory flow and to relate it to anatomic olfactory receptor location, physiological function, and biochemical experiment. This numerical technique can allow us to separate the contributions of imposed and inherent patterning mechanisms on the rat olfactory mucosa. PMID:17220517

  20. A simple and stable galactosemic cataract model for rats

    PubMed Central

    Ji, Lixia; Li, Caina; Shen, Ning; Huan, Yi; Liu, Quan; Liu, Shuainan; Shen, Zhufang

    2015-01-01

    Rat galactosemic cataract is commonly used in the investigation of sugar cataract. In current study, 21-day sprague-dawley (SD) rats were randomly divided into two groups (n=42), which were fed by normal water and galactose solution (12.5%-10%) for 18 days respectively. Every 3 days, lens opacity was observed by a slit lamp, and 6 rats of each group were executed for the analysis of aldose reductase (AR) activity, galactitol level and AR mRNA expression. Morphological results showed that small vacuoles initially appeared in the equatorial area before the 6th day, then subsequently extended to the whole anterior capsule, and eventually developed to mature cataract on the 18th day. AR of galactosemic lenses was significantly activated in the first stage and then slowly dropped to the end accompanied by the related changes of galactitol. AR mRNA expression also was upregulated and reached the peak at the 6th day. This study appears to confirm that galactosemic cataract can be induced for 21-day SD rats by only drinking 12.5% to 10% galactose solution, and this model is simple, economical and stable as to meet the research needs. PMID:26550203

  1. Capsular Contracture In Silicone Breast Implants: Insights From Rat Models.

    PubMed

    Vieira, Vilberto J; D'Acampora, Armando; Neves, Fernanda S; Mendes, Paulo R; Vasconcellos, Zulmar A DE; Neves, Rodrigo D'Eça; Figueiredo, Claudia P

    2016-09-01

    Breast augmentation with silicone implants is one of the most common procedures performed by plastic surgeons around the world. Capsular contracture is a frequent complication in breast augmentation and reconstructive surgery, that requires invasive intervention. The inflammatory response to implanted mammary prostheses appears to be directly associated to capsular contracture. This review discusses the evidences from rat models studies, on the role of inflammation and fibrosis in capsular contraction and its relation to silicone breast implants surface. PMID:27627068

  2. Culture Model of Rat Portal Myofibroblasts.

    PubMed

    El Mourabit, Haquima; Loeuillard, Emilien; Lemoinne, Sara; Cadoret, Axelle; Housset, Chantal

    2016-01-01

    Myofibroblasts are matrix-producing cells with contractile properties, usually characterized by de novo expression of alpha-smooth muscle actin, that arise in fibrotic diseases. Hepatic stellate cells (HSCs), known as perisinusoidal cells containing auto-fluorescent vitamin A, are the major although not exclusive source of myofibroblasts in the injured liver. Portal myofibroblasts (PMFs) have been defined as liver myofibroblasts derived from cells that are distinct from HSCs and located in the portal tract. Here, we describe the protocol we have established to obtain rat PMFs in culture. In this method, the biliary tree is (i) separated from the liver parenchyma by in situ enzymatic perfusion of the liver, (ii) minced and further digested in vitro, until bile duct segments are isolated by sequential filtration. Bile duct isolates free of HSC contaminants, form small cell clusters, which initially comprise a large majority of epithelial cells. In culture conditions (fetal bovine serum) that provide a growth advantage to mesenchymal cells over epithelial cells, the epithelial cells die and detach from the substrate, while spindle-shaped cells outgrow from the periphery of the cell clusters, as shown by video-microscopy. These cells are highly proliferative and after 4-5 days, the culture is composed exclusively of fully differentiated myofibroblasts, which express alpha-smooth muscle actin and collagen 1, and secrete abundant collagen. We found no evidence for epithelial-mesenchymal transition, i.e., no co-expression of alpha-smooth muscle actin and cytokeratin at any stage, while cytokeratin becomes undetectable in the confluent cells. PMFs obtained by this method express the genes that were previously reported to be overexpressed in non-HSC or portal fibroblast-derived liver myofibroblasts as compared to HSC-derived myofibroblasts, including the most discriminant, collagen 15, fibulin 2, and Thy-1. After one passage, PMFs retain the same phenotypic features as in

  3. Culture Model of Rat Portal Myofibroblasts

    PubMed Central

    El Mourabit, Haquima; Loeuillard, Emilien; Lemoinne, Sara; Cadoret, Axelle; Housset, Chantal

    2016-01-01

    Myofibroblasts are matrix-producing cells with contractile properties, usually characterized by de novo expression of alpha-smooth muscle actin, that arise in fibrotic diseases. Hepatic stellate cells (HSCs), known as perisinusoidal cells containing auto-fluorescent vitamin A, are the major although not exclusive source of myofibroblasts in the injured liver. Portal myofibroblasts (PMFs) have been defined as liver myofibroblasts derived from cells that are distinct from HSCs and located in the portal tract. Here, we describe the protocol we have established to obtain rat PMFs in culture. In this method, the biliary tree is (i) separated from the liver parenchyma by in situ enzymatic perfusion of the liver, (ii) minced and further digested in vitro, until bile duct segments are isolated by sequential filtration. Bile duct isolates free of HSC contaminants, form small cell clusters, which initially comprise a large majority of epithelial cells. In culture conditions (fetal bovine serum) that provide a growth advantage to mesenchymal cells over epithelial cells, the epithelial cells die and detach from the substrate, while spindle-shaped cells outgrow from the periphery of the cell clusters, as shown by video-microscopy. These cells are highly proliferative and after 4–5 days, the culture is composed exclusively of fully differentiated myofibroblasts, which express alpha-smooth muscle actin and collagen 1, and secrete abundant collagen. We found no evidence for epithelial-mesenchymal transition, i.e., no co-expression of alpha-smooth muscle actin and cytokeratin at any stage, while cytokeratin becomes undetectable in the confluent cells. PMFs obtained by this method express the genes that were previously reported to be overexpressed in non-HSC or portal fibroblast-derived liver myofibroblasts as compared to HSC-derived myofibroblasts, including the most discriminant, collagen 15, fibulin 2, and Thy-1. After one passage, PMFs retain the same phenotypic features as in

  4. High-fat diet-induced obesity Rat model: a comparison between Wistar and Sprague-Dawley Rat

    PubMed Central

    Marques, Cláudia; Meireles, Manuela; Norberto, Sónia; Leite, Joana; Freitas, Joana; Pestana, Diogo; Faria, Ana; Calhau, Conceição

    2016-01-01

    ABSTRACT In the past decades, obesity and associated metabolic complications have reached epidemic proportions. For the study of these pathologies, a number of animal models have been developed. However, a direct comparison between Wistar and Sprague-Dawley (SD) Rat as models of high-fat (HF) diet-induced obesity has not been adequately evaluated so far. Wistar and SD rats were assigned for 2 experimental groups for 17 weeks: standard (St) and high-fat (HF) diet groups. To assess some of the features of the metabolic syndrome, oral glucose tolerance tests, systolic blood pressure measurements and blood biochemical analysis were performed throughout the study. The gut microbiota composition of the animals of each group was evaluated at the end of the study by real-time PCR. HF diet increased weight gain, body fat mass, mesenteric adipocyte's size, adiponectin and leptin plasma levels and decreased oral glucose tolerance in both Wistar and SD rats. However, the majority of these effects were more pronounced or earlier detected in Wistar rats. The gut microbiota of SD rats was less abundant in Bacteroides and Prevotella but richer in Bifidobacterium and Lactobacillus comparatively to the gut microbiota of Wistar rats. Nevertheless, the modulation of the gut microbiota by HF diet was similar in both strains, except for Clostridium leptum that was only reduced in Wistar rats fed with HF diet. In conclusion, both Wistar and SD Rat can be used as models of HF diet-induced obesity although the metabolic effects caused by HF diet seemed to be more pronounced in Wistar Rat. Differences in the gut microbial ecology may account for the worsened metabolic scenario observed in Wistar Rat. PMID:27144092

  5. Modeling the mechanical properties of liver fibrosis in rats.

    PubMed

    Zhu, Ying; Chen, Xin; Zhang, Xinyu; Chen, Siping; Shen, Yuanyuan; Song, Liang

    2016-06-14

    The progression of liver fibrosis changes the biomechanical properties of liver tissue. This study characterized and compared different liver fibrosis stages in rats in terms of viscoelasticity. Three viscoelastic models, the Voigt, Maxwell, and Zener models, were applied to experimental data from rheometer tests and then the elasticity and viscosity were estimated for each fibrosis stage. The study found that both elasticity and viscosity are correlated with the various stages of liver fibrosis. The study revealed that the Zener model is the optimal model for describing the mechanical properties of each fibrosis stage, but there is no significant difference between the Zener and Voigt models in their performance on liver fibrosis staging. Therefore the Voigt model can still be effectively used for liver fibrosis grading. PMID:27017300

  6. Stem cell therapy in intracerebral hemorrhage rat model.

    PubMed

    Cordeiro, Marcos F; Horn, Ana P

    2015-04-26

    Intracerebral hemorrhage (ICH) is a very complex pathology, with many different not fully elucidated etiologies and prognostics. It is the most severe subtype of stroke, with high mortality and morbidity rates. Unfortunately, despite the numerous promising preclinical assays including neuroprotective, anti-hypertensive, and anti-inflammatory drugs, to this moment only symptomatic treatments are available, motivating the search for new alternatives. In this context, stem cell therapy emerged as a promising tool. However, more than a decade has passed, and there is still much to be learned not only about stem cells, but also about ICH itself, and how these two pieces come together. To date, rats have been the most widely used animal model in this research field, and there is much more to be learned from and about them. In this review, we first summarize ICH epidemiology, risk factors, and pathophysiology. We then present different methods utilized to induce ICH in rats, and examine how accurately they represent the human disease. Next, we discuss the different types of stem cells used in previous ICH studies, also taking into account the tested transplantation sites. Finally, we summarize what has been achieved in assays with stem cells in rat models of ICH, and point out some relevant issues where attention must be given in future efforts. PMID:25914768

  7. Stem cell therapy in intracerebral hemorrhage rat model

    PubMed Central

    Cordeiro, Marcos F; Horn, Ana P

    2015-01-01

    Intracerebral hemorrhage (ICH) is a very complex pathology, with many different not fully elucidated etiologies and prognostics. It is the most severe subtype of stroke, with high mortality and morbidity rates. Unfortunately, despite the numerous promising preclinical assays including neuroprotective, anti-hypertensive, and anti-inflammatory drugs, to this moment only symptomatic treatments are available, motivating the search for new alternatives. In this context, stem cell therapy emerged as a promising tool. However, more than a decade has passed, and there is still much to be learned not only about stem cells, but also about ICH itself, and how these two pieces come together. To date, rats have been the most widely used animal model in this research field, and there is much more to be learned from and about them. In this review, we first summarize ICH epidemiology, risk factors, and pathophysiology. We then present different methods utilized to induce ICH in rats, and examine how accurately they represent the human disease. Next, we discuss the different types of stem cells used in previous ICH studies, also taking into account the tested transplantation sites. Finally, we summarize what has been achieved in assays with stem cells in rat models of ICH, and point out some relevant issues where attention must be given in future efforts. PMID:25914768

  8. Efficacy of Female Rat Models in Translational Cardiovascular Aging Research

    PubMed Central

    Rice, K. M.; Fannin, J. C.; Gillette, C.; Blough, E. R.

    2014-01-01

    Cardiovascular disease is the leading cause of death in women in the United States. Aging is a primary risk factor for the development of cardiovascular disease as well as cardiovascular-related morbidity and mortality. Aging is a universal process that all humans undergo; however, research in aging is limited by cost and time constraints. Therefore, most research in aging has been done in primates and rodents; however it is unknown how well the effects of aging in rat models translate into humans. To compound the complication of aging gender has also been indicated as a risk factor for various cardiovascular diseases. This review addresses the systemic pathophysiology of the cardiovascular system associated with aging and gender for aging research with regard to the applicability of rat derived data for translational application to human aging. PMID:25610649

  9. In vivo photoacoustic imaging of osteosarcoma in a rat model

    NASA Astrophysics Data System (ADS)

    Hu, Jun; Yu, Menglei; Ye, Fei; Xing, Da

    2011-02-01

    Osteosarcoma is one of the most common primary malignant tumors of the bone and the second leading cause of cancer-related deaths in the pediatric age group. Confirmed diagnosis and prompt treatment of osteosarcoma are critical for effective prognosis. In this study, we investigate the application of photoacoustic imaging (PAI) for the detection of osteosarcoma in an animal model. Cross-section images of a normal rat leg and a tumorous rat leg were successfully reconstructed in vivo. Morphological changes and the development of the implanted osteosarcoma were accurately mapped with time-dependent photoacoustic images. Furthermore, we evaluate the use of gold nanorods as contrast agents for imaging osteosarcoma with PAI. This is the first study that uses PAI to detect osteosarcoma in vivo, and the results suggest that PAI has the potential clinical application for detecting osteosarcoma in the early stage.

  10. Rat models of asthma and chronic obstructive lung disease.

    PubMed

    Martin, James G; Tamaoka, Meiyo

    2006-01-01

    The rat has been extensively used to model asthma and somewhat less extensively to model chronic obstructive pulmonary disease (COPD). The features of asthma that have been successfully modeled include allergen-induced airway constriction, eosinophilic inflammation and allergen-induced airway hyperresponsiveness. T-cell involvement has been directly demonstrated using adoptive transfer techniques. Both CD4+ and CD8+ T cells are activated in response to allergen challenge in the sensitized rat and express Thelper2 cytokines (IL-4, IL-5 and IL-13). Repeated allergen exposure causes airway remodeling. Dry gas hyperpnea challenge also evokes increases in lung resistance, allowing exercise-induced asthma to be modeled. COPD is modeled using elastase-induced parenchymal injury to mimic emphysema. Cigarette smoke-induced airspace enlargement occurs but requires months of cigarette exposure. Inflammation and fibrosis of peripheral airways is an important aspect of COPD that is less well modeled. Novel approaches to the treatment of COPD have been reported including treatments aimed at parenchymal regeneration. PMID:16337418

  11. Novel isolated cecal pouch model for endoscopic observation in rats

    PubMed Central

    Koshino, Kurodo; Kanai, Nobuo; Yamato, Masayuki; Okano, Teruo; Yamamoto, Masakazu

    2015-01-01

    AIM: To create a new rat model for drug administration, cell transplantation, and endoscopic examination for the treatment of intestinal diseases. METHODS: F344/NJc l-rnu/rnu rats (10-wk-old males, 350-400 g) were used in this study. The rats were anesthetized via 2% isoflurane inhalation. The rat’s cecum was isolated from the intestines, and a pouch was created. The remainder of the intestines was rejoined to create an anastomosis. The “side-to-side” anastomosis (SSA) technique initially involves the creation of a 2-cm longitudinal incision into each intestinal wall. To create an anastomosis along the ileal and colonic walls, both intestines were cut, and a continuous suture procedure was performed that included all layers of both intestines. The serous membrane was sutured along the edge and on the anterior wall of the anastomosis. The “end-to-end” anastomosis (EEA) technique was compared with the SSA technique. In the EEA technique, the frontal surfaces of both cut intestinal lumens were joined together by continuous sutures. Additional sutures were made at the serosa. After the anastomotic intestine was successfully constructed, the two intestinal lumens that were cut at the isolated cecum were managed. In addition, one luminal side of the pouch remained open to create an artificial anus on the dorsum as a passage for the residual substances in the pouch. Finally, small animal endoscopy was used to observe the inside of the pouch. RESULTS: In this animal model, mucus and feces are excreted through the reconstructed passage. Accordingly, the cecal pouch mucosa was not obstructed or contaminated by feces, thus facilitating observations of the luminal surface of the intestine. The endoscopic observation of the cecal pouch provided clear visualization given the absence of feces. The membrane surface of the cecum was clearly observed. Two methods of creating an anastomotic intestine, the “SSA” and “EEA” techniques, were compared with regard to

  12. Exercise exerts neuroprotective effects on Parkinson's disease model of rats.

    PubMed

    Tajiri, Naoki; Yasuhara, Takao; Shingo, Tetsuro; Kondo, Akihiko; Yuan, Wenji; Kadota, Tomohito; Wang, Feifei; Baba, Tanefumi; Tayra, Judith Thomas; Morimoto, Takamasa; Jing, Meng; Kikuchi, Yoichiro; Kuramoto, Satoshi; Agari, Takashi; Miyoshi, Yasuyuki; Fujino, Hidemi; Obata, Futoshi; Takeda, Isao; Furuta, Tomohisa; Date, Isao

    2010-01-15

    Recent studies demonstrate that rehabilitation ameliorates physical and cognitive impairments of patients with stroke, spinal cord injury, and other neurological diseases and that rehabilitation also has potencies to modulate brain plasticity. Here we examined the effects of compulsive exercise on Parkinson's disease model of rats. Before 6-hydroxydopamine (6-OHDA, 20 microg) lesion into the right striatum of female SD rats, bromodeoxyuridine (BrdU) was injected to label the proliferating cells. Subsequently, at 24 h after the lesion, the rats were forced to run on the treadmill (5 days/week, 30 min/day, 11 m/min). As behavioral evaluations, cylinder test was performed at 1, 2, 3, and 4 weeks and amphetamine-induced rotational test was performed at 2 and 4 weeks with consequent euthanasia for immunohistochemical investigations. The exercise group showed better behavioral recovery in cylinder test and significant decrease in the number of amphetamine-induced rotations, compared to the non-exercise group. Correspondingly, significant preservation of tyrosine hydroxylase (TH)-positive fibers in the striatum and TH-positive neurons in the substantia nigra pars compacta (SNc) was demonstrated, compared to the non-exercise group. Additionally, the number of migrated BrdU- and Doublecortin-positive cells toward the lesioned striatum was increased in the exercise group. Furthermore, brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor increased in the striatum by exercise. The results suggest that exercise exerts neuroprotective effects or enhances the neuronal differentiation in Parkinson's disease model of rats with subsequent improvement in deteriorated motor function. PMID:19900418

  13. Evaluating antithrombotic activity of HY023016 on rat hypercoagulable model.

    PubMed

    Chen, Qiu-Fang; Li, Yun-Zhan; Wang, Xin-Hui; Su, You-Rui; Cui, Shuang; Miao, Ming-Xing; Jiang, Zhen-Zhou; Jiang, Mei-Ling; Jiang, Ai-Dou; Chen, Xiang; Xu, Yun-Gen; Gong, Guo-Qing

    2016-06-15

    The generation of thrombus is not considered as an isolated progression without other pathologic processes, which may also enhance procoagulant state. The purpose of this study was to assess whether HY023016, a novel dabigatran prodrug and an oral direct thrombin inhibitor, or dabigatran etexilate, another thrombin inhibitor can improve the state of whole blood hypercoagulability in vitro/vivo. By using whole blood flow cytometry we explored the effects of HY023016 and dabigatran etexilate on thrombin and ADP-induced human platelet-leukocyte aggregation generated in vitro. With the method of continuous infusion of thrombin intravenous, we successfully established a rat hypercoagulable model and evaluated the effect of HY023016 or dabigatran etexilate in vivo. HY023016 was able to inhibit thrombin- or ADP-induced platelet P-selectin or CD40L expression, leukocyte CD11b expression and formation of platelet-leukocyte aggregates in dose-dependent manner. Dabigatran etexilate was unable to affect ADP-induced platelet P-selectin or CD40L expression, leukocyte CD11b expression and formation of platelet-leukocyte aggregates. Based on rat hypercoagulable model, dabigatran etexilate could reverse thrombin-induced circulatory system hypercoagulable state in a concentration-dependent manner. Dabigatran etexilate also inhibited electrical stimulation induced formation of arterial thrombus in rat under hypercoagulable state, and extracorporal circulation-induced formation of thrombus in dose-dependent manner. Compared with dabigatran etexilate, HY023016 showed nearly equal or even better antithrombotic activity, regardless of reversing the cycle of rat hypercoagulable state or inhibiting platelet-leukocyte aggregation. In surrmary, HY023016 could effectively improve hypercoagulable state of circulatory system. PMID:27085896

  14. Experience Modulates Vicarious Freezing in Rats: A Model for Empathy

    PubMed Central

    Atsak, Piray; Orre, Marie; Bakker, Petra; Cerliani, Leonardo; Roozendaal, Benno

    2011-01-01

    The study of the neural basis of emotional empathy has received a surge of interest in recent years but mostly employing human neuroimaging. A simpler animal model would pave the way for systematic single cell recordings and invasive manipulations of the brain regions implicated in empathy. Recent evidence has been put forward for the existence of empathy in rodents. In this study, we describe a potential model of empathy in female rats, in which we studied interactions between two rats: a witness observes a demonstrator experiencing a series of footshocks. By comparing the reaction of witnesses with or without previous footshock experience, we examine the role of prior experience as a modulator of empathy. We show that witnesses having previously experienced footshocks, but not naïve ones, display vicarious freezing behavior upon witnessing a cage-mate experiencing footshocks. Strikingly, the demonstrator's behavior was in turn modulated by the behavior of the witness: demonstrators froze more following footshocks if their witness froze more. Previous experiments have shown that rats emit ultrasonic vocalizations (USVs) when receiving footshocks. Thus, the role of USV in triggering vicarious freezing in our paradigm is examined. We found that experienced witness-demonstrator pairs emitted more USVs than naïve witness-demonstrator pairs, but the number of USVs was correlated with freezing in demonstrators, not in witnesses. Furthermore, playing back the USVs, recorded from witness-demonstrator pairs during the empathy test, did not induce vicarious freezing behavior in experienced witnesses. Thus, our findings confirm that vicarious freezing can be triggered in rats, and moreover it can be modulated by prior experience. Additionally, our result suggests that vicarious freezing is not triggered by USVs per se and it influences back onto the behavior of the demonstrator that had elicited the vicarious freezing in witnesses, introducing a paradigm to study empathy

  15. The elusive rat model of conditioned placebo analgesia.

    PubMed

    McNabb, Christopher T; White, Michelle M; Harris, Amber L; Fuchs, Perry N

    2014-10-01

    Recent research on human placebo analgesia has suggested the need for rodent models to further elucidate the neural substrates of the placebo effect. This series of 3 experiments therefore was performed in an attempt to develop a model of placebo analgesia in rats. In each study, female Sprague-Dawley rats received an L5 spinal nerve ligation to induce a neuropathic pain condition. Each rat then underwent a 4-day conditioning procedure in which an active analgesic drug or its vehicle (unconditioned stimulus) was associated with the following cues (conditioned stimuli): novel testing room (environmental), vanilla scent cue (olfactory), dim incandescent lighting (visual), restraint procedure/injection (tactile), and time of day and injection-test latency (temporal). The analgesics for each experiment were as follows: Experiment 1 used 90 mg/kg gabapentin, experiment 2 used 3mg/kg loperamide hydrochloride, and experiment 3 used 6 mg/kg morphine sulfate. On the following test day, half of the animals received the opposite treatment, resulting in 4 conditioning manipulations: drug/drug, drug/vehicle, vehicle/drug, and vehicle/vehicle. Nociceptive thresholds were assessed with the mechanical paw withdrawal threshold test each day after the conditioning procedure. In all 3 experiments, no significant differences were detected on test day between control and placebo groups, indicating a lack of a conditioned placebo analgesic response. Our results contrast with prior research that implies the existence of a reliable and robust response to placebo treatment. We conclude that placebo analgesia in rats is not particularly robust and that it is difficult to achieve using conventional procedures and proper experimental design. PMID:25026214

  16. The utility of Apc-mutant rats in modeling human colon cancer

    PubMed Central

    Irving, Amy A.; Yoshimi, Kazuto; Hart, Marcia L.; Parker, Taybor; Clipson, Linda; Ford, Madeline R.; Kuramoto, Takashi; Dove, William F.; Amos-Landgraf, James M.

    2014-01-01

    Prior to the advent of genetic engineering in the mouse, the rat was the model of choice for investigating the etiology of cancer. Now, recent advances in the manipulation of the rat genome, combined with a growing recognition of the physiological differences between mice and rats, have reignited interest in the rat as a model of human cancer. Two recently developed rat models, the polyposis in the rat colon (Pirc) and Kyoto Apc Delta (KAD) strains, each carry mutations in the intestinal-cancer-associated adenomatous polyposis coli (Apc) gene. In contrast to mouse models carrying Apc mutations, in which cancers develop mainly in the small intestine rather than in the colon and there is no gender bias, these rat models exhibit colonic predisposition and gender-specific susceptibility, as seen in human colon cancer. The rat also provides other experimental resources as a model organism that are not provided by the mouse: the structure of its chromosomes facilitates the analysis of genomic events, the size of its colon permits longitudinal analysis of tumor growth, and the size of biological samples from the animal facilitates multiplexed molecular analyses of the tumor and its host. Thus, the underlying biology and experimental resources of these rat models provide important avenues for investigation. We anticipate that advances in disease modeling in the rat will synergize with resources that are being developed in the mouse to provide a deeper understanding of human colon cancer. PMID:25288683

  17. Generation of a New Model Rat: Nrf2 Knockout Rats Are Sensitive to Aflatoxin B1 Toxicity.

    PubMed

    Taguchi, Keiko; Takaku, Misaki; Egner, Patricia A; Morita, Masanobu; Kaneko, Takehito; Mashimo, Tomoji; Kensler, Thomas W; Yamamoto, Masayuki

    2016-07-01

    THE TRANSCRIPTION FACTOR NRF2: (NF-E2-related-factor 2) REGULATES A BATTERY OF ANTIOXIDATIVE STRESS-RESPONSE GENES AND DETOXICATION GENES, AND NRF2 KNOCKOUT LINES OF MICE HAVE BEEN CONTRIBUTING CRITICALLY TO THE CLARIFICATION OF ROLES THAT NRF2 PLAYS FOR CELL PROTECTION HOWEVER, THERE ARE APPARENT LIMITATIONS IN USE OF THE MOUSE MODELS FOR INSTANCE, RATS EXHIBIT MORE SUITABLE FEATURES FOR TOXICOLOGICAL OR PHYSIOLOGICAL EXAMINATIONS THAN MICE IN THIS STUDY, WE GENERATED 2 LINES OF NRF2 KNOCKOUT RATS BY USING A GENOME EDITING TECHNOLOGY; 1 LINE HARBORS A 7-BP DELETION Δ7 AND THE OTHER LINE HARBORS A 1-BP INSERTION +1 IN THE NRF2 GENE IN THE LIVERS OF RATS HOMOZYGOUSLY DELETING THE NRF2 GENE, AN ACTIVATOR OF NRF2 SIGNALING, CDDO-IM, COULD NOT INDUCE EXPRESSION OF REPRESENTATIVE NRF2 TARGET GENES TO EXAMINE ALTERED TOXICOLOGICAL RESPONSE, WE TREATED THE NRF2 KNOCKOUT RATS WITH AFLATOXIN B1 AFB1, A CARCINOGENIC MYCOTOXIN THAT ELICITS GENE MUTATIONS THROUGH BINDING OF ITS METABOLITES TO DNA AND FOR WHICH THE RAT HAS BEEN PROPOSED AS A REASONABLE SURROGATE FOR HUMAN TOXICITY INDEED, IN THE NRF2 KNOCKOUT RAT LIVERS THE ENZYMES OF THE AFB1 DETOXICATION PATHWAY WERE SIGNIFICANTLY DOWNREGULATED SINGLE DOSE ADMINISTRATION OF AFB1 INCREASED HEPATOTOXICITY AND BINDING OF AFB1-N7-GUANINE TO HEPATIC DNA IN NRF2 KNOCKOUT RATS COMPARED WITH WILD-TYPE NRF2 KNOCKOUT RATS REPEATEDLY TREATED WITH AFB1 WERE PRONE TO LETHALITY AND CDDO-IM WAS NO LONGER PROTECTIVE THESE RESULTS DEMONSTRATE THAT NRF2 KNOCKOUT RATS ARE QUITE SENSITIVE TO AFB1 TOXICITIES AND THIS RAT GENOTYPE EMERGES AS A NEW MODEL ANIMAL IN TOXICOLOGY. PMID:27071940

  18. Orchiectomized Fischer 344 male rat models body composition in hypogonadal state.

    PubMed

    Borst, Stephen E; Conover, Christine F

    2006-06-20

    The hypogonadal state in men is accompanied by substantial decreases in muscle and bone mass and by an increase in adiposity. Most of the strains of orchiectomized (ORX) rat that have been used to model this state display substantial losses in bone, but only subtle changes in adiposity and muscle mass. In order to identify a rat model displaying a robust catabolic response to ORX, we studied three strains: Fischer 344 (F344), Brown Norway and Wistar. ORX caused a significant and sustained decrease in weight gained by F344, but only a trend toward reduced weight gain in Brown Norway rats and a modest reduction weight gain in Wistar rats that was significant only after 56days. ORX suppressed food intake in F344 rats, and to a lesser degree in Brown Norway and Wistar rats. ORX reduced muscle mass significantly in F344 rats, but not in Brown Norway or Wistar rats. ORX increased adiposity moderately in F344 rats and substantially in Wistar rats. ORX caused a marked reduction in prostate mass and increase in bone resorption in all three strains. Thus, F344 was the only strain in which ORX produced substantial decreases in food intake, body weight and muscle mass with increased adiposity and increased bone resorption. We conclude that the F344 rat displays a broad range of catabolic effects following ORX and is the best rat model for studying the androgenic pathway and strategies for reversing catabolic changes induced by hypogonadism. PMID:16507309

  19. Studies on sensitivity of zebrafish as a model organism for Parkinson's disease: Comparison with rat model

    PubMed Central

    Makhija, Dinesh T.; Jagtap, Aarti G.

    2014-01-01

    Objective: To determine the utility of zebra fish as an animal model for Parkinson's disease (PD) in comparison with rat model. Materials and Methods: MTT assay was performed on rat and zebrafish brain synaptosomal fractions using rotenone as a neurotoxic agent. Quercetin and resveratrol were used as standards to compare anti-apoptotic activity in both organisms. Catalepsy was induced in zebrafish by exposing them to haloperidol (9 μM) solution. Drug-treated groups were exposed to bromocriptine and pramipexole, 30 min prior to haloperidol exposure at the dose of 2, 5, and 10 μg/mL. Swimming speed, time spent in the bottom of the tank, and complete cataleptic time were evaluated to assess behavioral changes. In rats, catalepsy was induced using haloperidol (1.25 mg/kg i.p.). Drug-treated groups received bromocriptine (2.5 mg/kg.) and pramipexole (1 mg/kg) orally. Bar test, block test, and locomotor activity were carried out to assess behavioral changes. Results: Resveratrol and quercetin showed comparable inhibition of apoptosis in rats and zebrafish. In anti-cataleptic study, bromocriptine and pramipexole-treated groups showed significant difference (P < 0.05) in behavioral parameters as compared to haloperidol control group in both the experimental organisms. Results obtained from fish model were in correlation with rat model. Conclusion: Findings of the present study revealed that zebrafish model is highly sensitive and can be used for basic screening of drugs against PD. PMID:24554909

  20. 7,8-dihydroxyflavone protects 6-OHDA and MPTP induced dopaminergic neurons degeneration through activation of TrkB in rodents.

    PubMed

    Luo, Dandan; Shi, Ying; Wang, Jun; Lin, Qing; Sun, Yi; Ye, Keqiang; Yan, Qiao; Zhang, Hai

    2016-05-01

    Brain-derived neurotrophic factor (BDNF) is a notably important neurotrophin which regulates neuronal survival and differentiation in the nervous system. However, its clinical usage is particularly limited. 7,8-dihydroxyflavone (7,8-DHF), which acts as a selective agonist of BDNF receptor TrkB, is reported to possess neuroprotective effects both in vitro and in vivo. Here we explored the potent neuroprotective effects of 7,8-DHF in 6-OHDA induced rat and MPTP induced mouse model of Parkinsonism. The results demonstrated that treatment with 7,8-DHF in drinking water for four weeks (two weeks before 6-OHDA+two weeks after 6-OHDA lesion) significantly improved dopamine-mediated behaviors in 6-OHDA rat model, and prevented the loss of dopaminergic neurons in the substantia nigra (SN). Phospho-Y816-TrkB immunostaining showed that TrkB phosphorylation was significantly elevated in the SN in 7,8-DHF pretreated group, indicating 7,8-DHF activated TrkB and likely contributed to its neuroprotective effects. 7,8-DHF also protected acute MPTP neurotoxicity in mice but did not affect the climbing behavior in pole test. Thus our study indicates the neuroprotective properties of 7,8-DHF through the activation of TrkB, which provides a novel therapeutic treatment for Parkinson's disease. PMID:27019033

  1. Triptolide ameliorates colonic fibrosis in an experimental rat model

    PubMed Central

    TAO, QINGSONG; WANG, BAOCHAI; ZHENG, YU; LI, GUANWEI; REN, JIANAN

    2015-01-01

    Triptolide is known to exert anti-inflammatory and immunomodulatory activities; however, its impact on intestinal fibrosis has not been previously examined. Based on our previous studies of the suppressive activity of triptolide on human colonic subepithelial myofibroblasts and the therapeutic efficacy of triptolide in Crohn’s disease, it was hypothesized that triptolide may have beneficial effects on intestinal fibrosis. In the present study, colonic fibrosis was induced in rats by 6 weekly repeated administration with a low-dose of 2,4,6-trinitrobenzene sulfonic acid (TNBS) and was then treated with triptolide or PBS daily (control) simultaneously. Extracellular matrix (ECM) deposition in the colon was examined with image analysis of Masson Trichrome staining. Total collagen levels in colonic homogenates were measured by a Sircol assay. Collagen Iα1 transcripts and collagen I protein were measured ex vivo in the isolated colonic subepithelial myofibroblasts by reverse transcription-quantitative polymerase chain reaction and immunoblot analysis, respectively. The results indicated that triptolide decreased ECM deposition and collagen production in the colon, and inhibited collagen Iα1 transcripts and collagen I protein expression in the isolated subepithelial myofibroblasts of the rats with colonic fibrosis. In conclusion, triptolide ameliorates colonic fibrosis in the experimental rat model, suggesting triptolide may be a promising compound for inflammatory bowel disease treatment. PMID:25845760

  2. Mindspan: Lessons from Rat Models of Neurocognitive Aging

    PubMed Central

    Gallagher, Michela; Stocker, Amy; Koh, Ming Teng

    2011-01-01

    Research on the biology of aging seeks to enhance understanding of basic mechanisms and thus support improvements in outcomes throughout the lifespan, including longevity itself, susceptibility to disease, and life-long adaptive capacities. The focus of this review is the use of rats as an animal model of cognitive change during aging, and specifically lessons learned from aging rats in behavioral studies of cognitive processes mediated by specialized neural circuitry. An advantage of this approach is the ability to compare brain aging across species where functional homology exists for specific neural systems; in this article we focus on behavioral assessments that target the functions of the medial temporal lobe and prefrontal cortex. We also take a critical look at studies using calorie restriction (CR) as a well-defined experimental approach to manipulating biological aging. We conclude that the effects of CR on cognitive aging in rats are less well established than commonly assumed, with much less supportive evidence relative to its benefits on longevity and susceptibility to disease, and that more research in this area is necessary. PMID:21411856

  3. Studies of different female rat models of hypothalamic obesity.

    PubMed

    Elfers, Clinton; Ralston, Melissa; Roth, Christian L

    2011-01-01

    Hypothalamic obesity (HO) is a major and unsolved problem in patients with medial hypothalamic lesions and is associated with hyperinsulinemia and hyperleptinemia. The purpose of this study was to create a rodent model that mimics metabolic changes in HO for use in therapeutic testing. Female Sprague-Dawley rats were used to test the individual and combined effects of two types of medial hypothalamic lesions: arcuate nucleus (ARC) lesions by injection of monosodium glutamate at neonatal age, and ventromedial nucleus (VMN) lesions by passing an anodal current through an electrode placed in the VMN at age 80 days. Adiposity in ARC-lesioned animals was associated with decreased food intake and stunted growth, while VMN lesions were associated with hyperphagia but not reduced growth. The greatest weight gain (weight at age 200 days 712 +/- 65 vs. 451 +/- 19 g in controls), hyperphagia (food intake 10 days following surgery 33 +/- 0.8 vs. 18.5 +/- 0.7 g/day in sham-treated rats), hyperinsulinemia and hyperleptinemia occurred in rats that received both ARC and VMN lesions. Thus, the combined medial hypothalamic lesions result in an obesity phenotype similar to that of patients that suffer from HO and are consequently more suitable for testing potential therapeutics for this disorder than lesions of single hypothalamic nuclei. PMID:21648279

  4. Antifibrotic effect of heparin on liver fibrosis model in rats

    PubMed Central

    Shah, Binita; Shah, Gaurang

    2012-01-01

    AIM: To evaluate the effect of chronic thrombin inhibition by heparin on experimentally induced chronic liver injury (liver fibrosis) in rats. METHODS: Chronic liver injury (liver fibrosis) was induced in Wistar rats by oral administration of carbon tetrachloride (CCl4) for 7 wk, an animal model with persistent severe hepatic fibrosis. Intravenous administration of the thrombin antagonist (heparin) started 1 wk after the start of CCl4 intoxication for 6 wk. After completion of treatment (7 wk), markers of hepatic dysfunction were measured and changes evaluated histopathologically. RESULTS: Higher serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), alkaline phosphatase (ALP), total, direct and indirect bilirubin levels, as well as lower fibrinogen levels, were found in CCl4 intoxicated rats. Heparin, silymarin and combination of drug (heparin and silymarin) treatment for 6 wk prevented a rise in SGOT, SGPT, ALP, total, direct and indirect bilirubin levels and improved fibrinogen levels. Deterioration in hepatic function determined by the fibrosis area was retarded, as evident from hepatic histopathology. Total protein levels were not changed in all groups. CONCLUSION: Heparin, a thrombin antagonist, preserved hepatic function and reduced severity of hepatic dysfunction/fibrogenesis. Combination of heparin and silymarin produced additional benefits on liver fibrosis. PMID:23494756

  5. Cocaine sensitization models an anhedonia-like condition in rats.

    PubMed

    Scheggi, Simona; Marchese, Giovanna; Grappi, Silvia; Secci, Maria Elena; De Montis, Maria Graziella; Gambarana, Carla

    2011-04-01

    Anhedonia is a core symptom of depression that also characterizes substance abuse-related mood disorders, in particular those secondary to stimulant abuse. This study investigated the long-lasting condition of cocaine sensitization as an inducing condition for anhedonia in rats. Cortical-mesolimbic dopamine plays a central role in assessing the incentive value of a stimulus and an increased dopamine output in these areas after a novel palatable meal seems to correlate with the ability to acquire an instrumental behaviour aimed at earning it again. This dopaminergic response is associated with consistent modifications in the phosphorylation pattern of some cAMP-dependent protein kinase (PKA) substrates and it is mediated by dopamine D1 receptor stimulation. Thus, since behavioural cocaine sensitization is characterized by tonically increased levels of phospho-Thr75 DARPP-32 that is a potent PKA inhibitor, we hypothesized that cocaine-sensitized rats might reveal deficits in palatable food responding. Indeed, non-food-deprived cocaine-sensitized rats showed no interest in palatable food, no dopaminergic response after a palatable meal in terms of increased dopamine output and DARPP-32 phosphorylation changes, and no ability to acquire a palatable food-sustained instrumental behaviour. Repeated administration of an established antidepressant compound, imipramine, corrected these deficits and reinstated the dopaminergic response in the cortico-mesolimbic areas to control values. Thus, the behavioural modifications observed in cocaine-sensitized rats satisfy some requirements for an experimental model of anhedonia since they are induced by repeated cocaine administration (aetiological validity), they mimic an anhedonia-like symptom (construct validity), and are reversed by the administration of imipramine (predictive validity). PMID:20519061

  6. Photon and electron absorbed fractions calculated from a new tomographic rat model

    NASA Astrophysics Data System (ADS)

    Peixoto, P. H. R.; Vieira, J. W.; Yoriyaz, H.; Lima, F. R. A.

    2008-10-01

    This paper describes the development of a tomographic model of a rat developed using CT images of an adult male Wistar rat for radiation transport studies. It also presents calculations of absorbed fractions (AFs) under internal photon and electron sources using this rat model and the Monte Carlo code MCNP. All data related to the developed phantom were made available for the scientific community as well as the MCNP inputs prepared for AF calculations in that phantom and also all estimated AF values, which could be used to obtain absorbed dose estimates—following the MIRD methodology—in rats similar in size to the presently developed model. Comparison between the rat model developed in this study and that published by Stabin et al (2006 J. Nucl. Med. 47 655) for a 248 g Sprague-Dawley rat, as well as between the estimated AF values for both models, has been presented.

  7. Photon and electron absorbed fractions calculated from a new tomographic rat model.

    PubMed

    Peixoto, P H R; Vieira, J W; Yoriyaz, H; Lima, F R A

    2008-10-01

    This paper describes the development of a tomographic model of a rat developed using CT images of an adult male Wistar rat for radiation transport studies. It also presents calculations of absorbed fractions (AFs) under internal photon and electron sources using this rat model and the Monte Carlo code MCNP. All data related to the developed phantom were made available for the scientific community as well as the MCNP inputs prepared for AF calculations in that phantom and also all estimated AF values, which could be used to obtain absorbed dose estimates--following the MIRD methodology--in rats similar in size to the presently developed model. Comparison between the rat model developed in this study and that published by Stabin et al (2006 J. Nucl. Med. 47 655) for a 248 g Sprague-Dawley rat, as well as between the estimated AF values for both models, has been presented. PMID:18758003

  8. Modeling postpartum depression in rats: theoretic and methodological issues

    PubMed Central

    Ming, LI; Shinn-Yi, CHOU

    2016-01-01

    The postpartum period is when a host of changes occur at molecular, cellular, physiological and behavioral levels to prepare female humans for the challenge of maternity. Alteration or prevention of these normal adaptions is thought to contribute to disruptions of emotion regulation, motivation and cognitive abilities that underlie postpartum mental disorders, such as postpartum depression. Despite the high incidence of this disorder, and the detrimental consequences for both mother and child, its etiology and related neurobiological mechanisms remain poorly understood, partially due to the lack of appropriate animal models. In recent decades, there have been a number of attempts to model postpartum depression disorder in rats. In the present review, we first describe clinical symptoms of postpartum depression and discuss known risk factors, including both genetic and environmental factors. Thereafter, we discuss various rat models that have been developed to capture various aspects of this disorder and knowledge gained from such attempts. In doing so, we focus on the theories behind each attempt and the methods used to achieve their goals. Finally, we point out several understudied areas in this field and make suggestions for future directions. PMID:27469254

  9. Modeling postpartum depression in rats: theoretic and methodological issues.

    PubMed

    Li, Ming; Chou, Shinn-Yi

    2016-07-18

    The postpartum period is when a host of changes occur at molecular, cellular, physiological and behavioral levels to prepare female humans for the challenge of maternity. Alteration or prevention of these normal adaptions is thought to contribute to disruptions of emotion regulation, motivation and cognitive abilities that underlie postpartum mental disorders, such as postpartum depression. Despite the high incidence of this disorder, and the detrimental consequences for both mother and child, its etiology and related neurobiological mechanisms remain poorly understood, partially due to the lack of appropriate animal models. In recent decades, there have been a number of attempts to model postpartum depression disorder in rats. In the present review, we first describe clinical symptoms of postpartum depression and discuss known risk factors, including both genetic and environmental factors. Thereafter, we discuss various rat models that have been developed to capture various aspects of this disorder and knowledge gained from such attempts. In doing so, we focus on the theories behind each attempt and the methods used to achieve their goals. Finally, we point out several understudied areas in this field and make suggestions for future directions. PMID:27469254

  10. Metabolic Cages for a Space Flight Model in the Rat

    NASA Technical Reports Server (NTRS)

    Harper, Jennifer S.; Mulenburg, Gerald M.; Evans, Juli; Navidi, Meena; Wolinsky, Ira; Arnaud, Sara B.

    1994-01-01

    A variety of space flight models are available to mimic the physiologic changes seen in the rat during weightlessness. The model reported by Wronski and Morey-Holton has been widely used by many investigators, in musculoskeletal physiologic studies especially, resulting in accumulation of an extensive database that enables scientists to mimic space flight effects in the 1-g environment of Earth. However, information on nutrition or gastrointestinal and renal function in this space flight model is limited by the difficulty in acquiring uncontaminated metabolic specimens for analysis. In the Holton system, a traction tape harness is applied to the tail, and the rat's hindquarters are elevated by attaching the harness to a pulley system. Weight-bearing hind limbs are unloaded, and there is a headward fluid shift. The tail-suspended rats are able to move freely about their cages on their forelimbs and tolerate this procedure with minimal signs of stress. The cage used in Holton's model is basically a clear acrylic box set on a plastic grid floor with the pulley and tail harness system attached to the open top of the cage. Food is available from a square food cup recessed into a corner of the floor. In this system, urine, feces, and spilled food fall through the grid floor onto absorbent paper beneath the cage and cannot be separated and recovered quantitatively for analysis in metabolic balance studies. Commercially available metabolic cages are generally cylindrical and have been used with a centrally located suspension apparatus in other space flight models. The large living area, three times as large as most metabolic cages, and the free range of motion unique to Holton's model, essential for musculoskeletal investigations, were sacrificed. Holton's cages can accommodate animals ranging in weight from 70 to 600 g. Although an alternative construction of Holton's cage has been reported, it does not permit collection of separate urine and fecal samples. We describe

  11. Febuxostat improves outcome in a rat model of cancer cachexia

    PubMed Central

    Konishi, Masaaki; Pelgrim, Loes; Tschirner, Anika; Baumgarten, Anna; von Haehling, Stephan; Palus, Sandra; Doehner, Wolfram; Anker, Stefan D; Springer, Jochen

    2015-01-01

    Background Activity of xanthine oxidase is induced in cancer cachexia, and its inhibition by allopurinol or oxypurinol improves survival and reduces wasting in the Yoshida hepatoma cancer cachexia model. Here, we tested the effects of the second-generation xanthine oxidase inhibitor febuxostat compared with placebo in the same model as used previously by our group. Methods Wistar rats (∽200 g) were treated daily with febuxostat at 5 mg/kg/day or placebo via gavage for a maximum of 17 days. Weight change, quality of life, and body composition were analysed. After sacrifice, proteasome activity in the gastrocnemius muscle was measured. Muscle-specific proteins involved in metabolism were analysed by western blotting. Results Treatment of the tumour-bearing rats with febuxostat led to a significantly improved survival compared with placebo (hazard ratio: 0.45, 95% confidence interval: 0.22–0.93, P = 0.03). Loss of body weight was reduced (−26.3 ± 12.4 g) compared with placebo (−50.2 ± 2.1 g, P < 0.01). Wasting of lean mass was attenuated (−12.7 ± 10.8 g) vs. placebo (−31.9 ± 2.1 g, P < 0.05). While we did not see an effect of febuxostat on proteasome activity at the end of the study, the pAkt/Akt ratio was improved by febuxostat (0.94 ± 0.09) vs. placebo (0.41 ± 0.05, P < 0.01), suggesting an increase in protein synthesis. Conclusions Febuxostat attenuated cachexia progression and improved survival of tumour-bearing rats. PMID:26136193

  12. Rehabilitative exercise in a rat model of doxorubicin cardiotoxicity.

    PubMed

    Hydock, David S; Lien, Chia-Ying; Jensen, Brock T; Parry, Traci L; Schneider, Carole M; Hayward, Reid

    2012-12-01

    The use of exercise to minimize doxorubicin (DOX)-induced cardiotoxicity is gaining attention. However, very few clinically relevant reports exist investigating the effects of exercise performed during and following DOX treatments. The purpose of this study, therefore, was to examine the effects of voluntary wheel running during and following DOX treatment using two models of late-onset DOX cardiotoxicity in the rat. Female Sprague-Dawley rats received either DOX or saline injections using one of two separate treatment regimens. These regimens involved either daily or weekly DOX injections with cumulative doses for both protocols totaling 15 mg/kg. Daily DOX injections were 1 mg/kg and lasted for 15 consecutive days while weekly DOX injections were 2.5 mg/kg and lasted for six consecutive weeks with control animals receiving matched saline injection regimens. Immediately following the initial DOX/saline injection, animals were randomly housed in cages with voluntary running wheels or standard rat cages throughout DOX/saline treatments and continued until reaching 10 weeks. Cardiac function was then assessed using echocardiography and an isolated working heart model, and myosin heavy chain (MHC) isoform distribution was assessed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis. When compared wth controls, daily DOX treatment resulted in reduced running wheel distances at weeks 2-10 (P < 0.05), and weekly DOX treatment resulted in reduced running wheel distances at weeks 2, 6 and 10 (P < 0.05). Nonetheless, wheel running during and following daily and weekly DOX dosing protected against DOX-induced cardiotoxicity by preserving maximal mitral and aortic blood flow velocities, left ventricular developed pressure and MHC isoform expression. In conclusion, the overall reduced volume of activity during and following daily and weekly DOX treatments attenuated DOX-induced cardiac dysfunction suggesting that low-volume endurance training may be an effective

  13. Hypertension and vulnerability to hemorrhagic shock in a rat model.

    PubMed

    Reynolds, Penny S; Song, Kyle Seokhan; Tamariz, Francisco J; Wayne Barbee, R

    2015-02-01

    Trauma mortality may be increased in the presence of preexisting diseases such as chronic hypertension. We hypothesized that systemic and microvascular alterations accompanying chronic hypertension would increase the vulnerability to hemorrhage relative to normotensive controls in a rat model of hemorrhagic shock. We present a novel comparative hemorrhage model of shock vulnerability, quantified by "vulnerability curves" expressing physiological response to hemorrhage as a function of three matched shock metrics: cumulative blood volume, mean arterial pressure (MAP), and oxygen delivery (Do2). Responses were central hemodynamics and respiratory and muscle oxygenation obtained for one hypertensive (spontaneously hypertensive [SHR]) and two normotensive (Sprague-Dawley, Wistar-Kyoto) rat strains. Hemorrhagic shock was induced by incremental (0.5 mL) hemorrhage to cardiovascular collapse in anesthetized and mechanically ventilated animals. Shock vulnerability of SHR rats was primarily pressure-driven; in general, SHR exhibited the expected patterns of more rapid deterioration in MAP and Vo2 over smaller ranges of blood loss and Do2. Sternotomy-related depression of CO and thus Do2 in SHR meant that we could not test hypotheses related to the role of Do2 and contribution to perfusion differences between normotensive and hypertensive subjects. Insensitivity of lactate to strain effects suggests that lactate may be a reliable biomarker of shock status. Unexpected similarities between Wistar-Kyoto and SHR suggest strain-related effects other than those related to hypertension per se contribute to hemorrhage response; body size effects and genetic relationships could not be ruled out. Future studies should incorporate phylogenetically based methods to examine the role of hypertension and physiological response to hemorrhage across multiple strains. PMID:25300030

  14. 2015 Guidelines for Establishing Genetically Modified Rat Models for Cardiovascular Research

    PubMed Central

    Flister, Michael J.; Prokop, Jeremy W.; Lazar, Jozef; Shimoyama, Mary; Dwinell, Melinda; Geurts, Aron

    2015-01-01

    The rat has long been a key physiological model for cardiovascular research; most of the inbred strains having been previously selected for susceptibility or resistance to various cardiovascular diseases (CVD). These CVD rat models offer a physiologically relevant background on which candidates of human CVD can be tested in a more clinically translatable experimental setting. However, a diverse toolbox for genetically modifying the rat genome to test molecular mechanisms has only recently become available. Here, we provide a high-level description of several strategies for developing genetically modified rat models of CVD. PMID:25920443

  15. Grape powder prevents cognitive, behavioral and biochemical impairments in a rat model of posttraumatic stress disorder

    PubMed Central

    Solanki, Naimesh; Alkadhi, Isam; Atrooz, Fatin; Patki, Gaurav; Salim, Samina

    2015-01-01

    Previously, using the single-prolonged stress (SPS) rat model of post-traumatic stress disorder, we reported that moderate treadmill exercise, via modulation of oxidative stress related mechanisms, rescued anxiety and depression-like behaviors and reversed SPS-induced memory impairment. In this study using the SPS model (2 h restrain, 20 min forced swimming, 15 min rest, and 1–2 min diethyl ether exposure), we hypothesized that antioxidant rich grape powder (GP) prevents SPS-induced behavioral and memory impairment in rats. Male Sprague Dawley rats were randomly assigned into: Control (CON; provided tap water), SPS (provided tap water), GP-SPS (provided 15 g/L GP in tap water for 3 wk followed by SPS), or GP-CON (3 wk of GP followed by control exposure). Anxiety and depression-like behaviors were significantly greater in SPS rats when compared to CON or GP treated rats and GP reversed these behavioral deficits. SPS rats made significantly more errors in both short- and long-term memory tests compared to CON or GP treated rats, which were prevented in GP-SPS rats. GP prevented SPS-induced increase in plasma corticosterone level. Furthermore, brain derived neurotrophic factor (BDNF) levels were significantly decreased in amygdala of SPS rats but not in GP-SPS rats compared to CON or GP-CON rats. Additionally, GP significantly increased acetylated Histone3, Histone deacetylase 5 (HDAC 5) in hippocampus and amygdala of SPS rats as compared to CON or GP-CON rats. In conclusion, we suggest protective role of GP in SPS-induced behavioral, cognitive and biochemical impairments in rats. Perhaps, epigenetic regulation of BDNF enables GP-mediated prevention of SPS-induced deficits in rats. PMID:25533441

  16. Grape powder prevents cognitive, behavioral, and biochemical impairments in a rat model of posttraumatic stress disorder.

    PubMed

    Solanki, Naimesh; Alkadhi, Isam; Atrooz, Fatin; Patki, Gaurav; Salim, Samina

    2015-01-01

    Previously, using the single-prolonged stress (SPS) rat model of posttraumatic stress disorder, we reported that moderate treadmill exercise, via modulation of oxidative stress-related mechanisms, rescued anxiety- and depression-like behaviors and reversed SPS-induced memory impairment. In this study using the SPS model (2-hour restrain, 20-minute forced swimming, 15-minute rest, and 1-2-minute diethyl ether exposure), we hypothesized that antioxidant rich grape powder (GP) prevents SPS-induced behavioral and memory impairment in rats. Male Sprague Dawley rats were randomly assigned into control (CON) (provided tap water), SPS (provided tap water), GP-SPS (provided 15 g/L GP in tap water for 3 weeks followed by SPS), or GP-CON (3 weeks of GP followed by CON exposure). Anxiety- and depression-like behaviors were significantly greater in SPS rats, when compared with CON- or GP-treated rats, and GP reversed these behavioral deficits. Single-prolonged stress rats made significantly more errors in both short- and long-term memory tests compared with CON- or GP-treated rats, which were prevented in GP-SPS rats. Grape powder prevented SPS-induced increase in plasma corticosterone level. Furthermore, brain-derived neurotrophic factor levels were significantly decreased in amygdala of SPS rats but not in GP-SPS rats compared with CON or (GP-CON) rats. In addition, GP significantly increased acetylated histone 3 and histone deacetylase 5 in hippocampus and amygdala of SPS rats as compared with CON or GP-CON rats. In conclusion, we suggest protective role of GP in SPS-induced behavioral, cognitive, and biochemical impairments in rats. Perhaps, epigenetic regulation of brain-derived neurotrophic factor enables GP-mediated prevention of SPS-induced deficits in rats. PMID:25533441

  17. A rat model of concurrent combined injuries (polytrauma)

    PubMed Central

    Akscyn, Robert M; Franklin, J Lee; Gavrikova, Tatyana A; Schwacha, Martin G; Messina, Joseph L

    2015-01-01

    Polytrauma, a combination of injuries to more than one body part or organ system, is common in modern warfare and in automobile and industrial accidents. The combination of injuries can include burn injury, fracture, hemorrhage, trauma to the extremities, and trauma to specific organ systems. To investigate the effects of combined injuries, we have developed a new and highly reproducible model of polytrauma. This model combines burn injury with soft tissue and gastrointestinal (GI) tract trauma. Male Sprague Dawley rats were subjected to a 15-20% total body surface area scald burn, or a single puncture of the cecum with a G30 needle, or the combination of both injuries (polytrauma). Unlike many ‘double hit’ models, the injuries in our model were performed simultaneously. We asked whether multiple minor injuries, when combined, would result in a distinct phenotype, different from single minor injuries or a more severe single injury. There were differences between the single injuries and polytrauma in the maintenance of blood glucose, body temperature, body weight, hepatic mRNA and circulating levels of TNF-α, IL-1β and IL-6, and hepatic ER-stress. It has been suggested that models utilizing combinatorial injuries may be needed to more accurately model the human condition. We believe our model is ideal for studying the complex sequelae of polytrauma, which differs from single injuries. Insights gained from this model may suggest better treatment options to improve patient outcomes. PMID:26884923

  18. A Model of Insulin Resistance and Nonalcoholic Steatohepatitis in Rats

    PubMed Central

    Svegliati-Baroni, Gianluca; Candelaresi, Cinzia; Saccomanno, Stefania; Ferretti, Gianna; Bachetti, Tiziana; Marzioni, Marco; De Minicis, Samuele; Nobili, Liliana; Salzano, Renata; Omenetti, Alessia; Pacetti, Deborah; Sigmund, Soeren; Benedetti, Antonio; Casini, Alessandro

    2006-01-01

    Insulin resistance induces nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH). We used a high-fat, high-calorie solid diet (HFD) to create a model of insulin resistance and NASH in nongenetically modified rats and to study the relationship between visceral adipose tissue and liver. Obesity and insulin resistance occurred in HFD rats, accompanied by a progressive increase in visceral adipose tissue tumor necrosis factor (TNF)-α mRNA and in circulating free fatty acids. HFD also decreased adiponectin mRNA and peroxisome proliferator-activated receptor (PPAR)-α expression in the visceral adipose tissue and the liver, respectively, and induced hepatic insulin resistance through TNF-α-mediated c-Jun N-terminal kinase (JNK)-dependent insulin receptor substrate-1Ser307 phosphorylation. These modifications lead to hepatic steatosis accompanied by oxidative stress phenomena, necroinflammation, and hepatocyte apoptosis at 4 weeks and by pericentral fibrosis at 6 months. Supplementation of n-3 polyunsaturated fatty acid, a PPARα ligand, to HFD-treated animals restored hepatic adiponectin and PPARα expression, reduced TNF-α hepatic levels, and ameliorated fatty liver and the degree of liver injury. Thus, our model mimics the most common features of NASH in humans and provides an ideal tool to study the role of individual pathogenetic events (as for PPARα down-regulation) and to define any future experimental therapy, such as n-3 polyunsaturated fatty acid, which ameliorated the degree of liver injury. PMID:16936261

  19. Respiratory Tract Lung Geometry and Dosimetry Model for Male Sprague-Dawley Rats

    SciTech Connect

    Miller, Frederick J.; Asgharian, Bahman; Schroeter, Jeffry D.; Price, Owen; Corley, Richard A.; Einstein, Daniel R.; Jacob, Rick E.; Cox, Timothy C.; Kabilan, Senthil; Bentley, Timothy

    2015-07-24

    While inhalation toxicological studies of various compounds have been conducted using a number of different strains of rats, mechanistic dosimetry models have only had tracheobronchial (TB) structural data for Long-Evans rats, detailed morphometric data on the alveolar region of Sprague-Dawley rats and limited alveolar data on other strains. Based upon CT imaging data for two male Sprague-Dawley rats, a 15-generation, symmetric typical path model was developed for the TB region. Literature data for the alveolar region of Sprague-Dawley rats were analyzed to develop an eight-generation model, and the two regions were joined to provide a complete lower respiratory tract model for Sprague-Dawley rats. The resulting lung model was used to examine particle deposition in Sprague-Dawley rats and to compare these results with predicted deposition in Long-Evans rats. Relationships of various physiologic variables and lung volumes were either developed in this study or extracted from the literature to provide the necessary input data for examining particle deposition. While the lengths, diameters and branching angles of the TB airways differed between the two Sprague-Dawley rats, the predicted deposition patterns in the three major respiratory tract regions were very similar. Between Sprague-Dawley and Long-Evans rats, significant differences in TB and alveolar predicted deposition fractions were observed over a wide range of particle sizes, with TB deposition fractions being up to 3- to 4-fold greater in Sprague-Dawley rats and alveolar deposition being significantly greater in Long-Evans rats. Thus, strain-specific lung geometry models should be used for particle deposition calculations and interspecies dose comparisons.

  20. Respiratory tract lung geometry and dosimetry model for male Sprague-Dawley rats.

    SciTech Connect

    Miller, Frederick J.; Asgharian, Bahman; Schroeter, Jeffry D.; Price, Owen; Corley, Richard A.; Einstein, Daniel R.; Jacob, Rick E.; Cox, Timothy C.; Kabilan, Senthil; Bentley, Timothy

    2014-08-26

    While inhalation toxicological studies of various compounds have been conducted using a number of different strains of rats, mechanistic dosimetry models have only had tracheobronchial (TB) structural data for Long-Evans rats, detailed morphometric data on the alveolar region of Sprague-Dawley rats and limited alveolar data on other strains. Based upon CT imaging data for two male Sprague-Dawley rats, a 15-generation, symmetric typical path model was developed for the TB region. Literature data for the alveolar region of Sprague-Dawley rats were analyzed to develop an eight-generation model, and the two regions were joined to provide a complete lower respiratory tract model for Sprague-Dawley rats. The resulting lung model was used to examine particle deposition in Sprague-Dawley rats and to compare these results with predicted deposition in Long-Evans rats. Relationships of various physiologic variables and lung volumes were either developed in this study or extracted from the literature to provide the necessary input data for examining particle deposition. While the lengths, diameters and branching angles of the TB airways differed between the two Sprague- Dawley rats, the predicted deposition patterns in the three major respiratory tract regions were very similar. Between Sprague-Dawley and Long-Evans rats, significant differences in TB and alveolar predicted deposition fractions were observed over a wide range of particle sizes, with TB deposition fractions being up to 3- to 4-fold greater in Sprague-Dawley rats and alveolar deposition being significantly greater in Long-Evans rats. Thus, strain-specific lung geometry models should be used for particle deposition calculations and interspecies dose comparisons.

  1. A BBDR-HPT Axis Model for the Pregnant Rat and Fetus: Evaluation of Iodide Deficiency

    EPA Science Inventory

    A biologically based dose response (BBDR) model for the hypothalamic-pituitarythyroid (HPT) axis for the pregnant rat and fetus is being developed to advance understanding of thyroid hormone disruptions and developmental neurotoxicity (DNT). The model for the pregnant rat and fet...

  2. Laser thresholds in pulp exposure: a rat animal model

    NASA Astrophysics Data System (ADS)

    White, Joel M.; Goodis, Harold E.; Kudler, Joel J.

    1995-05-01

    Laser technology is now being clinically investigated for the removal of carious enamel and dentin. This study used an animal model to evaluate histological pulpal effects from laser exposure. The molars of 24 Sprague-Dawley rats (n equals 264) were exposed to either a pulsed 1.06 micrometers Nd:YAG laser (120 microseconds, 320 micrometer diameter fiber), air rotor drill preparation or left untreated as controls. The following treatment conditions were investigated: control group (n equals 54); high speed drill with carbide bur (n equals 39); laser exposure at 50 mJ/p at 10 Hz (n equals 27), 100 mJ/p at 10 Hz (n equals 66) and 100 mJ/p at 20 Hz (n equals 39). A sixth treatment condition was investigated: root surface hypersensitivity, which included incremental laser exposure from 30 to 100 mJ/p at 10 Hz (n equals 39). The animals were euthanized either immediately after treatment, at one week, or at one month. The jaws were fixed and bioprepared. Remaining dentin thickness was measured, and ranged from 0.17 +/- 0.04 mm to 0.35 +/- 0.09 mm. The pulp tissue was examined for histologic inflammatory response. No evidence of pulpal involvement or adverse pulpal effects were found at any time period in teeth receiving 50 mJ/p. When histologic samples were compared with controls, all observations were similar. Of the 210 exposed teeth, 2 teeth receiving 100 mJ/p demonstrated abscess formation and were exfoliated. Further, in the rat molar when remaining dentin thickness was less than 0.5 mm, exposed to 100 mJ/p, threshold pulpal effects occurred. The response of rat pulp to laser exposure indicated no histologically measurable response to pulsed laser energy at 50 mJ/p.

  3. [Histostructural changes of rat cerebral cortex during hemorrhagic stroke modeling].

    PubMed

    Savos'ko, S I; Chaĭkovs'kyĭ, Iu B; Pogoriela, N Kh; Makarenko, O M

    2012-01-01

    Pathological changes during modeling of primary and secondary acute hemorrhagic stroke were studied in rats. We revealed differences in the activity of pharmacological action of medications under condition of acute stroke. The action of medications increased viability of neurons in both hemispheres of rat cerebrum at a right-side primary and secondary hemorrhagic stroke. Following secondary stroke, the amount of degenerative neurons amounted 25.5 +/- 0.8 cells/mm2, following the action ofcerebrolysin this value was 17.6 +/- 1.7 cells/ mm2 and after the action of cortexine and cerebral this value amounted 18.0 +/- 0.9 cells/mm2 and 10.7 +/- 0.4 cells/ mm2, respectively. In control animals the number of degenerative neurons did not exceed 2% and averaged 1.5 +/- 0.1 cells/mm2. Analysis of the morphological and statistical data showed that the most effective remedies under the primary and secondary hemorrhagic insult are cortexine and cerebral. Cerebral was found to be more effective. PMID:23233944

  4. [Scintigraphic imaging of macrophages involved in lung vasoreflex: rat model].

    PubMed

    Ndoye, O; Mbodj, M; Gassama Seck, S; Sizaret, P Y; Abeille, B; Le Pape, A

    2003-01-01

    At time of pathological situations, a pulmonary fixation of labelled substances injected by intravenous way is observed. This fixation would result from a phagocytosis of these substances by abnormal cells whose presence was induced in the endothelium: Pulmonary Intravascular Macrophages (PIM's). After activation by phagocytosis, these cells are able to secrete powerful vasoactive mediators capable of inducing cardiopulmonary accidents. Hepatic cholestase was induced in Wistar rats by ligation and section of common bile duct. The recruitment of PIM's was followed in vivo by phagocytosis scintigraphic imaging after labelled colloid injection. During the 35 days of evolution of the pathology, we observe a pulmonary fixation of the colloid agents which progresses up to 70% as well as a concomitant decease in the hepatic activity. Histologic examination showed numerous cells related to pulmonary capillaries' endothelium belonging to mononuclear phagocytes line and expressing an activated phenotype of monocytes. The scintigraphic and histological tests carried out enabled us to validate the model of induction of PIM's in rat by ligation of the choledoque one. The study of the vasoactive response via certain mediators can from now be approached, a Doppler technique on the pig aorta is being in the course of evaluation. PMID:15770812

  5. Effects of benidipine in a rat model for experimental angina.

    PubMed

    Ikeda, Jun-ichi; Matsubara, Masahiro; Yao, Kozo

    2006-12-01

    To compare the antianginal effects of 1,4-dihydropyridine-type calcium-channel blockers, we evaluated the effects of benidipine, amlodipine, nifedipine, and efonidipine on vasopressin-induced myocardial ischemia in rats, an experimental model of angina. Intravenous administration of benidipine (3 microg/kg), amlodipine (1000 microg/kg), and nifedipine (100 microg/kg) suppressed the vasopressin-induced S-wave depression, an index of myocardial ischemia. Efonidipine (100 microg/kg, i.v.) tended to inhibit the S-wave depression. At the antianginal dose of each drug, amlodipine, nifedipine, and efonidipine decreased blood pressure significantly, whereas benidipine had little effect on blood pressure at a dose of 3 microg/kg. These results indicate that benidipine, unlike the other 1,4-dihydropyridine-type calcium-channel blockers examined in this study, inhibits vasopressin-induced coronary vasospasm with fewer undesirable effects such as hypotension in rats, suggesting that benidipine may be useful in the treatment of angina pectoris. PMID:17139163

  6. A new model of progressive pulmonary fibrosis in rats

    SciTech Connect

    Last, J.A.; Gelzleichter, T.R.; Pinkerton, K.E.; Walker, R.M.; Witschi, H. )

    1993-08-01

    Sprague-Dawley rats were exposed for 6 h daily to 0.8 ppm of ozone and 14.4 ppm of nitrogen dioxide. Approximately 7 to 10 wk after the initiation of exposure, animals began to demonstrate respiratory insufficiency and severe weight loss. About half of the rats died between Days 55 and 78 of exposure; no overt ill effects were observed in animals exposed to filtered air, to ozone alone, or to nitrogen dioxide. Biochemical findings in animals exposed to ozone and nitrogen dioxide included increased lung content of DNA, protein, collagen, and elastin, which was about 300% higher than the control values. The collagen-specific crosslink hydroxy-pyridinium, a biomarker for mature collagen in the lung, was decreased by about 40%. These results are consistent with extensive breakdown and remodeling of the lung parenchyma and its associated vasculature. Histopathologic evaluation showed severe fibrosis, alveolar collapse, honeycombing, macrophage and mast cell accumulation, vascular smooth muscle hypertrophy, and other indications of severe progressive interstitial pulmonary fibrosis and end-stage lung disease. This unique animal model of progressive pulmonary fibrosis resembles the final stages of human idiopathic pulmonary fibrosis and should facilitate studying underlying mechanisms and potential therapy of progressive pulmonary fibrosis.

  7. Intranasal Delivery of pGDNF Nanoparticles for Parkinson's Disease

    NASA Astrophysics Data System (ADS)

    Harmon, Brendan Trevor

    -of-principle study with pCG, a new plasmid was created by Copernicus Therapeutics, Inc. to better mimic their long-lasting pGDNF plasmid while providing both GDNF as well as the reporter function of eGFP. This eGFP-GDNF plasmid was used to monitor expression and cell-types transfected. This expression plasmid, called pUGG, was first characterized in vitro to verify protein expression. Transfection experiments in SHEP-1 neuroblastoma cells, ventral midbrain cultures, and N27 dopaminergic cells all demonstrated that pUGG expressed bioactive eGFP and GDNF. However, cleavage of the two proteins did not occur and the expressed protein emerged as a fusion construct which was not detectable by GDNF-ELISA, although it was detected by GFP-ELISA. The next goal was to determine if pUGG was able to transfect cells in vivo in rat brain. Direct striatal injection of pUGG nanoparticles showed significant eGFP expression at the site of injection both 7 and 14 days post-administration with no difference in eGFP expression between the two time-points. GFP-immunohistochemistry at the striatal injection site revealed expression of eGFP-positive cells as well as evidence of GDNF's bioactivity as indicated by neurite outgrowth. Moving forward, we administered pUGG nanoparticles intranasally to rats and found significant expression seven days later throughout the brain, with highest levels in the forebrain areas (olfactory bulb and frontal cortex). Significant expression was also seen along the rostral-caudal axis of the brain compared with naked pUGG plasmid. The final goal of this work was to examine whether intranasal pGDNF pre-treatment could generate sufficient GDNF to protect SN dopamine neurons after a unilateral 6-hydroxydopmaine (6-OHDA) lesion, a common animal model for PD. Copernicus' pGDNF plasmid was utilized for the neuroprotection experiments to avoid possible confounds due to the GFP fusion produced by pUGG. Tyrosine hydroxylase-immunostaining density was used as a marker for dopamine

  8. Experimental models for cancellous bone healing in the rat

    PubMed Central

    Bernhardsson, Magnus; Sandberg, Olof; Aspenberg, Per

    2015-01-01

    Background and purpose — Cancellous bone appears to heal by mechanisms different from shaft fracture healing. There is a paucity of animal models for fractures in cancellous bone, especially with mechanical evaluation. One proposed model consists of a screw in the proximal tibia of rodents, evaluated by pull-out testing. We evaluated this model in rats by comparing it to the healing of empty drill holes, in order to explain its relevance for fracture healing in cancellous bone. To determine the sensitivity to external influences, we also compared the response to drugs that influence bone healing. Methods — Mechanical fixation of the screws was measured by pull-out test and related to the density of the new bone formed around similar, but radiolucent, PMMA screws. The pull-out force was also related to the bone density in drill holes at various time points, as measured by microCT. Results — The initial bone formation was similar in drill holes and around the screw, and appeared to be reflected by the pull-out force. Both models responded similarly to alendronate or teriparatide (PTH). Later, the models became different as the bone that initially filled the drill hole was resorbed to restore the bone marrow cavity, whereas on the implant surface a thin layer of bone remained, making it change gradually from a trauma-related model to an implant fixation model. Interpretation — The similar initial bone formation in the different models suggests that pull-out testing in the screw model is relevant for assessment of metaphyseal bone healing. The subsequent remodeling would not be of clinical relevance in either model. PMID:26200395

  9. Modeling the Nonlinear Motion of the Rat Central Airways.

    PubMed

    Ibrahim, G; Rona, A; Hainsworth, S V

    2016-01-01

    Advances in volumetric medical imaging techniques allowed the subject-specific modeling of the bronchial flow through the first few generations of the central airways using computational fluid dynamics (CFD). However, a reliable CFD prediction of the bronchial flow requires modeling of the inhomogeneous deformation of the central airways during breathing. This paper addresses this issue by introducing two models of the central airways motion. The first model utilizes a node-to-node mapping between the discretized geometries of the central airways generated from a number of successive computed tomography (CT) images acquired dynamically (without breath hold) over the breathing cycle of two Sprague-Dawley rats. The second model uses a node-to-node mapping between only two discretized airway geometries generated from the CT images acquired at end-exhale and at end-inhale along with the ventilator measurement of the lung volume change. The advantage of this second model is that it uses just one pair of CT images, which more readily complies with the radiation dosage restrictions for humans. Three-dimensional computer aided design geometries of the central airways generated from the dynamic-CT images were used as benchmarks to validate the output from the two models at sampled time-points over the breathing cycle. The central airway geometries deformed by the first model showed good agreement to the benchmark geometries within a tolerance of 4%. The central airway geometry deformed by the second model better approximated the benchmark geometries than previous approaches that used a linear or harmonic motion model. PMID:26592166

  10. Clinical and pathological manifestations of cardiovascular disease in rat models: the influence of acute ozone exposure

    EPA Science Inventory

    This paper shows that rat models of cardiovascular diseases have differential degrees of underlying pathologies at a young age. Rodent models of cardiovascular diseases (CVD) and metabolic disorders are used for examining susceptibility variations to environmental exposures. How...

  11. Effectiveness of Saccharomyces boulardii in a rat model of colitis

    PubMed Central

    Soyturk, Mujde; Saygili, Saba Mukaddes; Baskin, Huseyin; Sagol, Ozgul; Yilmaz, Osman; Saygili, Fatih; Akpinar, Hale

    2012-01-01

    AIM: To investigate the effects of Saccharomyces boulardii (S. boulardii) in an experimental rat model of trinitrobenzene sulfonic acid (TNBS)-induced colitis. METHODS: Thirty-two Wistar albino female rats were categorized into five groups. On the first day of the study, 50 mg TNBS was administered via a rectal catheter in order to induce colitis in all rats, except those in the control group. For 14 d, the rats were fed a standard diet, without the administration of any additional supplements to either the control or TNBS groups, in addition to 1 mg/kg per day S. boulardii to the S. boulardii group, 1 mg/kg per day methyl prednisolone (MP) to the MP group. The animals in the S. boulardii + MP group were coadministered these doses of S. boulardii and MP. During the study, weight loss, stool consistency, and the presence of obvious blood in the stool were evaluated, and the disease activity index (DAI) for colitis was recorded. The intestines were examined and colitis was macro- and microscopically scored. The serum and tissue levels of tumor necrosis factor-α (TNF-α) and nitric oxide (NO) were determined, and fungemia was evaluated in the blood samples. RESULTS: The mean DAI scores for the MP and S. boulardii + MP groups was significantly lower than the TNBS group (3.69 ± 0.61 vs 4.46 ± 0.34, P = 0.018 and 3.77 ± 0.73 vs 4.46 ± 0.34, P = 0.025, respectively). While no significant differences between the TNBS and the S. boulardii or MP groups could be determined in terms of serum NO levels, the level of serum NO in the S. boulardii + MP group was significantly higher than in the TNBS and S. boulardii groups (8.12 ± 4.25 μmol/L vs 3.18 ± 1.19 μmol/L, P = 0.013; 8.12 ± 4.25 μmol/L vs 3.47 ± 1.66 μmol/L, P = 0.012, respectively). The tissue NO levels in the S. boulardii, MP and S. boulardii + MP groups were significantly lower than the TNBS group (16.62 ± 2.27 μmol/L vs 29.72 ± 6.10 μmol/L, P = 0.002; 14.66 ± 5.18 μmol/L vs 29.72 ± 6.10 μmol/L, P

  12. The influence of aging on poststroke depression using a rat model via middle cerebral artery occlusion.

    PubMed

    Boyko, Matthew; Kutz, Ruslan; Gruenbaum, Benjamin F; Cohen, Hagit; Kozlovsky, Nitsan; Gruenbaum, Shaun E; Shapira, Yoram; Zlotnik, Alexander

    2013-12-01

    Poststroke depression (PSD) is the most frequent psychological sequela following stroke. While previous studies describe the impact of age on brain infarct volume, brain edema, and blood-brain barrier (BBB) breakdown following ischemia, the role of age on PSD has yet to be described. Here, we examine the influence of age on PSD progression in a rat model of PSD by middle cerebral artery occlusion (MCAO). One hundred forty-three rats were divided into three groups. 48 rats 20 weeks of age underwent a sham procedure, 51 rats 20 weeks of age had MCAO, and 44 rats 22-26 months of age had MCAO. Groups were further divided into two subgroups. The first subgroup was used to measure infarct lesion volume, brain edema, and BBB breakdown at 24 h. In the second subgroup at 3 weeks after MCAO, rats were subjected to a sucrose preference test, two-way shuttle avoidance task, forced swimming test, and a brain-derived neurotrophic factor (BDNF) protein level measurement. Total and striatal infarct volume, brain edema, and BBB breakdown in the striatum were increased in older rats, as compared with younger rats. While both old and young rats exhibited depressive-like behaviors on each of the behavioral tests and lower BDNF levels post-MCAO, as compared with control rats, there were no differences between old and young rats. Although older rats suffered from larger infarct volumes, increased brain edema and more BBB disruption following MCAO, the lack of behavioral differences between young and old rats suggests that there was no effect of rat age on the incidence of PSD. PMID:23761136

  13. Determinants of renal tissue hypoxia in a rat model of polycystic kidney disease.

    PubMed

    Ow, Connie P C; Abdelkader, Amany; Hilliard, Lucinda M; Phillips, Jacqueline K; Evans, Roger G

    2014-11-15

    Renal tissue oxygen tension (PO2) and its determinants have not been quantified in polycystic kidney disease (PKD). Therefore, we measured kidney tissue PO2 in the Lewis rat model of PKD (LPK) and in Lewis control rats. We also determined the relative contributions of altered renal oxygen delivery and consumption to renal tissue hypoxia in LPK rats. PO2 of the superficial cortex of 11- to 13-wk-old LPK rats, measured by Clark electrode with the rat under anesthesia, was higher within the cysts (32.8 ± 4.0 mmHg) than the superficial cortical parenchyma (18.3 ± 3.5 mmHg). PO2 in the superficial cortical parenchyma of Lewis rats was 2.5-fold greater (46.0 ± 3.1 mmHg) than in LPK rats. At each depth below the cortical surface, tissue PO2 in LPK rats was approximately half that in Lewis rats. Renal blood flow was 60% less in LPK than in Lewis rats, and arterial hemoglobin concentration was 57% less, so renal oxygen delivery was 78% less. Renal venous PO2 was 38% less in LPK than Lewis rats. Sodium reabsorption was 98% less in LPK than Lewis rats, but renal oxygen consumption did not significantly differ between the two groups. Thus, in this model of PKD, kidney tissue is severely hypoxic, at least partly because of deficient renal oxygen delivery. Nevertheless, the observation of similar renal oxygen consumption, despite markedly less sodium reabsorption, in the kidneys of LPK compared with Lewis rats, indicates the presence of inappropriately high oxygen consumption in the polycystic kidney. PMID:25209412

  14. The touchscreen operant platform for assessing cognitive functions in a rat model of depression.

    PubMed

    Tran, Thao Phuong; Christensen, Helle Lyng; Bertelsen, Freja Cecilia Brandt; Bouzinova, Elena; Møller, Arne; Wiborg, Ove

    2016-07-01

    In the present study we assessed alterations in cognitive functions in a chronic mild stress (CMS) rat model of depression. Cognitive functions were assessed in two different tasks applying the translational operant platform touchscreen technology; the visual discrimination/acquisition task was used to assess the ability to perceive and distinguish visual stimuli and to assess associative stimulus-reward learning. The visual discrimination/reversal learning task was used to assess functional brain plasticity or reprogramming of previously acquired stimulus-reward associations. These tasks permit the dissociation of multiple cognitive domains. The CMS model is a validated depression model with the useful feature that rats upon stress exposure show a graduated, individual stress response allowing the segregation of rats into different phenotypes including stress-resilient and anhedonic-like subgroups. Anhedonic-like rats are less likely to acquire the pairwise discrimination task, and they have a slower acquisition rate than controls. In the reversal learning task, resilient rats performed significantly better than anhedonic-like rats over time and 50% passed criterion as opposed to 25% for controls and only 14% for anhedonic-like rats. This indicates that resilient rats have higher cognitive flexibility than anhedonic-like rats. Thus they perform better in learning a novel task, which at the same time potentially implies an increased ability to inhibit previously rewarded behavior. PMID:27083126

  15. Curcumin reduces injury progression in a rat comb burn model.

    PubMed

    Singer, Adam J; Taira, Breena R; Lin, Fubao; Lim, Taeho; Anderson, Ryon; McClain, Steve A; Clark, Richard A F

    2011-01-01

    The oriental spice curcumin has anti-inflammatory and antioxidant effects. When given orally before injury, curcumin reduces burn progression in a rat comb burn model. The authors hypothesized that intravenous administration of curcumin after injury would reduce burn progression and that its effects are mediated through iron chelation. Two comb burns were created on the dorsum of Sprague-Dawley rats (weight, 300 g) using a brass comb with four rectangular prongs preheated in boiling water and applied for 30 seconds resulting in four rectangular 10 × 20 mm full-thickness burns separated by three 5 × 20 mm unburned interspaces (zone of ischemia). Animals were randomized to receive one of four doses of crude curcumin or one of six doses of purified curcumin intravenously 1 and 24 hours after injury. Another set of animals were randomized to deferoxamine or control vehicle. Wounds were observed at 7 days after injury for visual evidence of necrosis in the unburned interspaces. Full-thickness biopsies from the interspaces were evaluated with Hematoxylin and Eosin staining 7 days after injury for evidence of necrosis. The percentage of unburned interspaces undergoing necrosis at 1 week by purified curcumin doses was 0 μg/kg, 74%; 0.3 μg/kg, 58%; 1 μg/kg, 53%; 3 μg/kg, 37%; 10 μg/kg, 63%; 30 μg/kg, 53%; and 100 μg/kg, 26%. The differences among the groups were significant (P = .03). When compared with controls, the 1 and 3 μg/kg curcumin treatment groups had significantly less progression of interspaces to necrosis (P = .04 and .002) as did the 30 and 100 μg/kg treatment groups (P = .03 and <.001). Deferoxamine did not reduce burn progression. When administered intravenously 1 and 24 hours after injury, both crude and purified curcumin reduce the percentage of unburned interspaces that undergo necrosis in a rat hot comb burn model. The effects of purified curcumin appear to be bimodal, suggesting more than one mechanism of action. The effects of curcumin do not

  16. Fractional ventilation mapping using inert fluorinated gas MRI in rat models of inflammation and fibrosis.

    PubMed

    Couch, Marcus J; Fox, Matthew S; Viel, Chris; Gajawada, Gowtham; Li, Tao; Ouriadov, Alexei V; Albert, Mitchell S

    2016-05-01

    The purpose of this study was to extend established methods for fractional ventilation mapping using (19) F MRI of inert fluorinated gases to rat models of pulmonary inflammation and fibrosis. In this study, five rats were instilled with lipopolysaccharide (LPS) in the lungs two days prior to imaging, six rats were instilled with bleomycin in the lungs two weeks prior to imaging and an additional four rats were used as controls. (19) F MR lung imaging was performed at 3 T with rats continuously breathing a mixture of sulfur hexafluoride and O2 . Fractional ventilation maps were obtained using a wash-out approach, by switching the breathing mixture to pure O2 , and acquiring images following each successive wash-out breath. The mean fractional ventilation (r) was 0.29 ± 0.05 for control rats, 0.23 ± 0.10 for LPS-instilled rats and 0.19 ± 0.03 for bleomycin-instilled rats. Bleomycin-instilled rats had a significantly decreased mean r value compared with controls (P = 0.010). Although LPS-instilled rats had a slightly reduced mean r value, this trend was not statistically significant (P = 0.556). Fractional ventilation gradients were calculated in the anterior/posterior (A/P) direction, and the mean A/P gradient was -0.005 ± 0.008 cm(-1) for control rats, 0.013 ± 0.005 cm(-1) for LPS-instilled rats and 0.009 ± 0.018 cm(-1) for bleomycin-instilled rats. Fractional ventilation gradients were significantly different for control rats compared with LPS-instilled rats only (P = 0.016). The ventilation gradients calculated from control rats showed the expected gravitational relationship, while ventilation gradients calculated from LPS- and bleomycin-instilled rats showed the opposite trend. Histology confirmed that LPS-instilled rats had a significantly elevated alveolar wall thickness, while bleomycin-instilled rats showed signs of substantial fibrosis. Overall, (19) F MRI may be able to detect the effects of pulmonary

  17. Modeling interpopulation dispersal by banner-tailed kangaroo rats

    USGS Publications Warehouse

    Skvarla, J.L.; Nichols, J.D.; Hines, J.E.; Waser, P.M.

    2004-01-01

    Many metapopulation models assume rules of population connectivity that are implicitly based on what we know about within-population dispersal, but especially for vertebrates, few data exist to assess whether interpopulation dispersal is just within-population dispersal "scaled up." We extended existing multi-stratum mark-release-recapture models to incorporate the robust design, allowing us to compare patterns of within- and between-population movement in the banner-tailed kangaroo rat (Dipodomys spectabilis). Movement was rare among eight populations separated by only a few hundred meters: seven years of twice-annual sampling captured >1200 individuals but only 26 interpopulation dispersers. We developed a program that implemented models with parameters for capture, survival, and interpopulation movement probability and that evaluated competing hypotheses in a model selection framework. We evaluated variants of the island, stepping-stone, and isolation-by-distance models of interpopulation movement, incorporating effects of age, season, and habitat (short or tall grass). For both sexes, QAICc values clearly favored isolation-by-distance models, or models combining the effects of isolation by distance and habitat. Models with probability of dispersal expressed as linear-logistic functions of distance and as negative exponentials of distance fit the data equally well. Interpopulation movement probabilities were similar among sexes (perhaps slightly biased toward females), greater for juveniles than adults (especially for females), and greater before than during the breeding season (especially for females). These patterns resemble those previously described for within-population dispersal in this species, which we interpret as indicating that the same processes initiate both within- and between-population dispersal.

  18. HIV-1 Nef Breaches Placental Barrier in Rat Model

    PubMed Central

    Singh, Poonam; Agnihotri, Saurabh Kumar; Tewari, Mahesh Chandra; Kumar, Sadan; Sachdev, Monika; Tripathi, Raj Kamal

    2012-01-01

    The vertical transmission of HIV-1 from the mother to fetus is known, but the molecular mechanism regulating this transmission is not fully characterized. The fetus is highly protected by the placenta, which does not permit microbial pathogens to cross the placental barrier. In the present study, a rat model was established to observe the effect of HIV-1 protein Nef on placental barrier. Evans blue dye was used to assay permeability of placental barrier and fourteen day pregnant Sprague Dawley rats were injected intravenously with 2% Evans blue dye along with various concentrations of recombinant Nef. After an hour, animals were sacrificed and dye migration was observed through the assimilation of peripheral blood into fetus. Interestingly, traces of recombinant Nef protein were detected in the embryo as well as amniotic fluid and amniotic membrane along with placenta and uterus. Our study indicates that recombinant HIV-1-Nef protein breaches the placental barrier and allows the migration of Evans blue dye to the growing fetus. Further the concentration of Nef protein in blood is directly proportional to the intensity of dye migration and to the amount of Nef protein detected in uterus, placenta, amniotic membrane, amniotic fluid and embryo. Based on this study, it can be concluded that the HIV-1 Nef protein has a direct effect on breaching of the placental barrier in the model we have established in this study. Our observations will be helpful to understand the molecular mechanisms related to this breach of placental barrier by Nef in humans and may be helpful to identify specific Nef inhibitors. PMID:23240037

  19. In Situ Perfusion Model in Rat Colon for Drug Absorption Studies: Comparison with Small Intestine and Caco-2 Cell Model.

    PubMed

    Lozoya-Agullo, Isabel; González-Álvarez, Isabel; González-Álvarez, Marta; Merino-Sanjuán, Matilde; Bermejo, Marival

    2015-09-01

    Our aim is to develop and to validate the in situ closed loop perfusion method in rat colon and to compare with small intestine and Caco-2 cell models. Correlations with human oral fraction absorbed (Fa) and human colon fraction absorbed (Fa_colon) were developed to check the applicability of the rat colon model for controlled release (CR) drug screening. Sixteen model drugs were selected and their permeabilities assessed in rat small intestine and colon, and in Caco-2 monolayers. Correlations between colon/intestine/Caco-2 permeabilities versus human Fa and human Fa_colon have been explored to check model predictability and to apply a BCS approach in order to propose a cut off value for CR screening. Rat intestine perfusion with Doluisio's method and single-pass technique provided a similar range of permeabilities demonstrating the possibility of combining data from different laboratories. Rat colon permeability was well correlated with Caco-2 cell-4 days model reflecting a higher paracellular permeability. Rat colon permeabilities were also higher than human colon ones. In spite of the magnitude differences, a good sigmoidal relationship has been shown between rat colon permeabilities and human colon fractions absorbed, indicating that rat colon perfusion can be used for compound classification and screening of CR candidates. PMID:25891783

  20. MODELLING WORKING AND REFERENCE MEMORY IN RATS: EFFECTS OF SCOPOLAMINE ON DELAYED MATCHING-TO-POSITION

    EPA Science Inventory

    A model of working and reference memory in rats is described, based on a discrete-trial operant procedure with concurrent spatial matching and nonspatial discrimination components. orking memory was assessed by delivery food to rats for pressing one of two retractable levers afte...

  1. A RAT MODEL OF HEART FAILURE INDUCED BY ISOPROTERENOL AND A HIGH SALT DIET

    EPA Science Inventory

    Rat models of heart failure (HF) show varied pathology and time to disease outcome, dependent on induction method. We found that subchronic (4wk) isoproterenol (ISO) infusion in Spontaneously Hypertensive Heart Failure (SHHF) rats caused cardiac injury with minimal hypertrophy. O...

  2. Sodium Salicylate Reduced Insulin Resistance in the Retina of a Type 2 Diabetic Rat Model

    PubMed Central

    Jiang, Youde; Thakran, Shalini; Bheemreddy, Rajini; Coppess, William; Walker, Robert J.; Steinle, Jena J.

    2015-01-01

    Sodium salicylate has been reported to reduce markers of diabetic retinopathy in a type 1 rat model. Because rates of type 2 diabetes are on the rise, we wanted to determine whether salicylate could improve insulin resistance in a type 2 rat model, as well as improve retinal function. We treated lean and obese BBZDR/Wor type 2 diabetic rats with salicylate in their chow for 2 months. Prior to salicylate treatment, rats underwent an electroretinogram to measure retinal function. After 2 months of treatment, rats underwent an additional electroretinogram prior to sacrifice. In addition to the animal model, we also treated retinal endothelial cells (REC) and rat Müller cells with salicylate and performed the same analyses as done for the rat retinal lysates. To investigate the role of salicylate in insulin signaling, we measured TNFα and caspase 3 levels by ELISA, as well as performed Western blotting for insulin receptor substrate 1, insulin receptor, SOCS3, and pro- and anti-apoptotic markers. Data demonstrated that salicylate significantly improved retinal function, as well as reduced TNFα and SOCS3-induced insulin resistance in all samples. Overall, results suggest that salicylate is effective in reducing insulin resistance in the retina of type 2 diabetic rat models. PMID:25874611

  3. Grape powder treatment prevents anxiety-like behavior in a rat model of aging.

    PubMed

    Patki, Gaurav; Ali, Quaisar; Pokkunuri, Indira; Asghar, Mohammad; Salim, Samina

    2015-06-01

    Earlier, we have reported that grape powder (GP) treatment prevented pharmacologic and psychological stress-induced anxiety-like behavior and memory impairment in rats. Protective effects of GP were attributed to its antioxidant effects. In this study, we tested the hypothesis that age-associated behavioral and cognitive deficits such as anxiety and memory impairment will be ameliorated with GP treatment. Using a National Institute of Aging recommended rodent model of aging, we examined a potentially protective role of antioxidant-rich GP in age-associated anxiety-like behavior and memory impairment. Male Fischer 344 rats were randomly assigned into 4 groups: young rats (3 months old) provided with tap water or with 15 g/L GP dissolved in tap water for 3 weeks, aged rats (21 months old) provided with tap water or with GP-treated tap water for 3 weeks (AG-GP). Anxiety-like behavior was significantly greater in aged rats compared with young rats, GP-treated young rats, or aged control rats (P < .05). Also, GP treatment prevented age-induced anxiety-like behavior in AG-GP rats (P < .05). Neither short-term nor long-term age-associated memory deficits improved with GP treatment in AG-GP rats. Furthermore, aged rats showed increased level of physiological stress (corticosterone) and increased oxidative stress in the plasma (8-isoprostane) as well as in selected brain areas (protein carbonylation). Grape powder treatment prevented age-induced increase in corticosterone levels and plasma 8-isoprostane levels in aged rats (P < .05), whereas protein carbonylation was recovered in the amygdala region only (P < .05). Grape powder by regulating oxidative stress ameliorates age-induced anxiety-like behavior in rats, whereas age-associated memory deficits seem unaffected with GP treatment. PMID:26022140

  4. Effective Rat Lung Tumor Model for Stereotactic Body Radiation Therapy.

    PubMed

    Zhang, Zhang; Wodzak, Michelle; Belzile, Olivier; Zhou, Heling; Sishc, Brock; Yan, Hao; Stojadinovic, Strahinja; Mason, Ralph P; Brekken, Rolf A; Chopra, Rajiv; Story, Michael D; Timmerman, Robert; Saha, Debabrata

    2016-06-01

    Stereotactic body radiation therapy (SBRT) has found an important role in the treatment of patients with non-small cell lung cancer, demonstrating improvements in dose distribution and even tumor cure rates, particularly for early-stage disease. Despite its emerging clinical efficacy, SBRT has primarily evolved due to advances in medical imaging and more accurate dose delivery, leaving a void in knowledge of the fundamental biological mechanisms underlying its activity. Thus, there is a critical need for the development of orthotropic animal models to further probe the biology associated with high-dose-per-fraction treatment typical of SBRT. We report here on an improved surgically based methodology for generating solitary intrapulmonary nodule tumors, which can be treated with simulated SBRT using the X-RAD 225Cx small animal irradiator and Small Animal RadioTherapy (SmART) Plan treatment system. Over 90% of rats developed solitary tumors in the right lung. Furthermore, the tumor response to radiation was monitored noninvasively via bioluminescence imaging (BLI), and complete ablation of tumor growth was achieved with 36 Gy (3 fractions of 12 Gy each). We report a reproducible, orthotopic, clinically relevant lung tumor model, which better mimics patient treatment regimens. This system can be utilized to further explore the underlying biological mechanisms relevant to SBRT and high-dose-per-fraction radiation exposure and to provide a useful model to explore the efficacy of radiation modifiers in the treatment of non-small cell lung cancer. PMID:27223828

  5. Standardised Models for Inducing Experimental Peritoneal Adhesions in Female Rats

    PubMed Central

    Kraemer, Bernhard; Wallwiener, Christian; Rajab, Taufiek K.; Brochhausen, Christoph; Wallwiener, Markus; Rothmund, Ralf

    2014-01-01

    Animal models for adhesion induction are heterogeneous and often poorly described. We compare and discuss different models to induce peritoneal adhesions in a randomized, experimental in vivo animal study with 72 female Wistar rats. Six different standardized techniques for peritoneal trauma were used: brushing of peritoneal sidewall and uterine horns (group 1), brushing of parietal peritoneum only (group 2), sharp excision of parietal peritoneum closed with interrupted sutures (group 3), ischemic buttons by grasping the parietal peritoneum and ligating the base with Vicryl suture (group 4), bipolar electrocoagulation of the peritoneum (group 5), and traumatisation by electrocoagulation followed by closure of the resulting peritoneal defect using Vicryl sutures (group 6). Upon second look, there were significant differences in the adhesion incidence between the groups (P < 0.01). Analysis of the fraction of adhesions showed that groups 2 (0%) and 5 (4%) were significantly less than the other groups (P < 0.01). Furthermore, group 6 (69%) was significantly higher than group 1 (48%) (P < 0.05) and group 4 (47%) (P < 0.05). There was no difference between group 3 (60%) and group 6 (P = 0.2). From a clinical viewpoint, comparison of different electrocoagulation modes and pharmaceutical adhesion barriers is possible with standardised models. PMID:24809049

  6. The HIV-1 transgenic rat model of neuroHIV

    PubMed Central

    Vigorito, Michael; Connaghan, Kaitlyn P.; Chang, Sulie L.

    2016-01-01

    Despite the ability of current combination anti-retroviral therapy (cART) to limit the progression of HIV-1 to AIDS, HIV-positive individuals continue to experience neuroHIV in the form of HIV-associated neurological disorders (HAND), which can range from subtle to substantial neurocognitive impairment. NeuroHIV may also influence substance use, abuse, and dependence in HIV-positive individuals. Because of the nature of the virus, variables such as mental health co-morbidities make it difficult to study the interaction between HIV and substance abuse in human populations. Several rodent models have been developed in an attempt to study the transmission and pathogenesis of the HIV-1 virus. The HIV-1 transgenic (HIV-1Tg) rat is a reliable model of neuroHIV because it mimics the condition of HIV-infected patients on cART. Research using this model supports the hypothesis that the presence of HIV-1 viral proteins in the central nervous system increases the sensitivity and susceptibility of HIV-positive individuals to substance abuse. PMID:25733103

  7. The Dimethylnitrosamine Induced Liver Fibrosis Model in the Rat.

    PubMed

    Chooi, Kum Fai; Kuppan Rajendran, Dinesh Babu; Phang, Siew Siang Gary; Toh, Han Hui Alden

    2016-01-01

    Four to six week old, male Wistar rats were used to produce animal models of liver fibrosis. The process requires four weeks of administration of 10 mg/kg dimethylnitrosamine (DMN), given intraperitoneally for three consecutive days per week. Intraperitoneal injections were performed in the fume hood as DMN is a known hepatoxin and carcinogen. The model has several advantages. Firstly, liver changes can be studied sequentially or at particular stages of interest. Secondly, the stage of liver disease can be monitored by measurement of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) enzymes. Thirdly, the severity of liver damage at different stages can be confirmed by sacrifice of animals at designated time points, followed by histological examination of Masson's Trichome stained liver tissues. After four weeks of DMN dosing, the typical fibrosis score is 5 to 6 on the Ishak scale. The model can be reproduced consistently and has been widely used to assess the efficacy of potential anti-fibrotic agents. PMID:27340889

  8. Cell culture models using rat primary alveolar type I cells.

    PubMed

    Downs, Charles A; Montgomery, David W; Merkle, Carrie J

    2011-10-01

    There is a lack of cell culture models using primary alveolar type I (AT I) cells. The purpose of this study was to develop cell culture models using rat AT I cells and microvascular endothelial cells from the lung (MVECL). Two types of model systems were developed: single and co-culture systems; additionally a 3-dimensional model system was developed. Pure AT I cell (96.3 ± 2.7%) and MVECL (97.9 ± 1.1%) preparations were used. AT I cell morphology, mitochondrial number and distribution, actin filament arrangement and number of apoptotic cells at confluence, and telomere attrition were characterized. AT I cells maintained their morphometric characteristics through at least population doubling (PD) 35, while demonstrating telomere attrition through at least PD 100. Furthermore, AT I cells maintained the expression of their specific markers, T1α and AQ-5, through PD 42. For the co-cultures, AT I cells were grown on the top and MVECL were grown on the bottom of fibronectin-coated 24-well Transwell Fluroblok™ filter inserts. Neither cell type transmigrated the 1 μm pores. Additionally, AT I cells were grown in a thick layer of Matrigel(®) to create a 3-dimensional model in which primary AT I cells form ring-like structures that resemble an alveolus. The development of these model systems offers the opportunities to investigate AT I cells and their interactions with MVECL in response to pharmacological interventions and in the processes of disease, repair and regeneration. PMID:21624488

  9. Cell culture models using rat primary alveolar type I cells

    PubMed Central

    Downs, Charles A.; Montgomery, David W.; Merkle, Carrie J.

    2011-01-01

    There is a lack of cell culture models using primary alveolar type I (AT I) cells. The purpose of this study was to develop cell culture models using rat AT I cells and microvascular endothelial cells from the lung (MVECL). Two types of model systems were developed: single and co-culture systems; additionally a 3-dimensional model system was developed. Pure AT I cell (96.3 ±2.7%) and MVECL (97.9 ±1.1 %) preparations were used. AT I cell morphology, mitochondrial number and distribution, actin filament arrangement and number of apoptotic cells at confluence, and telomere attrition were characterized. AT I cells maintained their morphometric characteristics through at least population doubling (PD) 35, while demonstrating telomere attrition through at least PD 100. Furthermore, AT I cells maintained the expression of their specific markers, T1α and AQ-5, through PD 42. For the co-cultures, AT I cells were grown on the top and MVECL were grown on the bottom of fibronectin coated 24 well Transwell Fluroblok™ filter inserts. Neither cell type transmigrated the 1 micron pores. Additionally AT I cells were grown in a thick layer of Matrigel® to create a 3-dimensional model in which primary AT I cells form ring-like structures that resemble an alveolus. The development of these model systems offers the opportunities to investigate AT I cell cells and their interactions with MVECL in response to pharmacological interventions and in the processes of disease, repair and regeneration. PMID:21624488

  10. The Characterization of Obese Polycystic Ovary Syndrome Rat Model Suitable for Exercise Intervention

    PubMed Central

    Qiu, Shuwei; Jiang, Zhongli

    2014-01-01

    Objective To develop a new polycystic ovary syndrome (PCOS) rat model suitable for exercise intervention. Method Thirty six rats were randomly divided into three experimental groups: PCOS rats with high-fat diet (PF, n = 24), PCOS rats with ordinary diet (PO, n = 6), and control rats with ordinary diet (CO, n = 6). Two kinds of PCOS rat model were made by adjustment diet structure and testosterone injection for 28 days. After a successful animal model, PF model rats were randomly assigned to three groups: exercise with a continuation of high-fat diet (PF-EF, n = 6), sedentary with a continuation of high-fat diet (PF-SF, n = 6), exercise with an ordinary diet (PF-EO, n = 6). Fasting blood glucose (FBG) and insulin (FINS), estrogen (E2), progesterone (P), and testosterone (T) in serum were determined by RIA, and ovarian morphology was evaluated by Image-Pro plus 6.0. Results Body weight, Lee index, FINS increased significantly in PF rat model. Serum levels of E2 and T were significantly higher in PF and PO than in CO. Ovary organ index and ovarian areas were significant lower in PF than in CO. After intervention for 2 weeks, the levels of 1 h postprandial blood glucose (PBG1), 2 h postprandial blood glucose (PBG2), FINS and the serum levels of T decreased significantly in PF-EF rats and PF-EO rats. The ratio of FBG/FINS was significant higher in PF-EO rats than in PF-SF rats. Ovarian morphology showed that the numbers of preantral follicles and atretic follicles decreased significantly, and the numbers of antral follicles and corpora lutea increased significantly in the rats of PF-EF and PF-EO. Conclusion By combination of high-fat diet and testosterone injection, the obese PCOS rat model is conformable with the lifestyle habits of fatty foods and insufficient exercise, and has metabolic and reproductive characteristics of human PCOS. This model can be applied to study exercise intervention. PMID:24905232

  11. Simulating certain aspects of hypogravity: Effects on the mandibular incisors of suspended rats (PULEH model)

    NASA Technical Reports Server (NTRS)

    Simmons, D. J.; Winter, F.; Morey-Holton, E. R.

    1984-01-01

    The effect of a hypogravity simulating model on the rate of mandibular incisor formation, dentinogenesis and, amelogenesis in laboratory rats was studied. The model is the partial unloading by elevating the hindquarters. In this system, rat hindquarters are elevated 30 to 40 deg from the cage floors to completely unload the hindlimbs, but the animals are free to move about using their forelimbs. This model replicates the fluid sift changes which occur during the weightlessness of spaceflight and produces an osteopenia in the weight bearing skeletons. The histogenesis and/or mineralization rates of the mandibular incisor during the first 19d of PULEH in young growing rats are recorded.

  12. A Novel Model of Intravital Platelet Imaging Using CD41-ZsGreen1 Transgenic Rats

    PubMed Central

    Mizuno, Makoto; Tomizawa, Atsuyuki; Ohno, Kousaku; Jakubowski, Joseph A.; Sugidachi, Atsuhiro

    2016-01-01

    Platelets play pivotal roles in both hemostasis and thrombosis. Although models of intravital platelet imaging are available for thrombosis studies in mice, few are available for rat studies. The present effort aimed to generate fluorescent platelets in rats and assess their dynamics in a rat model of arterial injury. We generated CD41-ZsGreen1 transgenic rats, in which green fluorescence protein ZsGreen1 was expressed specifically in megakaryocytes and thus platelets. The transgenic rats exhibited normal hematological and biochemical values with the exception of body weight and erythroid parameters, which were slightly lower than those of wild-type rats. Platelet aggregation, induced by 20 μM ADP and 10 μg/ml collagen, and blood clotting times were not significantly different between transgenic and wild-type rats. Saphenous arteries of transgenic rats were injured with 10% FeCl3, and the formation of fluorescent thrombi was evaluated using confocal microscopy. FeCl3 caused time-dependent increases in the mean fluorescence intensity of injured arteries of vehicle-treated rats. Prasugrel (3 mg/kg, p.o.), administered 2 h before FeCl3, significantly inhibited fluorescence compared with vehicle-treated rats (4.5 ± 0.4 vs. 14.9 ± 2.4 arbitrary fluorescence units at 30 min, respectively, n = 8, P = 0.0037). These data indicate that CD41-ZsGreen1 transgenic rats represent a useful model for intravital imaging of platelet-mediated thrombus formation and the evaluation of antithrombotic agents. PMID:27128503

  13. A Novel Model of Intravital Platelet Imaging Using CD41-ZsGreen1 Transgenic Rats.

    PubMed

    Mizuno, Makoto; Tomizawa, Atsuyuki; Ohno, Kousaku; Jakubowski, Joseph A; Sugidachi, Atsuhiro

    2016-01-01

    Platelets play pivotal roles in both hemostasis and thrombosis. Although models of intravital platelet imaging are available for thrombosis studies in mice, few are available for rat studies. The present effort aimed to generate fluorescent platelets in rats and assess their dynamics in a rat model of arterial injury. We generated CD41-ZsGreen1 transgenic rats, in which green fluorescence protein ZsGreen1 was expressed specifically in megakaryocytes and thus platelets. The transgenic rats exhibited normal hematological and biochemical values with the exception of body weight and erythroid parameters, which were slightly lower than those of wild-type rats. Platelet aggregation, induced by 20 μM ADP and 10 μg/ml collagen, and blood clotting times were not significantly different between transgenic and wild-type rats. Saphenous arteries of transgenic rats were injured with 10% FeCl3, and the formation of fluorescent thrombi was evaluated using confocal microscopy. FeCl3 caused time-dependent increases in the mean fluorescence intensity of injured arteries of vehicle-treated rats. Prasugrel (3 mg/kg, p.o.), administered 2 h before FeCl3, significantly inhibited fluorescence compared with vehicle-treated rats (4.5 ± 0.4 vs. 14.9 ± 2.4 arbitrary fluorescence units at 30 min, respectively, n = 8, P = 0.0037). These data indicate that CD41-ZsGreen1 transgenic rats represent a useful model for intravital imaging of platelet-mediated thrombus formation and the evaluation of antithrombotic agents. PMID:27128503

  14. The Influence of a High Salt Diet on a Rat Model of Isoproterenol-Induced Heart Failure

    EPA Science Inventory

    Rat models of heart failure (HF) show varied pathology and time to disease outcome, dependent on induction method. We found that subchronic (4 weeks) isoproterenol (ISO) infusion exacerbated cardiomyopathy in Spontaneously Hypertensive Heart Failure (SHHF) rats. Others have shown...

  15. A Rat Excised Larynx Model of Vocal Fold Scar

    PubMed Central

    Welham, Nathan V.; Montequin, Douglas W.; Tateya, Ichiro; Tateya, Tomoko; Hee Choi, Seong; Bless, Diane M.

    2008-01-01

    Purpose To develop and evaluate a rat excised larynx model for the measurement of acoustic, aerodynamic and vocal fold vibratory changes resulting from vocal fold scar. Method Twenty four 4-month-old male Sprague Dawley rats were assigned to one of four experimental groups: Chronic vocal fold scar, chronic vocal fold scar treated with 100 ng basic fibroblast growth factor (bFGF), chronic vocal fold scar treated with saline (sham treatment), and unscarred untreated control. Following tissue harvest, histological and immunohistochemical data were collected to confirm extracellular matrix alteration in the chronic scar group, and acoustic, aerodynamic and high speed digital imaging data were collected using an excised larynx setup in all groups. Phonation threshold pressure (Pth), glottal resistance (Rg), glottal efficiency (Eg), vibratory amplitude and vibratory area were employed as dependent variables. Results Chronically scarred vocal folds were characterized by elevated collagen I and III and reduced hyaluronic acid abundance. Phonation was achieved and data were collected from all control and bFGF treated larynges, however phonation was not achieved with 3 of 6 chronically scarred and 1 of 6 saline treated larynges. Compared to control, the chronic scar group was characterized by elevated Pth, reduced Eg, and intra-larynx vibratory amplitude and area asymmetry. The bFGF group was characterized by Pth below control group levels, Eg comparable to control, and vocal fold vibratory amplitude and area symmetry comparable to control. The sham group was characterized by Pth comparable to control, Eg superior to control, and vocal fold vibratory amplitude and area symmetry comparable to control. Conclusions The excised larynx model reported here demonstrated robust deterioration across phonatory indices under the scar condition and sensitivity to treatment induced change under the bFGF condition. The improvement observed under the sham condition may reflect

  16. Virgin Coconut Oil Supplementation Prevents Bone Loss in Osteoporosis Rat Model

    PubMed Central

    Hayatullina, Zil; Muhammad, Norliza; Mohamed, Norazlina; Soelaiman, Ima-Nirwana

    2012-01-01

    Oxidative stress and free radicals have been implicated in the pathogenesis of osteoporosis. Therefore, antioxidant compounds have the potential to be used in the prevention and treatment of the disease. In this study, we investigated the effects of virgin coconut oil (VCO) on bone microarchitecture in a postmenopausal osteoporosis rat model. VCO is a different form of coconut oil as it is rich with antioxidants. Three-month-old female rats were randomly grouped into baseline, sham-operated, ovariectomized control (Ovx), and ovariectomized rats fed with 8% VCO in their diet for six weeks (Ovx+VCO). Bone histomorphometry of the right femora was carried out at the end of the study. Rats supplemented with VCO had a significantly greater bone volume and trabecular number while trabecular separation was lower than the Ovx group. In conclusion, VCO was effective in maintaining bone structure and preventing bone loss in estrogen-deficient rat model. PMID:23024690

  17. Establishment and identification of a hypoxia-ischemia brain damage model in neonatal rats

    PubMed Central

    YAO, DAN; ZHANG, WEIRAN; HE, XUE; WANG, JINHU; JIANG, KEWEN; ZHAO, ZHENGYAN

    2016-01-01

    The present study was designed to set up a reliable model of severe hypoxia-ischemia brain damage (HIBD) in neonatal rats and several methods were used to identify whether the model was successful. A total of 40 healthy 7-day-old Sprague-Dawley rats were randomly divided into 2 groups: The sham-surgery group (n=18) and the HIBD model group (n=22). The HIBD model was produced according to the traditional Rice method. The rats were anesthetized with ethyl ether. The left common carotid artery (CCA) was exposed, ligated and cut. Following this, the rats were exposed to hypoxia in a normobaric chamber filled with 8% oxygen and 92% nitrogen for 2 h. In the sham-surgery group, the left CCA was exposed but was not ligated, cut or exposed to hypoxia. The neurobehavioral changes of the rats were observed in the 24 h after HIBD. The brains were collected after 72 h to observe the pathological morphological changes of the brain tissue. The behavioral ability and neurobehavioral changes were studied in each group. The water maze test was used for evaluating the learning-memory ability when the rats were 28 days old. Compared with the sham-surgery group, all the HIBD model rats had a lag of motor development. The rats had evident changes in anatomy and Nissl staining, and cognitive impairment was shown through the result of the water maze. Therefore, the model of HIBD in neonatal rats is feasible and provides a reliable model for subsequent studies. PMID:27073628

  18. Model for voluntary wine and alcohol consumption in rats.

    PubMed

    Arola, L; Roig, R; Cascón, E; Brunet, M J; Fornós, N; Sabaté, M; Raga, X; Batista, J; Salvadó, M J; Bladé, C

    1997-08-01

    It has been suggested that moderate consumption of ethanol and wine has a protective effect on human health. Animal models used to date for alcohol consumption can not mimic real situations in humans because the consumption is forced and/or excessive. The present study proposes to determine the effects of a voluntary and ad lib consumption model more similar to that of human behavior. Male Wistar rats had free access to either standard diet and water or the same diet plus red wine, sweet wine, or a solution equivalent to red wine (13.5% ethanol) or to sweet wine (20% ethanol + 130 g/L sucrose) for 30 days or 6 months. Daily wine consumption was 15.8 +/- 0.9 and 2.0 +/- 0.2 ml/day for sweet and red wines, respectively. The consumption of each of the alcoholic solutions was similar to that of the wine they were simulating. Drinking wine or ethanol did not affect food and water intakes or growth rate. Plasma metabolites were not substantially affected by consumption of wine or ethanol. Although moderate and high wine consumption did not change the activity of plasma marker enzymes of tissue damage, the consumption of the 2 alcoholic solutions caused a long-term increase in the activity of aspartate aminotransferase. It seems that wine consumption protects the organism from hepatic lesions induced by ethanol alone. PMID:9251979

  19. Modeling fibrosis using fibroblasts isolated from scarred rat vocal folds.

    PubMed

    Kishimoto, Yo; Kishimoto, Ayami Ohno; Ye, Shuyun; Kendziorski, Christina; Welham, Nathan V

    2016-07-01

    Following injury, pathologically activated vocal fold fibroblasts (VFFs) can engage in disordered extracellular matrix (ECM) remodeling, leading to VF fibrosis and impaired voice function. Given the importance of scar VFFs to phenotypically appropriate in vitro modeling of VF fibrosis, we pursued detailed characterization of scar VFFs obtained from surgically injured rat VF mucosae, compared with those obtained from experimentally naïve, age-matched tissue. Scar VFFs initially exhibited a myofibroblast phenotype characterized by increased proliferation, increased Col1a1 transcription and collagen, type I synthesis, increased Acta2 transcription and α-smooth muscle actin synthesis, and enhanced contractile function. These features were most distinct at passage 1 (P1); we observed a coalescence of the scar and naïve VFF phenotypes at later passages. An empirical Bayes statistical analysis of the P1 cell transcriptome identified 421 genes that were differentially expressed by scar, compared with naïve, VFFs. These genes were primarily associated with the wound response, ECM regulation, and cell proliferation. Follow-up comparison of P1 scar VFFs and their in vivo tissue source showed substantial transcriptomic differences. Finally, P1 scar VFFs responded to treatment with hepatocyte growth factor and transforming growth factor-β3, two biologics with reported therapeutic value. Despite the practical limitations inherent to working with early passage cells, this experimental model is easily implemented in any suitably equipped laboratory and has the potential to improve the applicability of preclinical VF fibrosis research. PMID:27111284

  20. Mathematical Model of Ammonia Handling in the Rat Renal Medulla

    PubMed Central

    Noiret, Lorette; Baigent, Stephen; Jalan, Rajiv; Thomas, S. Randall

    2015-01-01

    The kidney is one of the main organs that produces ammonia and release it into the circulation. Under normal conditions, between 30 and 50% of the ammonia produced in the kidney is excreted in the urine, the rest being absorbed into the systemic circulation via the renal vein. In acidosis and in some pathological conditions, the proportion of urinary excretion can increase to 70% of the ammonia produced in the kidney. Mechanisms regulating the balance between urinary excretion and renal vein release are not fully understood. We developed a mathematical model that reflects current thinking about renal ammonia handling in order to investigate the role of each tubular segment and identify some of the components which might control this balance. The model treats the movements of water, sodium chloride, urea, NH3 and NH4+, and non-reabsorbable solute in an idealized renal medulla of the rat at steady state. A parameter study was performed to identify the transport parameters and microenvironmental conditions that most affect the rate of urinary ammonia excretion. Our results suggest that urinary ammonia excretion is mainly determined by those parameters that affect ammonia recycling in the loops of Henle. In particular, our results suggest a critical role for interstitial pH in the outer medulla and for luminal pH along the inner medullary collecting ducts. PMID:26280830

  1. The rat: a laboratory model for studies of the diving response.

    PubMed

    Panneton, W Michael; Gan, Qi; Juric, Rajko

    2010-04-01

    Underwater submersion in mammals induces apnea, parasympathetically mediated bradycardia, and sympathetically mediated peripheral vasoconstriction. These effects are collectively termed the diving response, potentially the most powerful autonomic reflex known. Although these physiological responses are directed by neurons in the brain, study of neural control of the diving response has been hampered since 1) it is difficult to study the brains of animals while they are underwater, 2) feral marine mammals are usually large and have brains of variable size, and 3) there are but few references on the brains of naturally diving species. Similar responses are elicited in anesthetized rodents after stimulation of their nasal mucosa, but this nasopharyngeal reflex has not been compared directly with natural diving behavior in the rat. In the present study, we compared hemodynamic responses elicited in awake rats during volitional underwater submersion with those of rats swimming on the water's surface, rats involuntarily submerged, and rats either anesthetized or decerebrate and stimulated nasally with ammonia vapors. We show that the hemodynamic changes to voluntary diving in the rat are similar to those of naturally diving marine mammals. We also show that the responses of voluntary diving rats are 1) significantly different from those seen during swimming, 2) generally similar to those elicited in trained rats involuntarily "dunked" underwater, and 3) generally different from those seen from dunking naive rats underwater. Nasal stimulation of anesthetized rats differed most from the hemodynamic variables of rats trained to dive voluntarily. We propose that the rat trained to dive underwater is an excellent laboratory model to study neural control of the mammalian diving response, and also suggest that some investigations may be done with nasal stimulation of decerebrate preparations to decipher such control. PMID:20093670

  2. Assessment of pharmacokinetic interaction of spirulina with glitazone in a type 2 diabetes rat model.

    PubMed

    Gupta, Annu; Nair, Anroop; Kumria, Rachna; Al-Dhubiab, Bandar-E; Chattopadhyaya, Ipshita; Gupta, Sumeet

    2013-12-01

    The objective of the current study was to assess the possible pharmacokinetic interactions of spirulina with glitazones in an insulin resistance rat model. Wistar male albino rats were equally divided into five groups: insulin resistant rats+spirulina (500 mg/kg)+pioglitazone (10 mg/kg), insulin resistant rats+pioglitazone (10 mg/kg), insulin resistant rats+spirulina (500 mg/kg)+rosiglitazone (10 mg/kg), insulin resistant rats+rosiglitazone (10 mg/kg), and insulin resistant rats+spirulina (500 mg/kg). Described doses of pioglitazone, rosiglitazone, or spirulina were per orally administered and the plasma drug concentrations were determined. The pharmacokinetic parameters such as Tmax, Cmax, AUC(0-α), t1/2, and Kel were determined by plotting the drug concentration as a function of time. The data observed in this acute study indicated that there was no statistically significant difference in any of the pharmacokinetic parameters (Tmax, Cmax, AUC(0-α), t1/2, and Kel) of glitazones (pioglitazone, rosiglitazone) or spirulina, when they were coadministered. Given the promising results, this study concludes that the coadministration of spirulina does not influence the pharmacokinetics of glitazones in a type 2 diabetes rat model. Further chronic in vivo studies are recommended to assess the real time effect. PMID:24328701

  3. Degraded neural and behavioral processing of speech sounds in a rat model of Rett syndrome.

    PubMed

    Engineer, Crystal T; Rahebi, Kimiya C; Borland, Michael S; Buell, Elizabeth P; Centanni, Tracy M; Fink, Melyssa K; Im, Kwok W; Wilson, Linda G; Kilgard, Michael P

    2015-11-01

    Individuals with Rett syndrome have greatly impaired speech and language abilities. Auditory brainstem responses to sounds are normal, but cortical responses are highly abnormal. In this study, we used the novel rat Mecp2 knockout model of Rett syndrome to document the neural and behavioral processing of speech sounds. We hypothesized that both speech discrimination ability and the neural response to speech sounds would be impaired in Mecp2 rats. We expected that extensive speech training would improve speech discrimination ability and the cortical response to speech sounds. Our results reveal that speech responses across all four auditory cortex fields of Mecp2 rats were hyperexcitable, responded slower, and were less able to follow rapidly presented sounds. While Mecp2 rats could accurately perform consonant and vowel discrimination tasks in quiet, they were significantly impaired at speech sound discrimination in background noise. Extensive speech training improved discrimination ability. Training shifted cortical responses in both Mecp2 and control rats to favor the onset of speech sounds. While training increased the response to low frequency sounds in control rats, the opposite occurred in Mecp2 rats. Although neural coding and plasticity are abnormal in the rat model of Rett syndrome, extensive therapy appears to be effective. These findings may help to explain some aspects of communication deficits in Rett syndrome and suggest that extensive rehabilitation therapy might prove beneficial. PMID:26321676

  4. Pulmonary Transcriptional Response to Ozone in Healthy and Cardiovascular Compromised Rat Models

    EPA Science Inventory

    The genetic cardiovascular disease (CVD) and associated metabolic impairments can influence the lung injury from inhaled pollutants. We hypothesized that comparative assessment of global pulmonary expression profile of healthy and CVD-prone rat models will provide mechanistic ins...

  5. Development of a Physiologically Based Pharmacokinetic Model for Triadimefon and Triadimenol in Rats and Humans

    EPA Science Inventory

    A physiologically based pharmacokinetic (PBPK) model was developed for the conazole fungicide triadimefon and its primary metabolite, triadimenol. Rat tissue:blood partition coefficients and metabolic constants were measured in vitro for both compounds. Kinetic time course data...

  6. Structure-Activity Relationship Models for Rat Carcinogenesis and Assessing the Role Mutagens Play in Model Predictivity

    PubMed Central

    Carrasquer, C. Alex; Batey, Kaylind; Qamar, Shahid; Cunningham, Albert R.; Cunningham, Suzanne L.

    2016-01-01

    We previously demonstrated that fragment based cat-SAR carcinogenesis models consisting solely of mutagenic or non-mutagenic carcinogens varied greatly in terms of their predictive accuracy. This led us to investigate how well the rat cancer cat-SAR model predicted mutagens and non-mutagens in their learning set. Four rat cancer cat-SAR models were developed: Complete Rat, Transgender Rat, Male Rat, and Female Rat, with leave-one-out (LOO) validation concordance values of 69%, 74%, 67%, and 73%, respectively. The mutagenic carcinogens produced concordance values in the range of 69–76% as compared to only 47–53% for non-mutagenic carcinogens. As a surrogate for mutagenicity comparisons between single site and multiple site carcinogen SAR models was analyzed. The LOO concordance values for models consisting of 1-site, 2-site, and 4+-site carcinogens were 66%, 71%, and 79%, respectively. As expected, the proportion of mutagens to non-mutagens also increased, rising from 54% for 1-site to 80% for 4+-site carcinogens. This study demonstrates that mutagenic chemicals, in both SAR learning sets and test sets, are influential in assessing model accuracy. This suggests that SAR models for carcinogens may require a two-step process in which mutagenicity is first determined before carcinogenicity can be accurately predicted. PMID:24697549

  7. Pharmacokinetics of Maxing Shigan decoction in normal rats and RSV pneumonia model rats by HPLC-MS/MS.

    PubMed

    Jiang, Li; Gao, Meng; Qu, Fei; Li, Hui-lan; Yu, Lan-bin; Rao, Yi; Wang, Yue-sheng; Xu, Guo-liang

    2015-07-01

    To establish a LC-MS/MS method to determine the concentrations of liquiritin, glycyrrhizin, glycyrrhetinic acid, amygdalin, amygdalin prunasin, ephedrine, pseudoephedrine and methylephedrine of Maxing Shigan decoction in rat plasma, and study the differences on their pharmacokinetic process in normal rats and RSV pneumonia model rats. After normal rats and RSV pneumonia model rats were orally administered with Maxing Shigan decoction, the blood was collected from retinal vein plexus of different time points. Specifically, tetrahydropalmatine was taken as internal standard for determining ephedrine, while chloramphenicol was taken as internal standard for determining other components. After plasma samples were pre-treated as the above, the supernatant was dried with nitrogen blowing concentrator and then redissolved with methylalcohol. The chromatography was eluted with mobile phase consisted of acetonitrile and 0.1% formic acid solution in a gradient manner. ESI sources were adopted to scan ingredients in ephedra in a positive ion scanning mode and other ingredientsin a negative ion scanning mode. The multiple-reaction monitoring (MRM) method was developed the plasma concentration of each active component. The pharmacokinetic parameters of each group were calculated by using Win-Nonlin 4.1 software and put into the statistical analysis. The result showed the plasma concentration of the eight active ingredients, i.e., liquiritin, glycyrrhizin, glycyrrhetinic acid, amygdalin, amygdalin prunasin, ephedrine, pseudoephedrine and methylephedrine within the ranges of 1.04-1040, 1.04-1040, 0.89-445, 1.05-4200, 1.25-2490, 0.3-480, 0.3-480, 0.3-480 microg x L(-1), with a good linearity and satisfactory precision, recovery and stability in the above ingredients. After modeling, except for glycyrrhetinic acid whose pharmacokinetic parameters were lacked due to the data missing, all of the rest components showed significant higher Cmax, AUC(0-1) and lower clearance rate (CL

  8. Hcn1 Is a Tremorgenic Genetic Component in a Rat Model of Essential Tremor

    PubMed Central

    Ohno, Yukihiro; Shimizu, Saki; Tatara, Ayaka; Imaoku, Takuji; Ishii, Takahiro; Sasa, Masashi; Serikawa, Tadao; Kuramoto, Takashi

    2015-01-01

    Genetic factors are thought to play a major role in the etiology of essential tremor (ET); however, few genetic changes that induce ET have been identified to date. In the present study, to find genes responsible for the development of ET, we employed a rat model system consisting of a tremulous mutant strain, TRM/Kyo (TRM), and its substrain TRMR/Kyo (TRMR). The TRM rat is homozygous for the tremor (tm) mutation and shows spontaneous tremors resembling human ET. The TRMR rat also carries a homozygous tm mutation but shows no tremor, leading us to hypothesize that TRM rats carry one or more genes implicated in the development of ET in addition to the tm mutation. We used a positional cloning approach and found a missense mutation (c. 1061 C>T, p. A354V) in the hyperpolarization-activated cyclic nucleotide-gated 1 channel (Hcn1) gene. The A354V HCN1 failed to conduct hyperpolarization-activated currents in vitro, implicating it as a loss-of-function mutation. Blocking HCN1 channels with ZD7288 in vivo evoked kinetic tremors in nontremulous TRMR rats. We also found neuronal activation of the inferior olive (IO) in both ZD7288-treated TRMR and non-treated TRM rats and a reduced incidence of tremor in the IO-lesioned TRM rats, suggesting a critical role of the IO in tremorgenesis. A rat strain carrying the A354V mutation alone on a genetic background identical to that of the TRM rats showed no tremor. Together, these data indicate that body tremors emerge when the two mutant loci, tm and Hcn1A354V, are combined in a rat model of ET. In this model, HCN1 channels play an important role in the tremorgenesis of ET. We propose that oligogenic, most probably digenic, inheritance is responsible for the genetic heterogeneity of ET. PMID:25970616

  9. Transgenic rat model of childhood-onset dermatitis by overexpressing telomerase reverse transcriptase (TERT).

    PubMed

    Kaneko, Ryosuke; Sato, Atsuko; Hamada, Shun; Yagi, Takeshi; Ohsawa, Ichiro; Ohtsuki, Mamitaro; Kobayashi, Eiji; Hirabayashi, Masumi; Murakami, Takashi

    2016-08-01

    Childhood-onset dermatitis is one of the most common skin disorders in children. Although various mouse models that mirror aspects of dermatitis have become available, there is still a need for an animal model that develops dermatitis in childhood and is more suitable for performing tissue transplantation experiments. There is emerging evidence that peripheral blood T lymphocytes from patients with dermatitis have significantly increased telomerase activity. Here, we developed telomerase reverse transcriptase (TERT)-expressing transgenic (Tg) rats that spontaneously developed eczematous skin inflammation in childhood. Newborn TERT-Tg rats developed visible dermatitis in 56 % of cases, and the skin lesions microscopically showed spongiosis and acanthosis with infiltration of lymphocytes, eosinophils and mast cells. TERT-Tg rats with dermatitis exhibited increased CD4 (2.5-fold) and CD8 (fivefold) T cell numbers compared with dermatitis-free TERT-Tg rats. Stronger TERT activity was observed in the peripheral lymphocytes of dermatitis-positive TERT-Tg rats than those of dermatitis-free TERT-Tg rats. RT-PCR analysis revealed that IL-4 was markedly elevated in the spleen of dermatitis-positive TERT-Tg rats, and that interferon-gamma was increased in the dermatitis lesions. Moreover, skin grafting of TERT-Tg rats with dermatitis onto T cell-deficient nude rats demonstrated that the inflamed skin lesions could not be maintained. Taken together, the results suggest that TERT activation in T lymphocytes is one of the potential predisposing factors for dermatitis. Moreover, our results demonstrated that the TERT-Tg rats mirror aspects of human childhood-onset dermatitis and that these animals represent a potential animal model system for studying childhood-onset dermatitis. PMID:26885830

  10. Extended duration local anesthetic agent in a rat paw model.

    PubMed

    Ickowicz, D E; Golovanevski, L; Domb, A J; Weiniger, C F

    2014-07-01

    Encapsulated local anesthetics extend postoperative analgesic effect following site-directed nerve injection; potentially reducing postoperative complications. Our study aim was to investigate efficacy of our improved extended duration formulation - 15% bupivacaine in poly(DL-lactic acid co castor oil) 3:7 synthesized by ring opening polymerization. In vitro, around 70% of bupivacaine was released from the p(DLLA-CO) 3:7 after 10 days. A single injection of the optimal formulation of 15% bupivacaine-polymer or plain (0.5%) bupivacaine (control), was injected via a 22G needle beside the sciatic nerve of Sprague-Dawley rats under anesthesia; followed (in some animals) by a 1cm longitudinal incision through the skin and fascia of the paw area. Behavioral tests for sensory and motor block assessment were done using Hargreave's hot plate score, von Frey filaments and rearing count. The 15% bupivacaine formulation significantly prolonged sensory block duration up to at least 48 h. Following surgery, motor block was observed for 48 h following administration of bupivacaine-polymer formulation and rearing was reduced (returning to baseline after 48 h). No significant differences in mechanical nociceptive response were observed. The optimized bupivacaine-polymer formulation prolonged duration of local anesthesia effect in our animal model up to at least 48 h. PMID:24726301

  11. Expression of bone matrix proteins in urolithiasis model rats.

    PubMed

    Yasui, T; Fujita, K; Sasaki, S; Sato, M; Sugimoto, M; Hirota, S; Kitamura, Y; Nomura, S; Kohri, K

    1999-08-01

    Urinary calcium stones are a pathological substance, and they show similarities to physiological mineralization and other pathological mineralizations. The expression of messenger (m) RNAs of osteopontin (OPN), matrix Gla protein (MGP), osteonectin (ON) and osteocalcin (OC) in bones and teeth has been described. We previously identified OPN as an important stone matrix protein. In addition, the spontaneous calcification of arteries and cartilage in mice lacking MGP was recently reported, a finding which indicates that MGP has a function as an inhibitor of mineralization. Here, we examined the mRNA expressions of OPN, MGP, ON, and OC in the kidneys of stone-forming model rats administered an oxalate precursor, ethylene glycol (EG) for up to 28 days. The Northern blotting showed that the mRNA expressions of OPN and MGP were markedly increased with the administration of EG, but their expression patterns differed. The OPN mRNA expression reached the maximal level at day 7 after the initiation of the EG treatment and showed no significant difference after 14 and 28 days, whereas the MGP mRNA expression rose gradually to day 28. The in situ hybridization demonstrated that the cell type expressing OPN mRNA was different from that expressing MGP. We suggest that OPN acts on calcification and MGP acts on suppression. PMID:10460895

  12. Modeling CICR in rat ventricular myocytes: voltage clamp studies

    PubMed Central

    2010-01-01

    Background The past thirty-five years have seen an intense search for the molecular mechanisms underlying calcium-induced calcium-release (CICR) in cardiac myocytes, with voltage clamp (VC) studies being the leading tool employed. Several VC protocols including lowering of extracellular calcium to affect Ca2+ loading of the sarcoplasmic reticulum (SR), and administration of blockers caffeine and thapsigargin have been utilized to probe the phenomena surrounding SR Ca2+ release. Here, we develop a deterministic mathematical model of a rat ventricular myocyte under VC conditions, to better understand mechanisms underlying the response of an isolated cell to calcium perturbation. Motivation for the study was to pinpoint key control variables influencing CICR and examine the role of CICR in the context of a physiological control system regulating cytosolic Ca2+ concentration ([Ca2+]myo). Methods The cell model consists of an electrical-equivalent model for the cell membrane and a fluid-compartment model describing the flux of ionic species between the extracellular and several intracellular compartments (cell cytosol, SR and the dyadic coupling unit (DCU), in which resides the mechanistic basis of CICR). The DCU is described as a controller-actuator mechanism, internally stabilized by negative feedback control of the unit's two diametrically-opposed Ca2+ channels (trigger-channel and release-channel). It releases Ca2+ flux into the cyto-plasm and is in turn enclosed within a negative feedback loop involving the SERCA pump, regulating[Ca2+]myo. Results Our model reproduces measured VC data published by several laboratories, and generates graded Ca2+ release at high Ca2+ gain in a homeostatically-controlled environment where [Ca2+]myo is precisely regulated. We elucidate the importance of the DCU elements in this process, particularly the role of the ryanodine receptor in controlling SR Ca2+ release, its activation by trigger Ca2+, and its refractory characteristics

  13. Candida albicans Airway Colonization Facilitates Subsequent Acinetobacter baumannii Pneumonia in a Rat Model.

    PubMed

    Tan, Xiaojiang; Chen, Ruilan; Zhu, Song; Wang, Huijun; Yan, Dongxing; Zhang, Xiangdong; Farmakiotis, Dimitrios; Mylonakis, Eleftherios

    2016-06-01

    The objective of the study was to determine the effects of Candida albicans respiratory tract colonization on Acinetobacter baumannii pneumonia in a rat model. Rats were colonized with C. albicans by instillation of 3 × 10(6) CFU into their airways, while sterile saline was instilled in the control group. The colonized rats were further divided into two groups: treated with amphotericin B or not. The rats were subsequently infected with A. baumannii (10(8) CFU by tracheobronchial instillation). A. baumannii lung CFU counts, cytokine lung levels, and rates of A. baumannii pneumonia were compared between groups. In vitro expression of A. baumannii virulence genes was measured by reverse transcription (RT)-PCR after 24-hour incubation with C. albicans or with Mueller-Hinton (MH) broth alone. Rats with Candida colonization developed A. baumannii pneumonia more frequently and had higher A. baumannii CFU burdens and heavier lungs than controls. After A. baumannii infection, lung interleukin 17 (IL-17) concentrations were lower and gamma interferon (IFN-γ) concentrations were higher in Candida-colonized rats than in controls. Candida-colonized rats treated with amphotericin B had a decreased rate of A. baumannii pneumonia and lower IFN-γ levels but higher IL-17 levels than untreated rats. Expression of basC, barB, bauA, ptk, plc2, and pld2 was induced while expression of ompA and abaI was suppressed in A. baumannii cultured in the presence of C. albicans C. albicans colonization facilitated the development of A. baumannii pneumonia in a rat model. Among Candida-colonized rats, antifungal treatment lowered the incidence of A. baumannii pneumonia. These findings could be due to modification of the host immune response and/or expression of A. baumannii virulence genes by Candida spp. PMID:27001817

  14. A Model of Best Vitelliform Macular Dystrophy in Rats

    PubMed Central

    Marmorstein, Alan D.; Stanton, J. Brett; Yocom, John; Bakall, Benjamin; Schiavone, Marc T.; Wadelius, Claes; Marmorstein, Lihua Y.; Peachey, Neal S.

    2010-01-01

    PURPOSE The VMD2 gene, mutated in Best macular dystrophy (BMD) encodes bestrophin, a 68-kDa basolateral plasma membrane protein expressed in retinal pigment epithelial (RPE) cells. BMD is characterized by a depressed light peak (LP) in the electro-oculogram. Bestrophin is thought to be the Cl channel that generates the LP. The goal was to generate an animal model of BMD and to determine the effects of bestrophin overexpression on the RPE-generated components of the ERG. METHODS Bestrophin or bestrophin mutants (W93C or R218C) were overexpressed in the RPE of rats by injection of replication-defective adenovirus. Immunofluorescence microscopy and ERG recordings were used to study subsequent effects. RESULTS Bestrophin was confined to the basolateral plasma membrane of the RPE. Neither wild-type (wt) nor mutant bestrophin affected the a- or b-waves of the ERG. Wt bestrophin, however, increased the c-wave and fast oscillation (FO), but not the LP. In contrast, both mutants had little or no effect on the c-wave and FO, but did reduce LP amplitude. LP amplitudes across a range of stimuli were not altered by wt bestrophin, though the luminance response function was desensitized. LP response functions were unaffected by bestrophin R218C but were significantly altered by bestrophin W93C. CONCLUSIONS A model of BMD was developed in the present study. Because overexpression of wt bestrophin shifted luminance response but did not alter the range of LP response amplitudes, the authors conclude that the rate-limiting step for generating LP amplitude occurs before activation of bestrophin or that bestrophin does not directly generate the LP conductance. PMID:15452084

  15. Physiologically based Pharmacokinetic Modeling of 1,4-Dioxane in Rats, Mice, and Humans

    SciTech Connect

    Sweeney, Lisa M.; Thrall, Karla D.; Poet, Torka S.; Corley, Rick; Weber, Thomas J.; Locey, B. J.; Clarkson, Jacquelyn; Sager, S.; Gargas, M. L.

    2008-01-01

    ABSTRACT 1,4-Dioxane (CAS No. 123-91-1) is used primarily as a solvent or as a solvent stabilizer. It can cause lung, liver and kidney damage at sufficiently high exposure levels. Two physiologically-based pharmacokinetic (PBPK) models of 1,4-dioxane and its major metabolite, hydroxyethoxyacetic acid (HEAA), were published in 1990. These models have uncertainties and deficiencies that could be addressed and the model strengthened for use in a contemporary cancer risk assessment for 1,4-dioxane. Studies were performed to fill data gaps and reduce uncertainties pertaining to the pharmacokinetics of 1,4-dioxane and HEAA in rats, mice, and humans. Three types of studies were performed:partition coefficient measurements, blood time course in mice, and in vitro pharmacokinetics using rat, mouse, and human hepatocytes. Updated PBPK models were developed based on these new data and previously available data. The optimized rate of metabolism for the mouse was significantly higher than the value previously estimated. The optimized rat kinetic parameters were similar to those in the 1990 models. Only two human studies were identified. Model predictions were consistent with one study, but did not fit the second as well. In addition, a rat nasal exposure was completed. The results confirmed water directly contacts rat nasal tissues during drinking water under bioassays. Consistent with previous PBPK models, nasal tissues were not specifically included in the model. Use of these models will reduce the uncertainty in future 1,4-dioxane risk assessments.

  16. Eldecalcitol prevents endothelial dysfunction in postmenopausal osteoporosis model rats.

    PubMed

    Serizawa, Kenichi; Yogo, Kenji; Tashiro, Yoshihito; Takeda, Satoshi; Kawasaki, Ryohei; Aizawa, Ken; Endo, Koichi

    2016-02-01

    Postmenopausal women have high incidence of cardiovascular events as estrogen deficiency can cause endothelial dysfunction. Vitamin D is reported to be beneficial on endothelial function, but it remains controversial whether vitamin D is effective for endothelial dysfunction under the treatment for osteoporosis in postmenopausal women. The aim of this study was to evaluate the endothelial protective effect of eldecalcitol (ELD) in ovariectomized (OVX) rats. ELD (20  ng/kg) was orally administrated five times a week for 4 weeks from 1 day after surgery. After that, flow-mediated dilation (FMD) as an indicator of endothelial function was measured by high-resolution ultrasound in the femoral artery of living rats. ELD ameliorated the reduction of FMD in OVX rats. ELD inhibited the increase in NOX4, nitrotyrosine, and p65 and the decrease in dimer/monomer ratio of nitric oxide synthase in OVX rat femoral arteries. ELD also prevented the decrease in peroxisome proliferator-activated receptor gamma (PPARγ) in femoral arteries and cultured endothelial cells. Although PPARγ is known to inhibit osteoblastogenesis, ELD understandably increased bone mineral density of OVX rats without increase in PPARγ in bone marrow. These results suggest that ELD prevented the deterioration of endothelial function under condition of preventing bone loss in OVX rats. This endothelial protective effect of ELD might be exerted through improvement of endothelial nitric oxide synthase uncoupling, which is mediated by an antioxidative effect through normalization of vascular PPARγ/NF-κB signaling. PMID:26537128

  17. Autoimmunity in type 1 diabetes mellitus: a rat model

    SciTech Connect

    Liu, Z.

    1987-01-01

    In this study, we have sought to isolate in vitro, from acutely diabetic BB rats, cytotoxic T lymphocytes, which exhibit specific cytotoxicity toward islet cells. Thoracic duct lymphocytes (TDL) from acutely diabetic BB rats cultured with irradiated MHC matched (RT1.u) islet cells and dendritic cells in vitro were shown to be specifically cytotoxic to MHC matched and mismatched allogeneic (RT1.1) and xenogeneic (hamster) islet target cells in a /sup 3/H-leucine release assay. Two cell lines (V1A8 and V1D11) derived from the TDL culture showed similar patterns of non-MHC restricted islet cell killing which could be blocked by islet cells and cultured rat insulinoma cells (RIN5mF) but not by non-islet cells of various tissue origins. Both V1A8 and V1D11 were not cytotoxic to Natural Killer (NK) sensitive target cells, G1TC and YAC-1. Conventional surface markers for rat helper and suppressor/cytotoxic T cells were not detectable on either cell lines. The V1D11 cell line was positive for W 3/13 (rat T/NK marker) on OX-19 (rat T/macrophage marker), whereas the V1A8 cell line was only positive for W 3/13.

  18. The response of Dahl salt-sensitive and salt-resistant female rats to a space flight model

    NASA Technical Reports Server (NTRS)

    Thierry-Palmer, Myrtle; Cephas, Stacy; Cleek, Tammy; Sayavongsa, Phouyong; Arnaud, Sara B.

    2003-01-01

    Vitamin D metabolism in the Dahl salt-sensitive (S) rat, a model of salt-induced hypertension, differs from that in the Dahl salt-resistant (R) rat. We have tested the hypothesis that differences in vitamin D metabolism would render the Dahl S rat more susceptible than the Dahl R rat to the effects of a space flight model. Dahl female rats were tail suspended (hind limb unloaded) for 28 days, while fed a low salt (3 g/kg sodium chloride) diet. Plasma 25-OHD concentrations of S rats were significantly lower than that of R rats. Plasma 1,25-(OH)2D concentration was 50% lower in unloaded than in loaded S rats, but was unaffected in unloaded R rats. The left soleus muscle weight and breaking strength of the left femur (torsion test) were 50% and 25% lower in unloaded than in loaded S and R rats. The mineral content of the left femur, however, was significantly lower (by 11%) only in unloaded S rats. We conclude that female S rats are more vulnerable than female R rats to decreases in plasma 1,25-(OH)2D concentration and femur mineral content during hind limb unloading, but equally vulnerable to muscle atrophy and reduced breaking strength of the femur.

  19. Voluntary Alcohol Intake following Blast Exposure in a Rat Model of Mild Traumatic Brain Injury

    PubMed Central

    Lim, Yi Wei; Meyer, Nathan P.; Shah, Alok S.; Budde, Matthew D.; Stemper, Brian D.; Olsen, Christopher M.

    2015-01-01

    Alcoholism is a frequent comorbidity following mild traumatic brain injury (mTBI), even in patients without a previous history of alcohol dependence. Despite this correlational relationship, the extent to which the neurological effects of mTBI contribute to the development of alcoholism is unknown. In this study, we used a rodent blast exposure model to investigate the relationship between mTBI and voluntary alcohol drinking in alcohol naïve rats. We have previously demonstrated in Sprague Dawley rats that blast exposure leads to microstructural abnormalities in the medial prefrontal cortex (mPFC) and other brain regions that progress from four to thirty days. The mPFC is a brain region implicated in alcoholism and drug addiction, although the impact of mTBI on drug reward and addiction using controlled models remains largely unexplored. Alcohol naïve Sprague Dawley rats were subjected to a blast model of mTBI (or sham conditions) and then tested in several common measures of voluntary alcohol intake. In a seven-week intermittent two-bottle choice alcohol drinking test, sham and blast exposed rats had comparable levels of alcohol intake. In a short access test session at the conclusion of the two-bottle test, blast rats fell into a bimodal distribution, and among high intake rats, blast treated animals had significantly elevated intake compared to shams. We found no effect of blast when rats were tested for an alcohol deprivation effect or compulsive drinking in a quinine adulteration test. Throughout the experiment, alcohol drinking was modest in both groups, consistent with other studies using Sprague Dawley rats. In conclusion, blast exposure had a minimal impact on overall alcohol intake in Sprague Dawley rats, although intake was increased in a subpopulation of blast animals in a short access session following intermittent access exposure. PMID:25910266

  20. [Metabolic therapy of nephrolithiasis in two different rat models of kidney disease].

    PubMed

    Trashkov, A P; Vasiliev, A G; Kovalenko, A L; Tagirov, N S

    2015-01-01

    108 albino male rats were used in two experimental rat models reproducing urolithiasis for the assessment of metabolic drug medicine Remaxol nephroprotective effect upon the development of this disease. "Ethyleneglycol" model consisted of adding 1% ethylene glycol solution in drinking water for 37 days and "fructose-induced" one--of adding 10% fructose solution in drinking water for the same period. Therapy included a 10-day course of daily i.v. injections of Remaxol (14 ml/kg). Both experimental models were successful in producing urolithiasis with considerable disturbances in the structure and functioning of kidneys up to revealing microconcrement formation. The "ethyleneglycol" model proved to cause maximum changes while the "Fructose-induced" model--only moderate ones. Metabolic correction of these changes was successful in nephroprotection effectively normalizing kidney functions and the total protein concentration, eliminating hyperglycemia and reducing creatinine and urea blood plasma concentration in both rat experimental models. PMID:26036006

  1. Streptozotocin induced diabetes as a model of phrenic nerve neuropathy in rats.

    PubMed

    Rodrigues Filho, Omar Andrade; Fazan, Valéria Paula Sassoli

    2006-03-15

    Phrenic neuropathies are increasingly recognized in peripheral neuropathies but reports on experimental models of the phrenic nerves diabetic neuropathy are scanty. In the present study, we investigated the phrenic nerve neuropathy, due to experimental diabetes induced by streptozotocin (STZ) and the evolution of this neuropathy in diabetic rats treated with insulin. Proximal and distal segments of the left and right phrenic nerves were morphologically and morphometrically evaluated, from rats rendered diabetic for 12 weeks, by injection of STZ. Control rats received vehicle. Treated rats received a single subcutaneous injection of insulin on a daily basis. The nerves were prepared for light microcopy study by means of conventional techniques. Morphometry was carried out with the aid of computer software. The phrenic nerves of diabetic rats showed smaller myelinated axon diameters compared to controls. The g ratio was significantly smaller for myelinated fibers from diabetic rats compared to controls. Insulin treatment prevented these alterations. Histograms of size distribution for myelinated fibers and axons from control rats were bimodal. For diabetic animals, the myelinated fiber histogram was bimodal while the axon distribution turned to be unimodal. Insulin treatment also prevented these alterations. Our results confirm the phrenic nerve neuropathy in this experimental model of diabetes and suggest that conventional insulin treatment was able to prevent and/or correct the myelinated axon commitment by diabetes. PMID:16125783

  2. In vitro modeling of rat mucosal mast cell function in Trichinella spiralis infection

    PubMed Central

    Thrasher, Seana M.; Scalfone, Lisa K.; Holowka, David; Appleton, Judith A.

    2012-01-01

    Summary Intestinal infection with the parasitic nematode, Trichinella spiralis, provides a robust context for the study of mucosal mast cell function. In rats, mucosal mast cells are exposed to parasites during the earliest stage of infection, affording an opportunity for mast cells to contribute to an innate response to infection. During secondary infection, degranulation of rat mucosal mast cells coincides with expulsion of challenge larvae from the intestine. The goal of this study was to evaluate rat bone marrow-derived mast cells (BMMC) and the rat basophilic leukemia cell line (RBL-2H3) as models for mucosal mast cells, using parasite glycoproteins and antibody reagents that have been tested extensively in rats in vivo. We found that BMMC displayed a more robust mucosal phenotype. Although T. spiralis glycoproteins bound to mast cell surfaces in the absence of antibodies, they did not stimulate degranulation, nor did they inhibit degranulation triggered by immune complexes. Parasite glycoproteins complexed with specific monoclonal IgGs provoked release of RMCPII and β-hexosaminidase from both cell types in a manner that replicated results observed previously in passively immunized rats. Our results document that RBL-2H3 cells and BMMC model rat mucosal mast cells in the contexts of innate and adaptive responses to T. spiralis. PMID:23094823

  3. A novel model of bisphosphonate-related osteonecrosis of the jaw in rats

    PubMed Central

    Yang, Huawei; Pan, Hui; Yu, Fang; Chen, Kai; Shang, Guangwei; Xu, Yuanzhi

    2015-01-01

    Objective: To establish a rat model of bisphosphonate-related osteonecrosis of the jaw (BRONJ) that realistically mimics major clinical manifestations of the disease. Methods: Female Sprague Dawley rats received intravenous zoledronate 80 μg/kg once a week via the tail vein. Three weeks after intravenous injection, maxillary first molars were extracted under general anesthesia. Then 1, 4 and 12 weeks after tooth extraction, the rats were euthanized, and the intact maxillas were harvested en bloc. Macroscopic analysis, histological analysis and cytokine analysis were performed. Untreated rats with tooth extraction were used as controls. Results: 12 weeks after extraction, rats treated with zoledronate developed BRONJ-like disease, including characteristic features of impaired soft tissue healing, exposed necrotic bone or sequestra, increased inflammatory infiltrates, while the controls showed normal bone healing. 4 weeks after extraction, rats treated with zoledronate exhibited the decreased receptor activator of nuclear factor kappa-B ligand (RANKL) values, the increased osteoprotegerin (OPG) values and the remarkable decreased RANKL/OPG ratio when compared with the controls. Conclusion: The rats treated with zoledronate can be considered a novel, reliable and reproducible animal model to better understand the pathophysiology and pathogenesis of BRONJ and to develop a therapeutic approach. PMID:26191212

  4. In vivo micro-CT analysis of bone remodeling in a rat calvarial defect model

    NASA Astrophysics Data System (ADS)

    Umoh, Joseph U.; Sampaio, Arthur V.; Welch, Ian; Pitelka, Vasek; Goldberg, Harvey A.; Underhill, T. Michael; Holdsworth, David W.

    2009-04-01

    The rodent calvarial defect model is commonly used to investigate bone regeneration and wound healing. This study presents a micro-computed tomography (micro-CT) methodology for measuring the bone mineral content (BMC) in a rat calvarial defect and validates it by estimating its precision error. Two defect models were implemented. A single 6 mm diameter defect was created in 20 rats, which were imaged in vivo for longitudinal experiments. Three 5 mm diameter defects were created in three additional rats, which were repeatedly imaged ex vivo to determine precision. Four control rats and four rats treated with bone morphogenetic protein were imaged at 3, 6, 9 and 12 weeks post-surgery. Scan parameters were 80 kVp, 0.45 mA and 180 mAs. Images were reconstructed with an isotropic resolution of 45 µm. At 6 weeks, the BMC in control animals (4.37 ± 0.66 mg) was significantly lower (p < 0.05) than that in treated rats (11.29 ± 1.01 mg). Linear regression between the BMC and bone fractional area, from 20 rats, showed a strong correlation (r2 = 0.70, p < 0.0001), indicating that the BMC can be used, in place of previous destructive analysis techniques, to characterize bone growth. The high precision (2.5%) of the micro-CT methodology indicates its utility in detecting small BMC changes in animals.

  5. A model of chronic heart failure in spontaneous hypertensive rats (SHR).

    PubMed

    Itter, G; Jung, W; Juretschke, P; Schoelkens, B A; Linz, W

    2004-04-01

    Common models of chronic heart failure (CHF) do not always result in parameters and symptoms that can be extrapolated to the clinical situation of patients with end-stage heart failure. The aim of this study was to establish and validate a new model of CHF in the rat. CHF was induced in Wistar Kyoto (WKY/NHsd) and spontaneously hypertensive (SHR/NHsd) rats by creating a permanent (8-week) occlusion of the left coronary artery 2 mm distal to the origin from the aorta by a modified technique. This resulted in a large infarction of the free left ventricular wall. The focus of attention was the validation of the geometric properties of the left ventricle and its contractility. The validation of the geometric properties of the left ventricle was done by a non-invasive magnetic resonance imaging (MRI) technique and by planimetry (stereology). Cardiodynamics (e.g. contractility) were evaluated in the isolated 'working heart' model. We were able to establish a new and predictive model of heart failure in the spontaneously hypertensive rat 8 weeks after coronary artery ligation. At this time point, the WKY rat did not show any symptoms of CHF. The model represents characteristic parameters and symptoms that can be extrapolated to the clinical situation of patients with end-stage heart failure (NYHA III-IV). Upon inspection, severe clinical symptoms of congestive heart failure were prominent, such as dyspnoea, subcutaneous oedema, pale-bluish limbs and impaired motion. Non-invasive sequential measurements by NMR techniques showed lung oedema, hydrothorax, large dilated left and right ventricular chambers and hypertrophy of the septum. The infarcted animals showed a reduced heart power, diminished contractility and enhanced heart work, much more so in the SHR/NHsd rat than in the WKY/NHsd rat. Furthermore the infarcted animals showed enhanced levels of hydroxyproline/proline ratios, again much more so in the SHR/NHsd rat than in the WKY/NHsd rat. PMID:15070453

  6. An acute model for IgA-mediated glomerular inflammation in rats induced by monoclonal polymeric rat IgA antibodies.

    PubMed Central

    Stad, R K; Bruijn, J A; van Gijlswijk-Janssen, D J; van Es, L A; Daha, M R

    1993-01-01

    An acute model for IgA-mediated glomerular inflammation in rats was induced by the in situ deposition of IgA directly into the glomerular mesangium. F(ab')2 anti-Thy1 MoAb was used to anchor an antigen, DNP (2,4-dinitrophenol), in the glomeruli of rats. Subsequent infusion of rat polymeric (p-) or monomeric (m-) IgA MoAb with specificity for DNP resulted in mesangial deposition of IgA in both groups of rats. However, acute proteinuria was observed only in p-IgA-treated rats and not in PBS- or m-IgA-treated rats. Immunofluorescence analysis revealed deposition of C3 in an identical pattern to that of IgA in the glomeruli of p-IgA-treated rats. No mesangial deposits of C4 or C1q were seen in these animals. Rats receiving m-IgA or PBS displayed no detectable C3, C4 or C1q deposition. The amount of proteinuria in p-IgA-treated rats was related to the amount of deposited C3. The presence of intraglomerular monocytes was only observed 2 days after p-IgA injection. By light microscopy, aneurysm formation, mesangial hypercellularity and matrix expansion were seen only in p-IgA-treated rats. However, by 37 days post-injection complete resolution of the lesions was observed. No histological renal changes were observed in PBS- or m-IgA-treated rats. In conclusion, an acute form of IgA-mediated nephritis in rats was induced by p-IgA but not by m-IgA. This reproducible model provides a basis for further study into the mechanisms of IgA-mediated glomerular inflammation. Images Fig. 3 PMID:8099859

  7. Anti-inflammatory activity of methyl palmitate and ethyl palmitate in different experimental rat models

    SciTech Connect

    Saeed, Noha M.; El-Demerdash, Ebtehal; Abdel-Rahman, Hanaa M.; Algandaby, Mardi M.; Al-Abbasi, Fahad A.; Abdel-Naim, Ashraf B.

    2012-10-01

    Methyl palmitate (MP) and ethyl palmitate (EP) are naturally occurring fatty acid esters reported as inflammatory cell inhibitors. In the current study, the potential anti-inflammatory activity of MP and EP was evaluated in different experimental rat models. Results showed that MP and EP caused reduction of carrageenan-induced rat paw edema in addition to diminishing prostaglandin E2 (PGE2) level in the inflammatory exudates. In lipopolysaccharide (LPS)-induced endotoxemia in rats, MP and EP reduced plasma levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). MP and EP decreased NF-κB expression in liver and lung tissues and ameliorated histopathological changes caused by LPS. Topical application of MP and EP reduced ear edema induced by croton oil in rats. In the same animal model, MP and EP reduced neutrophil infiltration, as indicated by decreased myeloperoxidase (MPO) activity. In conclusion, this study demonstrates the effectiveness of MP and EP in combating inflammation in several experimental models. -- Highlights: ► Efficacy of MP and EP in combating inflammation was displayed in several models. ► MP and EP reduced carrageenan-induced rat paw edema and prostaglandin E2 level. ► MP and EP decreased TNF-α and IL-6 levels in experimental endotoxemia. ► MP and EP reduced NF-κB expression and histological changes in rat liver and lung. ► MP and EP reduced croton oil-induced ear edema and neutrophil infiltration.

  8. Fractal analysis of alveolarization in hyperoxia-induced rat models of bronchopulmonary dysplasia.

    PubMed

    Porzionato, Andrea; Guidolin, Diego; Macchi, Veronica; Sarasin, Gloria; Grisafi, Davide; Tortorella, Cinzia; Dedja, Arben; Zaramella, Patrizia; De Caro, Raffaele

    2016-04-01

    No papers are available about potentiality of fractal analysis in quantitative assessment of alveolarization in bronchopulmonary dysplasia (BPD). Thus, we here performed a comparative analysis between fractal [fractal dimension (D) and lacunarity] and stereological [mean linear intercept (Lm), total volume of alveolar air spaces, total number of alveoli, mean alveolar volume, total volume and surface area of alveolar septa, and mean alveolar septal thickness] parameters in experimental hyperoxia-induced models of BPD. At birth, rats were distributed between the following groups: 1) rats raised in ambient air for 2 wk; 2) rats exposed to 60% oxygen for 2 wk; 3) rats raised in normoxia for 6 wk; and 4) rats exposed to 60% hyperoxia for 2 wk and to room air for further 4 wk. Normoxic 6-wk rats showed increased D and decreased lacunarity with respect to normoxic 2-wk rats, together with changes in all stereological parameters except for mean alveolar volume. Hyperoxia-exposed 2-wk rats showed significant changes only in total number of alveoli, mean alveolar volume, and lacunarity with respect to equal-in-age normoxic rats. In the comparison between 6-wk rats, the hyperoxia-exposed group showed decreased D and increased lacunarity, together with changes in all stereological parameters except for septal thickness. Analysis of receiver operating characteristic curves showed a comparable discriminatory power of D, lacunarity, and total number of alveoli; Lm and mean alveolar volume were less discriminative. D and lacunarity did not show significant changes when different segmentation thresholds were applied, suggesting that the fractal approach may be fit to automatic image analysis. PMID:26851258

  9. Protective Effect of Dihydromyricetin Against Lipopolysaccharide-Induced Acute Kidney Injury in a Rat Model

    PubMed Central

    Wang, Jun-Tao; Jiao, Peng; Zhou, Yun; Liu, Qian

    2016-01-01

    Background The present study investigated the effect of dihydromyricetin (DHM) on lipopolysaccharide (LPS)-induced acute kidney injury in a rat model. Material/Methods Kidney injury was induced in male Sprague-Dawley rats by injection of LPS through the tail vein. The rats were treated with 5 μg/kg body weight DHM within 12 h of the LPS administration. The urine of the rats was collected over a period of 48 h for determination of calcium and creatinine concentrations. Blood urea nitrogen in the serum was analyzed using a BC-2800 Vet Animal Auto Biochemistry Analyzer. On day 3 after treatment, the rats were sacrificed to extract the kidneys. Results Treatment of the endotoxemia rats with DHM caused a significant (P<0.05) decrease in the level of kidney injury molecule-1 and blood urea nitrogen. DHM treatment significantly (P<0.05) decreased the level of calcium in the kidney tissues compared to those of the untreated endotoxemia rats. The level of malonaldehyde (MDA) in the kidney tissues was significantly reduced in the endotoxemia rats by DHM treatment. The results from immunohistochemistry reveled a significant decrease in the expression of osteopontin (OPN) and CD44 levels. The endotoxemia rats showed significantly higher levels of TUNEL-positive stained nuclei compared to the normal controls. However, treatment of the endotoxemia rats with DHM resulted in a significant decrease in the population of TUNEL-positive cells. Conclusions DHM may be a promising candidate for the treatment of acute kidney injury. PMID:26866356

  10. A PHYSIOLOGICALLY BASED KINETIC MODEL OF RAT AND MOUSE GESTATION: DISPOSITION OF A WEAK ACID

    EPA Science Inventory

    A physiologically based toxicokinetic model of gestation in the rat mouse has been developed. The model is superimposed on the normal growth curve for nonpregnant females. It describes the entire gestation period including organogenesis. The model consists of uterus, mammary tiss...

  11. Deep brain stimulation exacerbates hypokinetic dysarthria in a rat model of Parkinson's disease.

    PubMed

    King, Nathaniel O; Anderson, Collin J; Dorval, Alan D

    2016-02-01

    Motor symptoms of Parkinson's disease (PD) follow the degeneration of dopaminergic neurons in the substantia nigra pars compacta. Deep brain stimulation (DBS) treats some parkinsonian symptoms, such as tremor, rigidity, and bradykinesia, but may worsen certain medial motor symptoms, including hypokinetic dysarthria. The mechanisms by which DBS exacerbates dysarthria while improving other symptoms are unclear and difficult to study in human patients. This study proposes an animal model of DBS-exacerbated dysarthria. We use the unilateral, 6-hydroxydopamine (6-OHDA) rat model of PD to test the hypothesis that DBS exacerbates quantifiable aspects of vocalization. Mating calls were recorded from sexually experienced male rats under healthy and parkinsonian conditions and during DBS of the subthalamic nucleus. Relative to healthy rats, parkinsonian animals made fewer calls with shorter and less complex vocalizations. In the parkinsonian rats, putatively therapeutic DBS further reduced call frequency, duration, and complexity. The individual utterances of parkinsonian rats spanned a greater bandwidth than those of healthy rats, potentially reducing the effectiveness of the vocal signal. This utterance bandwidth was further increased by DBS. We propose that the parkinsonism-associated changes in call frequency, duration, complexity, and dynamic range combine to constitute a rat analog of parkinsonian dysarthria. Because DBS exacerbates the parkinsonism-associated changes in each of these metrics, the subthalamic stimulated 6-OHDA rat is a good model of DBS-induced hypokinetic dysarthria in PD. This model will help researchers examine how DBS alleviates many motor symptoms of PD while exacerbating parkinsonian speech deficits that can greatly diminish patient quality of life. PMID:26498277

  12. Impaired function of the intestinal barrier in a novel sub-health rat model

    PubMed Central

    FENG, SISI; LIU, WEIDONG; ZUO, SHENGNAN; XIE, TINGYAN; DENG, HUI; ZHANG, QIUHUAN; ZHONG, BAIYUN

    2016-01-01

    Sub-health is a state featuring a deterioration in physiological function between health and illness, and the sub-health condition has surfaced as life-threatening in humans. The aim of the present study was to establish a sub-health model in rats, and investigate the function of the intestinal barrier in the sub-health rats and rats following intervention. To establish a sub-health model, the rats were subjected to a high-fat and sugar diet, motion restriction and chronic stress. Their serum glucose and triglyceride levels, immune function and adaptability were then measured. The levels of diamine oxidase and D-lactic acid in the plasma were analyzed as markers of the intestinal permeability. The protein and mRNA expression levels of anti-apoptotic YWHAZ in the colonic tissue was detected using immunohistochemical and reverse transcription-quantitative polymerase chain reaction analyses In the present study, the sub-health rat model was successfully established, and sub-health factors increased the intestinal permeability and reduced the expression of YWHAZ. Providing sub-health rats with normal living conditions did not improve the function of the intestinal barrier. In conclusion, the results of the present study demonstrated that intestinal disorders in the sub-health rat model may result from the damage caused by reduce intestinal barrier function as well as the decreased expression levels of YWHAZ. Additionally, rats in the sub-health condition did not recover following subsequent exposure to normal living conditions, suggesting that certain exercises or medical intervention may be necessary to improve sub-health symptoms. PMID:26957295

  13. β-D-Glucan Assay in Diagnosis and Monitoring the Systemic Candidiasis in a Rat Model

    PubMed Central

    Khodadadi, Hossein; Mirhendi, Hossein; Makimura, Koichi; Satoh, Kazuo; Karimi, Ladan; Izadi, Shahrokh

    2014-01-01

    Background: Determination of β-D-Glucan (BDG) in the serum aids to diagnose the invasive fungal infections. The current study evaluated the diagnostic potential value of BDG assay in monitoring the disease in experimental systemic candidiasis in a rat model. The results can provide a useful preliminary data to improve this approach in developing countries. Objectives: The present study aimed to evaluate β-D-Glucan assay in diagnosis and monitoring the systemic candidiasis in a rat model. Materials and Methods: Twenty one rats were infected with 106 Candida albicans blastospore per rat. Twelve rats were considered as the negative controls (six immunocompromised rats without infection and six intact rats). During a week, every 24 hours the BDG sera level was determined by both Fungitell and Wako kits. To confirm the systemic infection in each rat, the suspensions of their internal organs were cultivated on agar plates and the number of colony forming units (CFU) of C. albicans was counted. Results: All the infected rats were positive with BDG tests. An increasing level of BDG was observed during early days after injection. The cutoff value for discrimination of BDG positive sera was obtained from the negative sera by the Fungitell kit. The sensitivity, specificity, positive and negative predictive values assessed for the Fungitell kit were 95%, 66.6%, 90.47% and 80%, respectively. These criteria for those of Wako were 90%, 83.3%, 94.7% and 71.4%, respectively. Conclusions: While BDG assay seems to be a sensitive and specific adjunctive tool to diagnose and monitor the experimental systemic candidiasis, it seems that measuring the positive cutoff value in different laboratory conditions is necessary for favorable establishment of these tests. PMID:25371794

  14. Effect of Ozone on Intestinal Epithelial Homeostasis in a Rat Model

    PubMed Central

    Sukhotnik, Igor; Starikov, Alona; Coran, Arnold G.; Pollak, Yulia; Sohotnik, Rima; Shaoul, Ron

    2015-01-01

    Background: The positive effects of ozone therapy have been described in many gastrointestinal disorders. The mechanisms of this positive effect of ozone therapy are poorly understood. The purpose of the present study was to investigate whether the use of ozone may potentiate the gut intestinal mucosal homeostasis in a rat model. Methods: Adult rats weighing 250–280 g were randomly assigned to one of three experimental groups of 8 rats each: 1) Control rats were given 2 mL of water by gavage and intraperitoneally (IP) for 5 days; 2) O3-PO rats were treated with 2 mL of ozone/oxygen mixture by gavage and 2 mL of water IP for 5 days; 3) O3-IP rats were treated with 2 mL of water by gavage and 2 mL of ozone/oxygen mixture IP for 5 days. Rats were sacrificed on day 6. Bowel and mucosal weight, mucosal DNA and protein, villus height and crypt depth, and cell proliferation and apoptosis were evaluated following sacrifice. Results: The group of O3-IP rats demonstrated a greater jejunal and ileal villus height and crypt depth, a greater enterocyte proliferation index in jejunum, and lower enterocyte apoptosis in ileum compared to control animals. Oral administration of the ozone/oxygen mixture resulted in a less significant effect on cell turnover. Conclusions: Treatment with an ozone/oxygen mixture stimulates intestinal cell turnover in a rat model. Intraperitoneal administration of ozone resulted in a more significant intestinal trophic effect than oral administration. PMID:25717388

  15. Phenotypic characterization of recessive gene knockout rat models of Parkinson's disease.

    PubMed

    Dave, Kuldip D; De Silva, Shehan; Sheth, Niketa P; Ramboz, Sylvie; Beck, Melissa J; Quang, Changyu; Switzer, Robert C; Ahmad, Syed O; Sunkin, Susan M; Walker, Dan; Cui, Xiaoxia; Fisher, Daniel A; McCoy, Aaron M; Gamber, Kevin; Ding, Xiaodong; Goldberg, Matthew S; Benkovic, Stanley A; Haupt, Meredith; Baptista, Marco A S; Fiske, Brian K; Sherer, Todd B; Frasier, Mark A

    2014-10-01

    Recessively inherited loss-of-function mutations in the PTEN-induced putative kinase 1(Pink1), DJ-1 (Park7) and Parkin (Park2) genes are linked to familial cases of early-onset Parkinson's disease (PD). As part of its strategy to provide more tools for the research community, The Michael J. Fox Foundation for Parkinson's Research (MJFF) funded the generation of novel rat models with targeted disruption ofPink1, DJ-1 or Parkin genes and determined if the loss of these proteins would result in a progressive PD-like phenotype. Pathological, neurochemical and behavioral outcome measures were collected at 4, 6 and 8months of age in homozygous KO rats and compared to wild-type (WT) rats. Both Pink1 and DJ-1 KO rats showed progressive nigral neurodegeneration with about 50% dopaminergic cell loss observed at 8 months of age. ThePink1 KO and DJ-1 KO rats also showed a two to three fold increase in striatal dopamine and serotonin content at 8 months of age. Both Pink1 KO and DJ-1 KO rats exhibited significant motor deficits starting at 4months of age. However, Parkin KO rats displayed normal behaviors with no neurochemical or pathological changes. These results demonstrate that inactivation of the Pink1 or DJ-1 genes in the rat produces progressive neurodegeneration and early behavioral deficits, suggesting that these recessive genes may be essential for the survival of dopaminergic neurons in the substantia nigra (SN). These MJFF-generated novel rat models will assist the research community to elucidate the mechanisms by which these recessive genes produce PD pathology and potentially aid in therapeutic development. PMID:24969022

  16. Beneficial effects of melatonin in a rat model of sporadic Alzheimer's disease.

    PubMed

    Rudnitskaya, Ekaterina A; Maksimova, Kseniya Yi; Muraleva, Natalia A; Logvinov, Sergey V; Yanshole, Lyudmila V; Kolosova, Nataliya G; Stefanova, Natalia A

    2015-06-01

    Melatonin synthesis is disordered in patients with Alzheimer's disease (AD). To determine the role of melatonin in the pathogenesis of AD, suitable animal models are needed. The OXYS rats are an experimental model of accelerated senescence that has also been proposed as a spontaneous rat model of AD-like pathology. In the present study, we demonstrate that disturbances in melatonin secretion occur in OXYS rats at 4 months of age. These disturbances occur simultaneously with manifestation of behavioral abnormalities against the background of neurodegeneration and alterations in hormonal status but before the signs of amyloid-β accumulation. We examined whether oral administration of melatonin could normalize the melatonin secretion and have beneficial effects on OXYS rats before progression to AD-like pathology. The results showed that melatonin treatment restored melatonin secretion in the pineal gland of OXYS rats as well as the serum levels of growth hormone and IGF-1, the level of BDNF in the hippocampus and the healthy state of hippocampal neurons. Additionally, melatonin treatment of OXYS rats prevented an increase in anxiety and the decline of locomotor activity, of exploratory activity, and of reference memory. Thus, melatonin may be involved in AD progression, whereas oral administration of melatonin could be a prophylactic strategy to prevent or slow down the progression of some features of AD pathology. PMID:25515660

  17. Characterization of Dystrophin Deficient Rats: A New Model for Duchenne Muscular Dystrophy

    PubMed Central

    Tesson, Laurent; Remy, Séverine; Thepenier, Virginie; François, Virginie; Le Guiner, Caroline; Goubin, Helicia; Dutilleul, Maéva; Guigand, Lydie; Toumaniantz, Gilles; De Cian, Anne; Boix, Charlotte; Renaud, Jean-Baptiste; Cherel, Yan; Giovannangeli, Carine; Concordet, Jean-Paul; Anegon, Ignacio; Huchet, Corinne

    2014-01-01

    A few animal models of Duchenne muscular dystrophy (DMD) are available, large ones such as pigs or dogs being expensive and difficult to handle. Mdx (X-linked muscular dystrophy) mice only partially mimic the human disease, with limited chronic muscular lesions and muscle weakness. Their small size also imposes limitations on analyses. A rat model could represent a useful alternative since rats are small animals but 10 times bigger than mice and could better reflect the lesions and functional abnormalities observed in DMD patients. Two lines of Dmd mutated-rats (Dmdmdx) were generated using TALENs targeting exon 23. Muscles of animals of both lines showed undetectable levels of dystrophin by western blot and less than 5% of dystrophin positive fibers by immunohistochemistry. At 3 months, limb and diaphragm muscles from Dmdmdx rats displayed severe necrosis and regeneration. At 7 months, these muscles also showed severe fibrosis and some adipose tissue infiltration. Dmdmdx rats showed significant reduction in muscle strength and a decrease in spontaneous motor activity. Furthermore, heart morphology was indicative of dilated cardiomyopathy associated histologically with necrotic and fibrotic changes. Echocardiography showed significant concentric remodeling and alteration of diastolic function. In conclusion, Dmdmdx rats represent a new faithful small animal model of DMD. PMID:25310701

  18. Effect of electroacupuncture on gastric interstitial cells of Cajal in a rat model of diabetic gastroparesis

    PubMed Central

    LIN, GUOHUA; ZHANG, JIAWEI; LI, LIXIA; ZOU, ZHUOCHENG; CHEN, CHUYUN; XUE, LIFEI; ZHAO, LANFENG

    2016-01-01

    The aim of the present study was to observe the effect of electroacupuncture (EA) on the gastric interstitial cells of Cajal (ICCs) in a rat model of diabetic gastroparesis (DGP). The gastric tissues were collected from 75 rats, which had been divided into three equal groups (n=25/group): Blank, model and EA. Hematoxylin and eosin and immunohistochemical staining were used to observe the cellular morphology and distribution of c-kit-positive gastric ICCs; light microscopy was used to count the number of ICCs; and electron microscopy was used to observe the ultrastructure of the rat ICCs. Compared with the model group, the gastromucosal glandular and smooth muscle cells of the EA group were more regularly arranged, with fewer vacuoles; there was an increased cellular gap and the vacuolar degeneration on the gastric walls was mild. Image analysis showed that the blank group exhibited the greatest number of c-kit-positive ICCs, and the number of c-kit-positive ICCs in the blank group was significantly different from that in the model and EA groups (P<0.01): Blank group > EA group > model group. In conclusion, DGP rats exhibited a reduced number of gastric ICCs, altered ultrastructural morphology and a reduced number of cell organelles, particularly mitochondria, compared with the blank group. EA may help to reverse the various pathological changes of gastric ICCs in rat models of DGP. PMID:27284337

  19. Allogeneic/xenogeneic transplantation of peptide-labeled mitochondria in Parkinson's disease: restoration of mitochondria functions and attenuation of 6-hydroxydopamine-induced neurotoxicity.

    PubMed

    Chang, Jui-Chih; Wu, Shey-Lin; Liu, Ko-Hung; Chen, Ya-Hui; Chuang, Chieh-Sen; Cheng, Fu-Chou; Su, Hong-Lin; Wei, Yau-Huei; Kuo, Shou-Jen; Liu, Chin-San

    2016-04-01

    Although restoration of mitochondrial function in mitochondrial diseases through peptide-mediated allogeneic mitochondrial delivery (PMD) has been demonstrated in vitro, the in vivo therapeutic efficacy of PMD in Parkinson's disease (PD) has yet to be determined. In this study, we compared the functionality of mitochondrial transfer with or without Pep-1 conjugation in neurotoxin (6-hydroxydopamine, 6-OHDA)-induced PC12 cells and PD rat models. We injected mitochondria into the medial forebrain bundle (MFB) of the PD rats after subjecting the nigrostriatal pathway to a unilateral 6-OHDA lesion for 21 days, and we verified the effectiveness of the mitochondrial graft in enhancing mitochondrial function in the soma of the substantia nigra (SN) neuron through mitochondrial transport dynamics in the nigrostriatal circuit. The result demonstrated that only PMD with allogeneic and xenogeneic sources significantly sustained mitochondrial function to resist the neurotoxin-induced oxidative stress and apoptotic death in the rat PC12 cells. The remaining cells exhibited a greater capability of neurite outgrowth. Furthermore, allogeneic and xenogeneic transplantation of peptide-labeled mitochondria after 3 months improved the locomotive activity in the PD rats. This increase was accompanied by a marked decrease in dopaminergic neuron loss in the substantia nigra pars compacta (SNc) and consistent enhancement of tyrosine hydroxylase-positive immunoreaction of dopaminergic neurons in the SNc and striatum. We also observed that in the SN dopaminergic neuron in the treated PD rats, mitochondrial complex I protein and mitochondrial dynamics were restored, thus ameliorating the oxidative DNA damage. Moreover, we determined signal translocation of graft allogeneic mitochondria from the MFB to the calbindin-positive SN neuron, which demonstrated the regulatory role of mitochondrial transport in alleviating 6-OHDA-induced degeneration of dopaminergic neurons. PMID:26730494

  20. Calcium Balance in Mature Rats Exposed to a Space Flight Model

    NASA Technical Reports Server (NTRS)

    Wolinsky, Ira

    1996-01-01

    Negative calcium balances are seen in humans during spaceflight and bed rest, an analog of space flight. Due to the infrequency and costliness of space flight and the difficulties, cost, and restraints in using invasive procedures in bed rest studies, several ground based animal models of space flight have been employed. The most useful and well developed of these models is hind limb unloading in the rat. In this model the hind limbs are non-weight bearing (unloaded) but still mobile; there is a cephalad fluid shift similar to that seen in astronauts in flight; the animals are able to feed, groom and locomote using their front limbs; the procedure is reversible; and, importantly, the model has been validated by comparison to space flight. Several laboratories have studied calcium balance using rats in hind limb unweighting. Roer and Dillaman used young male rats to study calcium balance in this model for 25 days. They found no differences in dietary calcium intake, percent calcium absorption, urinary and fecal excretion, hence indicating no differences in calcium balance between control and unloaded rats. In another study, employing 120 day old females, rats' hind limbs were unloaded for 28 days. While negative calcium balances were observed during a 25 day recovery period no balance measurements were possible during unweighting since the researchers did not employ appropriate metabolic cages. In a recent study from this laboratory, using 200 g rats in the space flight model for two weeks, we found depressed intestinal calcium absorption and increased fecal calcium excretion (indicating less positive calcium balances) and lower circulating 1,25-dihydroxyvitamin D. The above studies indicate that there remains a dearth of information on calcium balance during the hind limb unloading rat space flight model, especially in mature rats, whose use is a better model for planned manned space flight than juvenile or growing animals. With the aid of a newly designed

  1. Metabolic Cage for a Space Flight Model in the Rat

    NASA Technical Reports Server (NTRS)

    Harper, Jennifer S.; Mulenburg, Gerald M.; Evans, Juli; Navidi, Meena; Wolinsky, Ira; Arnaud, Sara B.

    1994-01-01

    The new cage facilitates the collection of 24-h specimens of separated urine and feces apparently uncontaminated by food, as required for precise nutritional and metabolic studies, while maintaining the large floor area and suspension method of Holton's design (3). Although the cage was evaluated, using 6-month-old rats weighing 408 to 488 g, it can be easily adjusted for smaller rats. It also was successfully used to collect post-flight urine after the recent Spacelab Life Sciences-2 space shuttle flight. With its flexibility and ease of use, this new cage design adds a new tool to study the physiologic effects of simulated space flight and other disuse conditions.

  2. Effect of Bile Acid on Fetal Lung in Rat Model of Intrahepatic Cholestasis of Pregnancy

    PubMed Central

    Yu, Ling; Ding, Yiling; Huang, Ting; Huang, Xiaoxia

    2014-01-01

    Objective. To determine the correlation between maternal bile acid (BA) level and fetal pulmonary surfactant in rats and study the effects of BA on fetal lung in rat model of intrahepatic cholestasis of pregnancy. Methods. Forty pregnant rats were treated with (A) 5.5 mg/kg BA, (B) 1.4 mg/kg BA, and (C) 1 ml physiological saline. Levels of total bile acid (TBA), ALT, AST, TBIL, DBIL, and SP-A were determined and the lungs of fetal rats were analyzed for pathological changes. Results. Groups A and B intervened with BA showed significant higher level of TBA in both maternal and fetal serum, more mortality rate of fetal rats, more concentration of SP-A in fetal serum, and wider alveolus mesenchyme of fetal rats than the control Group C. Higher level of BA associated with increased fetal risk and lower numerical density of mitochondria in type II alveolar epithelial cells. The levels of TBA in maternal serum were found to have significant positive correlation with those in fetal serum and SP-A level but negatively with the area of alveolus and the numerical density of lamellar body. Conclusions. The TBA level in maternal serum showed significant association with lung pathological changes in fetal rats. PMID:24778648

  3. Sensitization of the Hypothalamic-Pituitary-Adrenal Axis in a Male Rat Chronic Stress Model.

    PubMed

    Franco, Alier J; Chen, Chun; Scullen, Tyler; Zsombok, Andrea; Salahudeen, Ahmed A; Di, Shi; Herman, James P; Tasker, Jeffrey G

    2016-06-01

    Stress activation of the hypothalamic-pituitary-adrenal (HPA) axis is regulated by rapid glucocorticoid negative feedback. Chronic unpredictable stress animal models recapitulate certain aspects of major depression in humans, which have been attributed to impaired glucocorticoid negative feedback. We tested for an attenuated HPA sensitivity to fast glucocorticoid feedback inhibition in male rats exposed to a chronic variable stress (CVS) paradigm. In vitro, parvocellular neuroendocrine cells of the hypothalamic paraventricular nucleus recorded in slices from CVS rats showed an increase in basal excitatory synaptic inputs and a decrease in basal inhibitory synaptic inputs compared with neurons from control rats. There was no difference between control and CVS-treated rats in the rapid glucocorticoid suppression of excitatory synaptic inputs, a fast feedback mechanism. In vivo, CVS-treated rats showed an increase in ACTH secretion at baseline and after both iv CRH and acute stress and no impairment of the corticosterone suppression of the ACTH response, compared with controls. In an in vitro pituitary preparation, an increase in basal ACTH release, a small increase in CRH-induced ACTH release, and no decrement in the glucocorticoid suppression of ACTH release were seen in pituitaries from CVS rats. Thus, CVS does not suppress rapid glucocorticoid negative feedback at the hypothalamus or pituitary, but increases the synaptic excitability of paraventricular nucleus CRH neurons and the CRH sensitivity of the pituitary. Therefore, increased HPA activity in chronically stressed male rats is due to sensitization of the HPA axis, rather than to desensitization to rapid glucocorticoid feedback. PMID:27054552

  4. The Effects of Methylphenidate on Goal-directed Behavior in a Rat Model of ADHD

    PubMed Central

    Natsheh, Joman Y.; Shiflett, Michael W.

    2015-01-01

    Although attentional and motor alterations in Attention Deficit Hyperactivity Disorder (ADHD) have been well characterized, less is known about how this disorder impacts goal-directed behavior. To investigate whether there is a misbalance between goal-directed and habitual behaviors in an animal model of ADHD, we tested adult [P75–P105] Spontaneously Hypertensive Rats (SHR; ADHD rat model) and Wistar–Kyoto rats (WKY), the normotensive control strain, on an instrumental conditioning paradigm with two phases: a free-operant training phase in which rats separately acquired two distinct action–outcome contingencies, and a choice test conducted in extinction prior to which one of the food outcomes was devalued through specific satiety. To assess the effects of Methylphenidate (MPH), a commonly used ADHD medication, on goal-directed behavior, we injected rats with either MPH or saline prior to the choice test. Both rat strains acquired an instrumental response, with SHR responding at greater rates over the course of training. During the choice test WKY demonstrated goal-directed behavior, responding more frequently on the lever that delivered, during training, the still-valued outcome. In contrast, SHR showed no goal-directed behavior, responding equally on both levers. However, MPH administration prior to the choice test restored goal-directed behavior in SHR, and disrupted this behavior in WKY rats. This study provides the first experimental evidence for selective impairment in goal-directed behavior in rat models of ADHD, and how MPH acts differently on SHR and WKY animals to restore or impair this behavior, respectively. PMID:26635568

  5. The Effects of Methylphenidate on Goal-directed Behavior in a Rat Model of ADHD.

    PubMed

    Natsheh, Joman Y; Shiflett, Michael W

    2015-01-01

    Although attentional and motor alterations in Attention Deficit Hyperactivity Disorder (ADHD) have been well characterized, less is known about how this disorder impacts goal-directed behavior. To investigate whether there is a misbalance between goal-directed and habitual behaviors in an animal model of ADHD, we tested adult [P75-P105] Spontaneously Hypertensive Rats (SHR; ADHD rat model) and Wistar-Kyoto rats (WKY), the normotensive control strain, on an instrumental conditioning paradigm with two phases: a free-operant training phase in which rats separately acquired two distinct action-outcome contingencies, and a choice test conducted in extinction prior to which one of the food outcomes was devalued through specific satiety. To assess the effects of Methylphenidate (MPH), a commonly used ADHD medication, on goal-directed behavior, we injected rats with either MPH or saline prior to the choice test. Both rat strains acquired an instrumental response, with SHR responding at greater rates over the course of training. During the choice test WKY demonstrated goal-directed behavior, responding more frequently on the lever that delivered, during training, the still-valued outcome. In contrast, SHR showed no goal-directed behavior, responding equally on both levers. However, MPH administration prior to the choice test restored goal-directed behavior in SHR, and disrupted this behavior in WKY rats. This study provides the first experimental evidence for selective impairment in goal-directed behavior in rat models of ADHD, and how MPH acts differently on SHR and WKY animals to restore or impair this behavior, respectively. PMID:26635568

  6. Spaceflight and bone turnover - Correlation with a new rat model of weightlessness

    NASA Technical Reports Server (NTRS)

    Morey, E. R.

    1979-01-01

    Earlier manned spaceflight studies have revealed that the near-weightless environment of orbital flight produce certain biological effects in humans, including abnormalities in mineral metabolism. The data collected were compatible with bone mineral loss. Cosmos 782 and 936 experiments have shown a decrease in rat bone formation rate. In this paper, a rat model of weightlessness is described, which is unique in that the animal is free to move about a 360-deg arc. The model meets the requirements for an acceptable system. Data from the model and spaceflight are presented. Many of the responses noted in suspended animals indicate that the model closely mimics results from rats and man exposed to near-weightlessness during orbital spaceflight.

  7. Behavioral outcome measures used for human neural stem cell transplantation in rat stroke models

    PubMed Central

    Jensen, Matthew B.; Han, Dong Y.; Sawaf, Abdullah Al; Krishnaney-Davison, Rajeev

    2011-01-01

    Stroke is a leading cause of death and disability, leading to the development of various stroke models to test new treatments, most commonly in the rat. Human stroke trials focus on disability, related primarily to neurological deficits. To better model the clinical application of these treatments, many behavioral tests have been developed using the rat stroke model. We performed a systematic review of all the behavioral outcome measures used in published studies of human neural stem cell transplantation in rat stroke models. The reviewed tests include motor, sensory, cognitive, activity, and combination tests. For each test, we give a brief description, trace the origin of the test, and discuss test performance in the reviewed studies. We conclude that while many behavioral tests are available for this purpose, there does not appear to be consensus on an optimal testing strategy. PMID:22053257

  8. Herbal compound Naoshuantong capsule attenuates retinal injury in ischemia/reperfusion rat model by inhibiting apoptosis

    PubMed Central

    Huang, Chuangxin; Gao, Yang; Yu, Qiang; Feng, Liangqi

    2015-01-01

    Objectives: Ischemic ophthalmopathy threatens people’s lives and health. The herbal compound medication, Naoshuantong capsule, plays a critical role in the treatment of cardiac-cerebral vascular diseases; however, the roles and mechanisms of action of Naoshuantong capsule in ischemic ophthalmopathy is unknown. The objective of the present study was to determine the effect and mechanism of action of Naoshuantong capsule on ischemic ophthalmopathy in rats. Methods: In this study a rat model of ischemic ophthalmopathy was constructed using a high intra-ocular pressure-induced ischemia/reperfusion model. The effects of Naoshuantong capsule on ischemic ophthalmopathy were detected using electroretinography, and changes in retinal ultrastructure were examined by HE staining and electron microscopy. The mechanism of action of Naoshuantong capsule on ischemic ophthalmopathy was explored by immunofluorescence and real-time PCR. Results: Rat models of ischemic ophthalmopathy were successfully constructed by intra-ocular hypertension, which presented decreased amplitudes of the electroretinogram (ERG-b) wave and total retinal thickness, intracellular damage, increased expression of Bax and caspase 3, and decreased expression of Bcl-2. Treatment with Naoshuantong capsule attenuated the changes and damage to the ischemic retina in the rat model, inhibited the over-expression of Bax and caspase 3, and increased the expression of Bcl-2. Conclusion: Our study indicated that Naoshuantong capsule attenuates retinal damage in rat models of ischemic ophthalmopathy, possibly by inhibiting apoptosis. PMID:26550135

  9. The Effects and Possible Mechanisms of Puerarin to Treat Endometriosis Model Rats

    PubMed Central

    Zhao, Li; Zhang, Danying; Zhai, Dongxia; Shen, Wei; Bai, Lingling; Liu, Yiqun; Cai, Zailong; Li, Ji; Yu, Chaoqin

    2015-01-01

    Objective. To explore the effects of puerarin to treat endometriosis (EMT) model rats and the possible regulatory mechanisms. Methods. EMT model rats were surgically induced by autotransplantion of endometrial tissues. The appropriate dosage of puerarin to treat EMT model rats was determined by observing the pathologic morphology of ectopic endometrial tissues and by detecting the levels of estradiol (E2) and prostaglandin E2 (PGE2) of both serum and ectopic endometrial tissues. The related genes and proteins of ectopic endometrial tissues were analyzed by Real-time PCR and immunohistochemistry (IHC) to explore the possible mechanisms. Results. Puerarin could reduce the levels of E2 and PGE2 and prevent the growth of ectopic endometrium tissues by inhibiting the expression of aromatase cytochrome P450 (p450arom) and cyclooxygenase-2 (cox-2); puerarin could adjust the anabolism of E2 by upregulating the expression of 17β-hydroxysteroid-2 (17β-hsd-2) and downregulating the expression of 17β-hydroxysteroid-1 (17β-hsd-1) of the ectopic endometrium tissues; puerarin could increase the expression of ERβ and improve the inflammatory microenvironment of EMT model rats. Conclusions. Our data suggest that puerarin has a therapeutic effect on EMT model rats and could be a potential therapeutic agent for the treatment of EMT in clinic. PMID:25815028

  10. Metabolic brain activity suggestive of persistent pain in a rat model of neuropathic pain

    PubMed Central

    Thompson, Scott J; Millecamps, Magali; Aliaga, Antonio; Seminowicz, David A; Low, Lucie A; Bedell, Barry J; Stone, Laura S; Schweinhardt, Petra; Bushnell, M Catherine

    2014-01-01

    Persistent pain is a central characteristic of neuropathic pain conditions in humans. Knowing whether rodent models of neuropathic pain produce persistent pain is therefore crucial to their translational applicability. We investigated the Spared Nerve Injury (SNI) model of neuropathic pain and the formalin pain model in rats using Positron Emission Tomography (PET) with the metabolic tracer [18F]fluorodeoxyglucose (FDG) to determine if there is ongoing brain activity suggestive of persistent pain. For the formalin model, under brief anesthesia we injected one hindpaw with 5% formalin and the FDG tracer into a tail vein. We then allowed the animals to awaken and observed pain behavior for 30 min during the FDG uptake period. The rat was then anesthetized and placed in the scanner for static image acquisition, which took place between minutes 45 and 75 post-tracer injection. A single reference rat brain magnetic resonance image (MRI) was used to align the PET images with the Paxinos and Watson rat brain atlas. Increased glucose metabolism was observed in the somatosensory region associated with the injection site (S1 hindlimb contralateral), S1 jaw/upper lip and cingulate cortex. Decreases were observed in the prelimbic cortex and hippocampus. Second, SNI rats were scanned 3 weeks post-surgery using the same scanning paradigm, and region-of-interest analyses revealed increased metabolic activity in the contralateral S1 hindlimb. Finally, a second cohort of SNI rats were scanned while anesthetized during the tracer uptake period, and the S1 hindlimb increase was not observed. Increased brain activity in the somatosensory cortex of SNI rats resembled the activity produced with the injection of formalin, suggesting that the SNI model may produce persistent pain. The lack of increased activity in S1 hindlimb with general anesthetic demonstrates that this effect can be blocked, as well as highlights the importance of investigating brain activity in awake and behaving

  11. Antipsychotic-like effect of minocycline in a rat model

    PubMed Central

    Dokuyucu, Recep; Kokacya, Hanifi; Inanir, Sema; Copoglu, Umit Sertan; Erbas, Oytun

    2014-01-01

    Objectives: Tetracycline antibiotic drug minocycline has strongly neuroprotective and anti-inflammatory effects. Minocycline has also remarkable brain tissue penetration, is clinically entirely tolerated and properly absorbed when taken orally. In our study, we class with the effects of minocycline and chlorpromazine, a conventional antipsychotic drug, by evaluating the novelty-induced rearing, apomorphine-induced stereotypic behavior, and brain MDA levels in rats. Materials and Methods: Four groups of rat (n = 7) were applied with minocycline (50 and 100 mg/kg, i.p.), chlorpromazine (1 mg/kg, i.p.), or isotonic saline (1 mL/kg, i.p.). One hour later, apomorphine (2 mg/kg, s.c.) was applied to each rat. Result: Our results showed that both doses of minocycline significantly decreased the rearing behavior in rats, whereas the decrease with chlorpromazine was higher. Minocycline also decreased the stereotypy scores in a dose-dependent manner. Conclusion: We concluded that minocycline has beneficial effects on rearing behavior and stereotypy, which are accepted to be indicators of antipsychotic effect. Taken together, minocycline, as an anti-oxidant and cytoprotective agent, can be useful in neuroprotection especially on early stages of psychosis or prepsychotic patients with insignificant symptoms. Minocycline is worthy of being investigated for its anti-psychotic effects as a primary or an adjunctive drug. PMID:25419368

  12. Effect of Angiotensin(1-7) on Heart Function in an Experimental Rat Model of Obesity

    PubMed Central

    Blanke, Katja; Schlegel, Franziska; Raasch, Walter; Bader, Michael; Dähnert, Ingo; Dhein, Stefan; Salameh, Aida

    2015-01-01

    Aim: Obesity is a risk factor for the development of cardiovascular diseases. Recently it was shown that overexpression of the Mas-receptor antagonist angiotensin(1-7) could prevent from diet-induced obesity. However, it remained unclear whether diet-induced obesity and angiotensin(1-7) overexpression might also have effects on the cardiovascular system in these rats. Methods:Twenty three male Sprague Dawley rats were fed with standard chow (SD+chow, n = 5) or a cafeteria diet (SD+CD, n = 6) for 5 months. To investigate the effect of angiotensin(1-7) transgenic rats, expressing an angiotensin(1-7)-producing fusion protein in testis were used. These transgenic rats also received a 5 month's feeding period with either chow (TGR+chow, n = 6) or cafeteria diet (TGR+CD, n = 6), respectively. Hemodynamic measurements (pressure-volume loops) were carried out to assess cardiac function and blood pressure. Subsequently, hearts were explanted and investigated according to the Langendorff technique. Furthermore, cardiac remodeling in these animals was investigated histologically. Results:After 5 months cafeteria diet feeding rats showed a significantly increased body weight, which could be prevented in transgenic rats. However, there was no effect on cardiac performance after cafeteria diet in non-transgenic and transgenic rats. Moreover, overexpression of angiotensin(1-7) deteriorated cardiac contractility as indicated by impaired dp/dt. Furthermore, histological analysis revealed that cafeteria diet led to myocardial fibrosis in both, control and transgenic rats and this was not inhibited by an overproduction of angiotensin(1-7). Conclusion:These results indicate that an overexpression of circulating angiotensin(1-7) prevents a cafeteria diet-induced increase in body weight, but does not affect cardiac performance in this experimental rat model of obesity. Furthermore, overexpression of angiotensin(1-7) alone resulted in an impairment of cardiac function. PMID:26733884

  13. Rat molar teeth as a study model for direct pulp capping research in dentistry.

    PubMed

    Dammaschke, Till

    2010-01-01

    The aim of this review is to evaluate the suitability of rat molar teeth in preclinical evaluation of medical devices for direct pulp capping. The ISO standard 7405 states clearly that only non-rodent mammals are suitable species for animal research in dentistry. Furthermore, without clear justification a considerable number of researchers previously rejected results of animal experiments concerning preclinical evaluation of the biocompatibility of dental materials undertaken in rat molar teeth. However, in the past 50 years about 70 studies have been published using rat molar teeth in order to evaluate direct pulp capping, pulpotomies and tissue reactions after pulp exposure. Numerous studies showed that the healing of rat molar pulp tissue after direct pulp capping is histologically comparable with humans and other animal species pulp tissue. Rat molar teeth, including pulp tissue, can be seen anatomically, histologically, biologically, and physiologically as miniature human molar teeth. Hence, the essential biological reactions of the pulp tissue and the interaction during the different stages of wound healing of rat molar teeth are comparable with that of other mammals. Rat molar teeth are a valid study model in order to provide valuable data concerning pulp tissue reaction after direct pulp capping and related questions in dentistry. Therefore, the use of rats may significantly reduce the number of currently used higher animals in research. Tests in higher developed animals should be limited to experiments which clarify inconsistent results. However, some technical difficulties, like the small size of rat molar teeth must be dealt with before undertaking any research. PMID:19854755

  14. Erectile response to topical, intraurethral and intracorporal pharmacotherapy in a rat model of spinal cord injury.

    PubMed

    Rivas, D A; Chancellor, M B; Huang, B; Salzman, S K

    1995-10-01

    In order to compare the erectile response to topical, intraurethral and intracorporal administration of vasoactive substances in neurologically intact and spinal cord injured (SCI) rats, a standard rat model of SCI using impact trauma at the level of T10 was employed, comparing the tumescence of 24 SCI and 25 control rats. Four weeks after SCI, the effect of vasoactive substances on erectile function was evaluated. Under ketamine anesthesia, the penis was exposed and intracorporal pressure (ICP) was monitored using saline infusion cavernosometry through a 24-gauge catheter inserted into one corpus cavernosum. Changes in ICP were recorded in response to the topical and intraurethral (IU) application of minoxidil (0.1 ml, 2% solution) and 2% nitroglycerin (NTG) ointment (0.1 gm), as well as the intracorporal (IC) administration of papaverine (0.0001-0.10 mg/kg). Results indicated that the mean baseline ICP was 8 +/- 5 mmHg for SCI and 9 +/- 4 mmHg for control rats. No response to topical therapy onto the undegloved penis was noted in either SCI or control rats. IU application of minoxidil to the degloved phallus developed ICP greater than that achieved with topical minoxidil; the topical application of NTG was less effective. In SCI rats, IC papaverine injection achieved an ICP of 56.9 +/- 24.3 mmHg, whereas papaverine in control rats generated an ICP of 43.5 +/- 38.8 mmHg. A greater increase in ICP at lower doses of each agent occurred in SCI than in control rats. We conclude that only the degloved phallus responded to topical vasoactive pharmacotherapy. Although both topical and IU applications of NTG and minoxidil increase ICP, tumescence was significantly less than that achieved with IC injection of papaverine. The IU application of minoxidil demonstrated significantly greater activity than other topical therapies. SCI rats displayed a supersensitive response to all modes of pharmacologic erectile therapy. PMID:8591071

  15. Functional mitochondrial analysis in acute brain sections from adult rats reveals mitochondrial dysfunction in a rat model of migraine

    PubMed Central

    Fried, Nathan T.; Moffat, Cynthia; Seifert, Erin L.

    2014-01-01

    Mitochondrial dysfunction has been implicated in many neurological disorders that only develop or are much more severe in adults, yet no methodology exists that allows for medium-throughput functional mitochondrial analysis of brain sections from adult animals. We developed a technique for quantifying mitochondrial respiration in acutely isolated adult rat brain sections with the Seahorse XF Analyzer. Evaluating a range of conditions made quantifying mitochondrial function from acutely derived adult brain sections from the cortex, cerebellum, and trigeminal nucleus caudalis possible. Optimization of this technique demonstrated that the ideal section size was 1 mm wide. We found that sectioning brains at physiological temperatures was necessary for consistent metabolic analysis of trigeminal nucleus caudalis sections. Oxygen consumption in these sections was highly coupled to ATP synthesis, had robust spare respiratory capacities, and had limited nonmitochondrial respiration, all indicative of healthy tissue. We demonstrate the effectiveness of this technique by identifying a decreased spare respiratory capacity in the trigeminal nucleus caudalis of a rat model of chronic migraine, a neurological disorder that has been associated with mitochondrial dysfunction. This technique allows for 24 acutely isolated sections from multiple brain regions of a single adult rat to be analyzed simultaneously with four sequential drug treatments, greatly advancing the ability to study mitochondrial physiology in adult neurological disorders. PMID:25252946

  16. Role of oxidative stress in surgical cavernous nerve injury in a rat model.

    PubMed

    Wang, Hui; Ding, Xie-Gang; Li, Shi-Wen; Zheng, Hang; Zheng, Xin-Min; Navin, Shrestha; Li, Lu; Wang, Xing-Huan

    2015-06-01

    This study investigates the role of oxidative stress in surgical cavernous nerve (CN) injury in a rat model. Eighty-four male Sprague-Dawley rats were randomly divided into three groups: group 1, sham-operated rats; group 2, bilateral CN-crushed rats; and group 3, bilateral CN-transection-and-sutured-immediately rats. Oxidative stress was evaluated by malondialdehyde levels, super oxide dismutase (SOD) activities, and glutathione peroxidase (GPX) activities in serum. Erectile function was assessed by CN electrostimulation at 3 months with mean maximal intracavernous pressure (ICP) and maximal ICP per mean arterial pressure. Nerve injury was assessed by toluidine blue staining of CNs and nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase staining of penile tissue. GPX protein expression and nitrotyrosine-3 (NT-3) levels in penile tissue were measured. Erectile function and the number of myelinated axons of CNs and NADPH-diaphorase-positive nerve fibers were statistically decreased between groups, from sham to crush to transection. For markers, both nerve-injury groups showed increased oxidative stress markers at early time points, with the transection group showing greater oxidative stress than the crushed group and values normalizing to sham levels by week 12. GPX expression and NT-3 levels in penile tissue were in concordance with the results of SOD and GPX. These results show that oxidative stress plays an important role in injured CNs, and different methods of CN injury can lead to different degrees of oxidative stress in a rat model. PMID:25597854

  17. Generation of muscular dystrophy model rats with a CRISPR/Cas system.

    PubMed

    Nakamura, Katsuyuki; Fujii, Wataru; Tsuboi, Masaya; Tanihata, Jun; Teramoto, Naomi; Takeuchi, Shiho; Naito, Kunihiko; Yamanouchi, Keitaro; Nishihara, Masugi

    2014-01-01

    Duchenne muscular dystrophy (DMD) is an X-linked lethal muscle disorder caused by mutations in the Dmd gene encoding Dystrophin. DMD model animals, such as mdx mice and canine X-linked muscular dystrophy dogs, have been widely utilized in the development of a treatment for DMD. Here, we demonstrate the generation of Dmd-mutated rats using a clustered interspaced short palindromic repeats (CRISPR)/Cas system, an RNA-based genome engineering technique that is also adaptive to rats. We simultaneously targeted two exons in the rat Dmd gene, which resulted in the absence of Dystrophin expression in the F0 generation. Dmd-mutated rats exhibited a decline in muscle strength, and the emergence of degenerative/regenerative phenotypes in the skeletal muscle, heart, and diaphragm. These mutations were heritable by the next generation, and F1 male rats exhibited similar phenotypes in their skeletal muscles. These model rats should prove to be useful for developing therapeutic methods to treat DMD. PMID:25005781

  18. A rat model of slow Wallerian degeneration (WldS) with improved preservation of neuromuscular synapses.

    PubMed

    Adalbert, Robert; Gillingwater, Thomas H; Haley, Jane E; Bridge, Katherine; Beirowski, Bogdan; Berek, Livia; Wagner, Diana; Grumme, Daniela; Thomson, Derek; Celik, Arzu; Addicks, Klaus; Ribchester, Richard R; Coleman, Michael P

    2005-01-01

    The slow Wallerian degeneration phenotype, Wld(S), which delays Wallerian degeneration and axon pathology for several weeks, has so far been studied only in mice. A rat model would have several advantages. First, rats model some human disorders better than mice. Second, the larger body size of rats facilitates more complex surgical manipulations. Third, rats provide a greater yield of tissue for primary culture and biochemical investigations. We generated transgenic Wld(S) rats expressing the Ube4b/Nmnat1 chimeric gene in the central and peripheral nervous system. As in Wld(S) mice, their axons survive up to 3 weeks after transection and remain functional for at least 1 week. Protection of axotomized nerve terminals is stronger than in mice, particularly in one line, where 95-100% of neuromuscular junctions remained intact and functional after 5 days. Furthermore, the loss of synaptic phenotype with age was much less in rats than in mice. Thus, the slow Wallerian degeneration phenotype can be transferred to another mammalian species and synapses may be more effectively preserved after axotomy in species with longer axons. PMID:15654865

  19. A rat model of saliva secretory immunoglobulin: a suppression caused by intense exercise.

    PubMed

    Kimura, F; Aizawa, K; Tanabe, K; Shimizu, K; Kon, M; Lee, H; Akimoto, T; Akama, T; Kono, I

    2008-06-01

    We aimed to develop a valid model of immunosuppression induced by intense exercise in rats. Rats were divided into three groups. In the rest (Rest) group, saliva was collected from resting rats on 4 consecutive days. In the exercise (Ex) group, rats ran on a treadmill until exhaustion (exercise time: 60.0 +/- 3.7 min), and their saliva was collected before and after exercise; the salivary glands were removed after exercise. In the control (Con) group, saliva collection and gland removal were also performed, but the rats did not exercise. Secretory immunoglobulin A (SIgA) concentrations in saliva and polymeric immunoglobulin receptor (pIgR) mRNA expression in the glands were measured. There was no significant change in SIgA concentration in the Rest group over 4 days. In the Ex group, SIgA concentration decreased significantly after exercise compared with before, whereas there was no significant change in the Con group. The expression of pIgR mRNA was significantly lower in the Ex group post-exercise than in the Con group. Our procedure for saliva collection appeared suitable, and the exercise-induced SIgA suppression was probably caused by a decline in pIgR mRNA expression. We propose to use this reproducible and reliable rat model of exercise-induced SIgA suppression in future studies. PMID:17555544

  20. Bone marrow mesenchymal stem cells combined with minocycline improve spinal cord injury in a rat model

    PubMed Central

    Chen, Dayong; Zeng, Wei; Fu, Yunfeng; Gao, Meng; Lv, Guohua

    2015-01-01

    The aims of this study were to assess that the effects of bone marrow mesenchymal stem cells (BMSCs) combination with minocycline improve spinal cord injury (SCI) in rat model. In the present study, the Wistar rats were randomly divided into five groups: control group, SCI group, BMSCs group, Minocycline group and BMSCs + minocycline group. Basso, Beattie and Bresnahan (BBB) test and MPO activity were used to assess the effect of combination therapy on locomotion and neutrophil infiltration. Inflammation factors, VEGF and BDNF expression, caspase-3 activation, phosphorylation-p38MAPK, proNGF, p75NTR and RhoA expressions were estimated using commercial kits or western blot, respectively. BBB scores were significantly increased and MPO activity was significantly undermined by combination therapy. In addition, combination therapy significantly decreased inflammation factors in SCI rats. Results from western blot showed that combination therapy significantly up-regulated the protein of VEGF and BDNF expression and down-regulated the protein of phosphorylation-p38MAPK, proNGF, p75NTR and RhoA expressions in SCI rats. Combination therapy stimulation also suppressed the caspase-3 activation in SCI rats. These results demonstrated that the effects of bone marrow mesenchymal stem cells combination with minocycline improve SCI in rat model. PMID:26722382

  1. Spontaneously hypertensive rats (SHR) as a putative animal model of childhood hyperkinesis: SHR behavior compared to four other rat strains.

    PubMed

    Sagvolden, T; Pettersen, M B; Larsen, M C

    1993-12-01

    Childhood hyperkinesis or attention-deficit hyperactivity disorder (ADHD) is a behavior disorder of which the main symptoms are attention problems and hyperactivity. The main objective of the present study was to investigate whether the spontaneously hypertensive rat (SHR) strain is a useful animal model of ADHD. Five different rat strains were tested: SHR, Wistar-Kyoto (WKY), Wistar, Sprague-Dawley (SPRD), and PVG (hooded) rats. The protocol consisted of three different test procedures: 1) A 7.5-min free-exploration open-field test (home cage accessible), where the SHR was less active than Wistar and SPRD but more active than WKY; SHR showed longer latencies to leave the home cage than both Wistar and SPRD rats, spending less time in the field, ambulating and rearing less than Wistar and SPRD but more than WKY. Within session, the SHR tended to be more active at the end of the session than at the start, while the opposite tended to be the case in the other groups. 2) A 7.5-min forced exploration open-field test (home cage not accessible), where the results showed that the SHR is less active than both the Wistar and Sprague-Dawley strains, but more active than PVG and WKY. 3) A two-component multiple schedule of reinforcement with a fixed interval 2 min signalled by houselight on and a 5-min extinction signalled by houselight off. Lever pressing by SHR was markedly different from that of the other four strains, which were quite Except early in the interval, SHR pressed the lever more than any of the other groups.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8295939

  2. Method of Isolated Ex Vivo Lung Perfusion in a Rat Model: Lessons Learned from Developing a Rat EVLP Program

    PubMed Central

    Nelson, Kevin; Bobba, Christopher; Eren, Emre; Spata, Tyler; Tadres, Malak; Hayes,, Don; Black, Sylvester M.

    2015-01-01

    The number of acceptable donor lungs available for lung transplantation is severely limited due to poor quality. Ex-Vivo Lung Perfusion (EVLP) has allowed lung transplantation in humans to become more readily available by enabling the ability to assess organs and expand the donor pool. As this technology expands and improves, the ability to potentially evaluate and improve the quality of substandard lungs prior to transplant is a critical need. In order to more rigorously evaluate these approaches, a reproducible animal model needs to be established that would allow for testing of improved techniques and management of the donated lungs as well as to the lung-transplant recipient. In addition, an EVLP animal model of associated pathologies, e.g., ventilation induced lung injury (VILI), would provide a novel method to evaluate treatments for these pathologies. Here, we describe the development of a rat EVLP lung program and refinements to this method that allow for a reproducible model for future expansion. We also describe the application of this EVLP system to model VILI in rat lungs. The goal is to provide the research community with key information and “pearls of wisdom”/techniques that arose from trial and error and are critical to establishing an EVLP system that is robust and reproducible. PMID:25741794

  3. Method of isolated ex vivo lung perfusion in a rat model: lessons learned from developing a rat EVLP program.

    PubMed

    Nelson, Kevin; Bobba, Christopher; Eren, Emre; Spata, Tyler; Tadres, Malak; Hayes, Don; Black, Sylvester M; Ghadiali, Samir; Whitson, Bryan A

    2015-01-01

    The number of acceptable donor lungs available for lung transplantation is severely limited due to poor quality. Ex-Vivo Lung Perfusion (EVLP) has allowed lung transplantation in humans to become more readily available by enabling the ability to assess organs and expand the donor pool. As this technology expands and improves, the ability to potentially evaluate and improve the quality of substandard lungs prior to transplant is a critical need. In order to more rigorously evaluate these approaches, a reproducible animal model needs to be established that would allow for testing of improved techniques and management of the donated lungs as well as to the lung-transplant recipient. In addition, an EVLP animal model of associated pathologies, e.g., ventilation induced lung injury (VILI), would provide a novel method to evaluate treatments for these pathologies. Here, we describe the development of a rat EVLP lung program and refinements to this method that allow for a reproducible model for future expansion. We also describe the application of this EVLP system to model VILI in rat lungs. The goal is to provide the research community with key information and "pearls of wisdom"/techniques that arose from trial and error and are critical to establishing an EVLP system that is robust and reproducible. PMID:25741794

  4. Dramatic differences in susceptibility to l-DOPA-induced dyskinesia between mice that are aged before or after a nigrostriatal dopamine lesion.

    PubMed

    Bez, Francesco; Francardo, Veronica; Cenci, M Angela

    2016-10-01

    Mice with striatal 6-hydroxydopamine (6-OHDA) lesions are widely used as a model to study the effects of neurorestorative, symptomatic, or antidyskinetic treatments for Parkinson's disease (PD). The standard praxis is to utilize young adult mice with relatively acute 6-OHDA lesions. However, long post-lesion intervals may be required for longitudinal studies of treatment interventions, and the long-term stability of the model's behavioral and cellular phenotypes is currently unknown. In this study, C57Bl/6J mice sustained unilateral striatal 6-OHDA lesions at approx. 2months of age, and were allowed to survive for 1, 10 or 22months. Another group of mice sustained the lesion at the age of 23months and survived for one month thereafter. Baseline and drug-induced motor behaviors were examined using a battery of tests (utilizing also a novel video-based methodology). The extent of nigral dopamine cell loss was stable across post-lesion intervals and ages. However, a prominent sprouting of both dopaminergic and serotonergic fibers was detected in the caudate-putamen in animals that survived until 10 and 22months post-lesion. This phenomenon was associated with a recovery of baseline motor deficits, and with a lack of dyskinetic responses upon treatment with either l-DOPA or apomorphine. By contrast, mice sustaining the lesion at 23months of age showed a striking susceptibility to the dyskinetic effects of both l-DOPA and apomorphine, which was associated with a pronounced drug-induced upregulation of ∆FosB in the ventrolateral striatum. The results reveal a remarkable compensatory capacity of a damaged nigrostriatal pathway in ageing mice, and how this impacts on the response to dopaminergic therapies for PD. PMID:27312773

  5. Segmental Transarterial Embolization in a Translational Rat Model of Hepatocellular Carcinoma

    PubMed Central

    Gade, Terence P.F.; Hunt, Stephen J.; Harrison, Neil; Nadolski, Gregory J.; Weber, Charles; Pickup, Stephen; Furth, Emma E.; Schnall, Mitchell D.; Soulen, Michael C.; Simon, M. Celeste

    2016-01-01

    Purpose To develop a clinically relevant, minimally invasive technique for transarterial embolization in a translational rat model of hepatocellular carcinoma (HCC). Materials and Methods Oral diethylnitrosamine was administered to 53 male Wistar rats ad libitum for 12 weeks. Tumor induction was monitored using magnetic resonance imaging. Minimally invasive lobar or segmental transarterial embolization was performed through a left common carotid artery approach. Necropsy was performed to evaluate periprocedural mortality. Histologic analysis of tumors that received embolization was performed to assess percent tumor necrosis. Results Severe cirrhosis and autochthonous HCCs were characterized in a cohort of rats composed of two groups of rats identically treated with diethylnitrosamine with median survival times of 101 days and 105 days (n = 10/group). A second cohort was used to develop minimally invasive transarterial embolization of HCCs (n = 10). In a third cohort, lobar embolization was successfully performed in 9 of 10 rats and demonstrated a high rate of periprocedural mortality (n = 5). Necropsy performed for periprocedural mortality after lobar embolization demonstrated extensive tissue necrosis within the liver (n = 3) and lungs (n = 2), indicating nontarget embolization as the likely cause of mortality. In a fourth cohort of rats, a segmental embolization technique was successfully applied in 10 of 13 rats. Segmental embolization resulted in a reduction in periprocedural mortality (P = .06) relative to selective embolization and a 19% increase in average tumor necrosis (P = .04). Conclusions Minimally invasive, segmental embolization mimicking the currently applied clinical approach is feasible in a translational rat model of HCC and offers the critical advantage of reduced nontarget embolization relative to lobar embolization. PMID:25863596

  6. Emission-particle-induced ventilatory abnormalities in a rat model of pulmonary hypertension.

    PubMed Central

    Gardner, Sarah Y; McGee, John K; Kodavanti, Urmila P; Ledbetter, Allen; Everitt, Jeffrey I; Winsett, Darrell W; Doerfler, Donald L; Costa, Daniel L

    2004-01-01

    Preexistent cardiopulmonary disease in humans appears to enhance susceptibility to the adverse effects of ambient particulate matter. Previous studies in this laboratory have demonstrated enhanced inflammation and mortality after intratracheal instillation (IT) and inhalation (INH) of residual oil fly ash (ROFA) in a rat model of pulmonary hypertension induced by monocrotaline (MCT). The present study was conducted to examine the effects of ROFA in this model on ventilatory function in unanesthetized, unrestrained animals. Sixty-day-old male CD rats were injected with MCT (60 mg/kg) or vehicle (VEH) intraperitoneally 10 days before IT of ROFA (8.3 mg/kg) or saline (SAL) (control) or nose-only INH of ROFA [15 mg/m3 for 6 hr on 3 consecutive days or air (control)]. At 24 and 72 hr after exposure, rats were studied individually in a simultaneous gas uptake/whole-body plethysmograph. Lungs were removed at 72 hr for histology. Pulmonary test results showed that tidal volume (VT) decreased 24 hr after IT of ROFA in MCT-treated rats. Breathing frequency, minute volume (VE), and the ventilatory equivalent for oxygen increased in MCT- and VEH-treated rats 24 hr after IT or INH of ROFA and remained elevated 72 hr post-IT. O2 uptake (VO2) decreased after IT of ROFA in MCT-treated rats. Carbon monoxide uptake decreased 24 hr after IT of ROFA, returning to control values in VEH-treated rats but remaining low in MCT-treated rats 72 hr post-IT. ROFA exposure induced histologic changes and abnormalities in several ventilatory parameters, many of which were enhanced by MCT treatment. PMID:15175175

  7. SYSTEMIC BIOMARKERS AND CARDIAC GENE EXPRESSION PROFILES OF RAT DISEASE MODELS EMPLOYED IN AIR POLLUTION STUDIES

    EPA Science Inventory

    Cardiovascular disease (CVD) models are used for identification of mechanisms of susceptibility to air pollution. We hypothesized that baseline systemic biomarkers and cardiac gene expression in CVD rat models will have influence on their ozone-induced lung inflammation. Male 12-...

  8. A Comparison of Neuroinflammation to Implanted Microelectrodes in Rat and Mouse Models

    PubMed Central

    Potter-Baker, Kelsey A.; Ravikumar, Madhumitha; Burke, Alan A.; Meador, William D.; Householder, Kyle T.; Buck, Amy C.; Sunil, Smrithi; Stewart, Wade G.; Anna, Jake P.; Tomaszewski, William H.; Capadona, Jeffrey R.

    2014-01-01

    Rat models have emerged as a common tool to study neuroinflammation to intracortical microelectrodes. While a number of studies have attempted to understand the factors resulting in neuroinflammation using rat models, a complete understanding of key mechanistic pathways remains elusive. Transgenic mouse models, however, could facilitate a deeper understanding of mechanistic pathways due to an ease of genetic alteration. Therefore, the goal of the present study is to compare neuroinflammation following microelectrode implantation s between the rat and the mouse model. Our study suggests that subtle differences in the classic neuroinflammatory markers exist between the animal models at both two and sixteen weeks post implantation. Most notably, neuronal densities surrounding microelectrodes were significantly lower in the rat model at two weeks, while similar densities were observed between the animal models at sixteen weeks. Physiological differences between the species and slight alterations in surgical methods are likely key contributors to the observed differences. Moving forward, we propose that differences in the time course of neuroinflammation between the animal models should be considered when trying to understand and prevent intracortical microelectrode failure. PMID:24755527

  9. A comparison of neuroinflammation to implanted microelectrodes in rat and mouse models.

    PubMed

    Potter-Baker, Kelsey A; Ravikumar, Madhumitha; Burke, Alan A; Meador, William D; Householder, Kyle T; Buck, Amy C; Sunil, Smrithi; Stewart, Wade G; Anna, Jake P; Tomaszewski, William H; Capadona, Jeffrey R

    2014-07-01

    Rat models have emerged as a common tool to study neuroinflammation to intracortical microelectrodes. While a number of studies have attempted to understand the factors resulting in neuroinflammation using rat models, a complete understanding of key mechanistic pathways remains elusive. Transgenic mouse models, however, could facilitate a deeper understanding of mechanistic pathways due to an ease of genetic alteration. Therefore, the goal of the present study is to compare neuroinflammation following microelectrode implantation between the rat and the mouse model. Our study suggests that subtle differences in the classic neuroinflammatory markers exist between the animal models at both two and sixteen weeks post implantation. Most notably, neuronal densities surrounding microelectrodes were significantly lower in the rat model at two weeks, while similar densities were observed between the animal models at sixteen weeks. Physiological differences between the species and slight alterations in surgical methods are likely key contributors to the observed differences. Moving forward, we propose that differences in the time course of neuroinflammation between the animal models should be considered when trying to understand and prevent intracortical microelectrode failure. PMID:24755527

  10. Efficacy of Polaprezinc for Acute Radiation Proctitis in a Rat Model

    SciTech Connect

    Doi, Hiroshi; Kamikonya, Norihiko; Takada, Yasuhiro; Fujiwara, Masayuki; Tsuboi, Keita; Inoue, Hiroyuki; Tanooka, Masao; Nakamura, Takeshi; Shikata, Toshiyuki; Tsujimura, Tohru; Hirota, Shozo

    2011-07-01

    Purpose: The purpose of the present study was to standardize the experimental rat model of radiation proctitis and to examine the efficacy of polaprezinc on radiation proctitis. Methods and Materials: A total of 54 female Wistar rats (5 weeks old) were used. The rats were divided into three groups: those treated with polaprezinc (PZ+), those treated with base alone, exclusive of polaprezinc (PZ-), and those treated without any medication (control). All the rats were irradiated to the rectum. Polaprezinc was prepared as an ointment. The ointment was administered rectally each day after irradiation. All rats were killed on the 10th day after irradiation. The mucosal changes were evaluated endoscopically and pathologically. The results were graded from 0 to 4 and compared according to milder or more severe status, as applicable. Results: According to the endoscopic findings, the proportion of mild changes in the PZ+, PZ-, and control group was 71.4%, 25.0%, and 14.3% respectively. On pathologic examination, the proportion of low-grade findings in the PZ+, PZ-, and control group was 80.0%, 58.3%, and 42.9% for mucosal damage, 85.0%, 41.7%, and 42.9% for a mild degree of inflammation, and 50.0%, 33.3%, and 4.8% for a shallow depth of inflammation, respectively. The PZ+ group tended to have milder mucosal damage than the other groups, according to all criteria used. In addition, significant differences were observed between the PZ+ and control groups regarding the endoscopic findings, degree of inflammation, and depth of inflammation. Conclusions: This model was confirmed to be a useful experimental rat model for radiation proctitis. The results of the present study have demonstrated the efficacy of polaprezinc against acute radiation-induced rectal disorders using the rat model.

  11. Rat model of cholelithiasis with human gallstones implanted in cholestasis-induced virtual gallbladder

    PubMed Central

    Cona, Marlein Miranda; Liu, Yewei; Yin, Ting; Feng, Yuanbo; Chen, Feng; Mulier, Stefaan; Li, Yue; Zhang, Jian; Oyen, Raymond; Ni, Yicheng

    2016-01-01

    AIM: To facilitate translational research on cholelithiasis, we have developed a rat model of human gallstones by exploiting the unique biliopancreatic features of this species. METHODS: Under anesthesia, 16 adult rats of equal genders underwent two times of abdominal surgery. First, their common bile duct (CBD) was ligated to cause cholestasis by total biliary obstruction (TBO). On day 0, 1, 3, 7, 14, 21 and 28 after TBO, magnetic resonance imaging (MRI) was conducted to monitor the dilatation of the CBD, and blood was sampled to analyze total serum bilirubin (TSB). Secondly, on day 30, the abdomen was re-opened and gallstone(s) collected from human patients were implanted in the dilated CBD as a virtual gallbladder (VGB), which was closed by suture ligation. This rat cholelithiasis model was examined by MRI, clinical observation, microcholangiography and histology. RESULTS: All rats survived two laparotomies. After ligation, the CBD was dilated to a stable size of 4 to 30 mm in diameter on day 21-28, which became a VGB. The rats initially showed signs of jaundice that diminished over time, which paralleled with the evolving TSB levels from 0.6 ± 0.3 mg/dL before ligation, through a peak of 10.9 ± 1.9 mg/dL on day 14, until a nearly normalized value after day 28. The dilated CBD with thickened wall allowed an incision for implantation of human gallstones of 1-10 mm in diameter. The rat cholelithiasis was proven by in vivo MRI and postmortem microcholangiography and histomorphology. CONCLUSION: A rat model cholelithiasis with human gallstones has been established, which proves feasible, safe, reliable, nontoxic and cost-effective. Given the gallstones of human origin, applications of this model may be of help in translational research such as optical detection and lysis of gallstones by systemic drug administration. PMID:27376020

  12. Fused pulmonary lobes is a rat model of human Fraser syndrome

    SciTech Connect

    Kiyozumi, Daiji; Nakano, Itsuko; Takahashi, Ken L.; Hojo, Hitoshi; Aoyama, Hiroaki; Sekiguchi, Kiyotoshi

    2011-07-29

    Highlights: {yields} Fused pulmonary lobes (fpl) mutant rats exhibit similar phenotypes to Fraser syndrome. {yields} The fpl gene harbors a nonsense mutation in Fraser syndrome-associated gene Frem2. {yields} Fpl mutant is defined as a first model of human Fraser syndrome in rats. -- Abstract: Fused pulmonary lobes (fpl) is a mutant gene that is inherited in an autosomal recessive manner and causes various developmental defects, including fusion of pulmonary lobes, and eyelid and digit anomalies in rats. Since these developmental defects closely resemble those observed in patients with Fraser syndrome, a recessive multiorgan disorder, and its model animals, we investigated whether the abnormal phenotypes observed in fpl/fpl mutant rats are attributable to a genetic disorder similar to Fraser syndrome. At the epidermal basement membrane in fpl/fpl mutant neonates, the expression of QBRICK, a basement membrane protein whose expression is attenuated in Fraser syndrome model mice, was greatly diminished compared with control littermates. Quantitative RT-PCR analyses of Fraser syndrome-related genes revealed that Frem2 transcripts were markedly diminished in QBRICK-negative embryos. Genomic DNA sequencing of the fpl/fpl mutant identified a nonsense mutation that introduced a stop codon at serine 2005 in Frem2. These findings indicate that the fpl mutant is a rat model of human Fraser syndrome.

  13. Paeoniflorin ameliorates rheumatoid arthritis in rat models through oxidative stress, inflammation and cyclooxygenase 2

    PubMed Central

    JIA, ZHILIN; HE, JIAO

    2016-01-01

    Paeoniflorin has anti-inflammatory, anti-allergy, immune regulatory and pain-relieving effects, amongst other roles. However, the mechanisms underlying the protective effects of paeoniflorin on rheumatoid arthritis (RA) remain under investigation; the objective of the current study was to evaluate these protective effects in the context of an RA model. Rats were randomly divided into 5 groups, as follows: The control group, the RA rat model group, and the paeoniflorin groups, in which paeoniflorin was administered at concentrations of 5, 10 and 20 mg/kg for 3 weeks. The pain thresholds and arthritic symptoms of the RA rats were measured. Oxidative stress and inflammatory cytokines were also analyzed and western blot analysis was used to evaluate cyclooxygenase-2 (COX-2) protein expression levels. Paeoniflorin significantly increased the pain threshold and decreased the arthritic symptoms in the RA rat model. Notably, paeoniflorin reduced the malondialdehyde concentration and increased the activity of superoxide dismutase, catalase and glutathione peroxidase. Furthermore, paeoniflorin attenuated the activity of nuclear factor-κB p65 unit, tumor necrosis factor-α, interleukin (IL)-1β and IL-6, and reduced the COX-2 protein expression level. The present study indicates that paeoniflorin ameliorates disease in rat models of RA through oxidative stress, inflammation and alterations to COX-2 expression. PMID:26893662

  14. AGN-2979, an inhibitor of tryptophan hydroxylase activation, does not affect serotonin synthesis in Flinders Sensitive Line rats, a rat model of depression, but produces a significant effect in Flinders Resistant Line rats

    PubMed Central

    Kanemaru, Kazuya; Nishi, Kyoko; Diksic, Mirko

    2009-01-01

    The neurotransmitter, serotonin, is involved in several brain functions, including both normal, physiological functions, and pathophysiological functions. Alterations in any of the normal parameters of serotonergic neurotransmission can produce several different psychiatric disorders, including major depression. In many instances, brain neurochemical variables are not able to be studied properly in humans, thus making the use of good animal models extremely valuable. One of these animal models is the Flinders Sensitive Line (FSL) of rats, which has face, predictive and constructive validities in relation to human depression. The objective of this study was to quantify the effect of the tryptophan hydroxylase (TPH) activation inhibitor, AGN-2979, on the FSL rats (rats with depression-like behaviour), and compare it to the effect on the Flinders Resistant Line (FRL) of rats used as the control rats. The effect was evaluated by measuring changes in regional serotonin synthesis in the vehicle treated rats (FSL-VEH and FRL-VEH) relative to those measured in the AGN-2979 treated rats (FSL-AGN and FRL-AGN). Regional serotonin synthesis was measured autoradiographically in more than thirty brain regions. The measurements were performed using α-[14C]methyl-L-tryptophan as the tracer. The results indicate that AGN-2979 did not produce a significant reduction of TPH activity in the AGN-2979 group relative to the vehicle group (a reduction would have been observed if there had been an activation of TPH by the experimental set up) in the FSL rats. On the other hand, there was a highly significant reduction of synthesis in the FRL rats treated by AGN-2979, relative to the vehicle group. Together, the results demonstrate that in the FSL rats, AGN-2979 does not affect serotonin synthesis. This suggests that there was no activation of TPH in the FSL rats during the experimental procedure, but such activation did occur in the FRL rats. Because of this finding, it could be

  15. Glutamatergic signaling and low prodynorphin expression are associated with intact memory and reduced anxiety in rat models of healthy aging.

    PubMed

    Ménard, Caroline; Quirion, Rémi; Bouchard, Sylvain; Ferland, Guylaine; Gaudreau, Pierrette

    2014-01-01

    The LOU/C/Jall (LOU) rat strain is considered a model of healthy aging due to its increased longevity, maintenance of stable body weight (BW) throughout life and low incidence of age-related diseases. However, aging LOU rat cognitive and anxiety status has yet to be investigated. In the present study, male and female LOU rat cognitive performances (6-42 months) were assessed using novel object recognition and Morris Water Maze tasks. Recognition memory remained intact in all LOU rats up to 42 months of age. As for spatial memory, old LOU rat performed similarly as young animals for learning acquisition, reversal learning, and retention. While LOU rat BW remained stable despite aging, 20-month-old ad-libitum-fed (OAL) male Sprague Dawley rats become obese. We determined if long-term caloric restriction (LTCR) prevents age-related BW increase and cognitive deficits in this rat strain, as observed in the obesity-resistant LOU rats. Compared to young animals, recognition memory was impaired in OAL but intact in 20-month-old calorie-restricted (OCR) rats. Similarly, OAL spatial learning acquisition was impaired but LTCR prevented the deficits. Exacerbated stress responses may favor age-related cognitive decline. In the elevated plus maze and open field tasks, LOU and OCR rats exhibited high levels of exploratory activity whereas OAL rats displayed anxious behaviors. Expression of prodynorphin (Pdyn), an endogenous peptide involved in stress-related memory impairments, was increased in the hippocampus of OAL rats. Group 1 metabotropic glutamate receptor 5 and immediate early genes Homer 1a and Arc expression, both associated with successful cognitive aging, were unaltered in aging LOU rats but lower in OAL than OCR rats. Altogether, our results, supported by principal component analysis and correlation matrix, suggest that intact memory and low anxiety are associated with glutamatergic signaling and low Pdyn expression in the hippocampus of non-obese aging rats. PMID

  16. Glutamatergic signaling and low prodynorphin expression are associated with intact memory and reduced anxiety in rat models of healthy aging

    PubMed Central

    Ménard, Caroline; Quirion, Rémi; Bouchard, Sylvain; Ferland, Guylaine; Gaudreau, Pierrette

    2014-01-01

    The LOU/C/Jall (LOU) rat strain is considered a model of healthy aging due to its increased longevity, maintenance of stable body weight (BW) throughout life and low incidence of age-related diseases. However, aging LOU rat cognitive and anxiety status has yet to be investigated. In the present study, male and female LOU rat cognitive performances (6–42 months) were assessed using novel object recognition and Morris Water Maze tasks. Recognition memory remained intact in all LOU rats up to 42 months of age. As for spatial memory, old LOU rat performed similarly as young animals for learning acquisition, reversal learning, and retention. While LOU rat BW remained stable despite aging, 20-month-old ad-libitum-fed (OAL) male Sprague Dawley rats become obese. We determined if long-term caloric restriction (LTCR) prevents age-related BW increase and cognitive deficits in this rat strain, as observed in the obesity-resistant LOU rats. Compared to young animals, recognition memory was impaired in OAL but intact in 20-month-old calorie-restricted (OCR) rats. Similarly, OAL spatial learning acquisition was impaired but LTCR prevented the deficits. Exacerbated stress responses may favor age-related cognitive decline. In the elevated plus maze and open field tasks, LOU and OCR rats exhibited high levels of exploratory activity whereas OAL rats displayed anxious behaviors. Expression of prodynorphin (Pdyn), an endogenous peptide involved in stress-related memory impairments, was increased in the hippocampus of OAL rats. Group 1 metabotropic glutamate receptor 5 and immediate early genes Homer 1a and Arc expression, both associated with successful cognitive aging, were unaltered in aging LOU rats but lower in OAL than OCR rats. Altogether, our results, supported by principal component analysis and correlation matrix, suggest that intact memory and low anxiety are associated with glutamatergic signaling and low Pdyn expression in the hippocampus of non-obese aging rats. PMID

  17. Rethinking food anticipatory activity in the activity-based anorexia rat model.

    PubMed

    Wu, Hemmings; van Kuyck, Kris; Tambuyzer, Tim; Luyten, Laura; Aerts, Jean-Marie; Nuttin, Bart

    2014-01-01

    When a rat is on a limited fixed-time food schedule with full access to a running wheel (activity-based anorexia model, ABA), its activity level will increase hours prior to the feeding period. This activity, called food-anticipatory activity (FAA), is a hypothesized parallel to the hyperactivity symptom in human anorexia nervosa. To investigate in depth the characteristics of FAA, we retrospectively analyzed the level of FAA and activities during other periods in ABA rats. To our surprise, rats with the most body weight loss have the lowest level of FAA, which contradicts the previously established link between FAA and the severity of ABA symptoms. On the contrary, our study shows that postprandial activities are more directly related to weight loss. We conclude that FAA alone may not be sufficient to reflect model severity, and activities during other periods may be of potential value in studies using ABA model. PMID:24473370

  18. Evaluation of deltamethrin kinetics and dosimetry in the maturing rat using a PBPK model

    SciTech Connect

    Tornero-Velez, Rogelio; Mirfazaelian, Ahmad; Kim, Kyu-Bong; Anand, Sathanandam S.; Kim, Hyo J.; Haines, Wendy T.; Bruckner, James V.; Fisher, Jeffrey W.

    2010-04-15

    Immature rats are more susceptible than adults to the acute neurotoxicity of pyrethroid insecticides like deltamethrin (DLM). A companion kinetics study (Kim et al., in press) revealed that blood and brain levels of the neuroactive parent compound were inversely related to age in rats 10, 21, 40 and 90 days old. The objective of the current study was to modify a physiologically based pharmacokinetic (PBPK) model of DLM disposition in the adult male Sprague-Dawley rat (Mirfazaelian et al., 2006), so blood and target organ dosimetry could be accurately predicted during maturation. Age-specific organ weights and age-dependent changes in the oxidative and hydrolytic clearance of DLM were modeled with a generalized Michaelis-Menten model for growth and the summary equations incorporated into the PBPK model. The model's simulations compared favorably with empirical DLM time-courses in plasma, blood, brain and fat for the four age-groups evaluated (10, 21, 40 and 90 days old). PND 10 pups' area under the 24-h brain concentration time curve (AUC{sub 0-24h}) was 3.8-fold higher than that of the PND 90 adults. Our maturing rat PBPK model allows for updating with age- and chemical-dependent parameters, so pyrethroid dosimetry can be forecast in young and aged individuals. Hence, this model provides a methodology for risk assessors to consider age-specific adjustments to oral Reference Doses on the basis of PK differences.

  19. Abnormal Expression of Urea Transporter Protein in a Rat Model of Hepatorenal Syndrome Induced by Succinylated Gelatin

    PubMed Central

    Song, Weiping; Qi, Xiaolong; Zhang, Wenhui; Zhao, C Yingying; Cao, Yan; Wang, Fei; Yang, Changqing

    2015-01-01

    Background Hepatorenal syndrome (HRS) is a serious complication of advanced chronic liver disease. Abdominal compartment syndrome (ACS) occurs with dysfunction of multiple organs when abdominal pressure increases. Here, we report on a novel model of ACS with ascites and a model of HRS in rats to observe the urea transporter protein (UT) expression in the 2 models. Material/Methods A liver cirrhosis model was induced by CCl4. After changes of liver histopathology were observed, rats were injected intraperitoneally with succinylated gelatin to establish a model of ACS and HRS. Then, changes in BUN, Cr, and renal histopathology were detected. Moreover, the UT in ACS and HRS were also quantified. Results The surfaces of liver in the cirrhotic group became coarse, with visible small nodules and became yellow and greasy. The normal structure of the hepatic lobules were destroyed, and hyperplasia of fibrotic tissue and pseudo-lobe was observed. The levels of BUN and Cr were significantly increased in rats suffering from ACS and HRS, respectively, compared to their control groups. In addition, the mRNA levels of UT-A2 and UT-A3 decreased in rats with HRS compared to cirrhotic rats. However, there was no significant difference between the mRNA levels of UT-A2, UT-A3, and UT-B in rats with ACS vs. normal rats. Conclusions It is feasible to model ACS in rats by injecting succinylated gelatin into the abdominal cavity. Increasing the intra-abdominal pressure by succinylated gelatin is also a novel approach for modeling HRS in cirrhotic rats. Compared with control rats, there is an abnormal mRNA expression of UT in ACS rats and HRS rats. PMID:26414230

  20. Preventive effect of American ginseng against premature ovarian failure in a rat model.

    PubMed

    Ge, Pengling; Xing, Nannan; Ren, Yanhai; Zhu, Lei; Han, Dongwei; Kuang, Haixue; Li, Ji

    2014-12-01

    Preclinical Research Premature ovarian failure (POF) is defined by the WHO as the loss of physiological ovarian function before the age of 40. The effect of American ginseng and its underlying mechanisms in preventing and treating premature ovarian failure (POF) was studied in female Sprague-Dawley rats where POF was induced by ip administration of 4-vinylcyclohexene diepoxide (VCD). Rat behavior, serum hormone levels, ovarian and uterine size, pathological features, and ovarian tissue expression of genes associated with POF were assessed in controls, untreated POF model rats, and POF model rats treated with low- (1.125 g/kg), medium- (2.25 g/kg), and high-dose (4.5 g/kg) American ginseng. Compared with untreated POF model rats, those treated with medium- and high-dose American ginseng had more stable behavior and better coat appearance as well as serum hormone levels closer to those in control rats. Moreover, treatment with medium- or high-dose American ginseng increased ovarian and uterine size. Hematoxylin and eosin-staining revealed mature follicles and endometrium with an alternating concave/convex surface structure with visible capillaries and glands in ginseng- treated POF rats. PLA2G4A expression was positively correlated with POF, while the expression levels of PAPPA, STC2, CCL2, and NELL1 were negatively correlated with POF. Our study showed that American ginseng may effectively prevent POF and alleviate POF symptoms by regulating serum hormone levels and altering the expression levels of genes related to POF in ovarian tissue. PMID:25424468

  1. Modeling perimenopause in Sprague-Dawley rats by chemical manipulation of the transition to ovarian failure.

    PubMed

    Frye, Jennifer B; Lukefahr, Ashley L; Wright, Laura E; Marion, Sam L; Hoyer, Patricia B; Funk, Janet L

    2012-06-01

    Various age-related diseases increase in incidence during perimenopause. However, our understanding of the effects of aging compared with hormonal changes of perimenopause in mediating these disease risks is incomplete, in part due to the lack of an experimental perimenopause model. We therefore aimed to determine whether manipulation of the transition to ovarian failure in rats via the use of 4-vinylcyclohexene diepoxide (VCD) could be used to model and accelerate hormonal changes characteristic of perimenopause. We examined long-term (11 to 20 mo), dose-dependent effects of VCD on reproductive function in 1- and 3-mo-old female Sprague-Dawley rats. Twenty-five daily doses of VCD (80 or 160 mg/kg daily compared with vehicle alone) depleted ovarian follicles in a dose-dependent fashion in rats of both ages, accelerated the onset of acyclicity, and caused dose-dependent increases in follicle-stimulating hormone that exceeded those naturally occurring with age in control rats but left serum levels of 17β-estradiol unchanged, with continued ovarian production of androstenedione. High-dose VCD caused considerable nonovarian toxicities in 3-mo-old Sprague-Dawley rats, making this an unsuitable model. In contrast, 1-mo-old rats had more robust dose-dependent increases in follicle-stimulating hormone without evidence of systemic toxicity in response to either VCD dose. Because perimenopause is characterized by an increase in follicle-stimulating hormone with continued secretion of ovarian steroids, VCD acceleration of an analogous hormonal milieu in 1-mo-old Sprague-Dawley rats may be useful for probing the hormonal effects of perimenopause on age-related disease risk. PMID:22776052

  2. Modeling Perimenopause in Sprague–Dawley Rats by Chemical Manipulation of the Transition to Ovarian Failure

    PubMed Central

    Frye, Jennifer B; Lukefahr, Ashley L; Wright, Laura E; Marion, Sam L; Hoyer, Patricia B; Funk, Janet L

    2012-01-01

    Various age-related diseases increase in incidence during perimenopause. However, our understanding of the effects of aging compared with hormonal changes of perimenopause in mediating these disease risks is incomplete, in part due to the lack of an experimental perimenopause model. We therefore aimed to determine whether manipulation of the transition to ovarian failure in rats via the use of 4-vinylcyclohexene diepoxide (VCD) could be used to model and accelerate hormonal changes characteristic of perimenopause. We examined long-term (11 to 20 mo), dose-dependent effects of VCD on reproductive function in 1- and 3-mo-old female Sprague–Dawley rats. Twenty-five daily doses of VCD (80 or 160 mg/kg daily compared with vehicle alone) depleted ovarian follicles in a dose-dependent fashion in rats of both ages, accelerated the onset of acyclicity, and caused dose-dependent increases in follicle-stimulating hormone that exceeded those naturally occurring with age in control rats but left serum levels of 17β−estradiol unchanged, with continued ovarian production of androstenedione. High-dose VCD caused considerable nonovarian toxicities in 3-mo-old Sprague–Dawley rats, making this an unsuitable model. In contrast, 1-mo-old rats had more robust dose-dependent increases in follicle-stimulating hormone without evidence of systemic toxicity in response to either VCD dose. Because perimenopause is characterized by an increase in follicle-stimulating hormone with continued secretion of ovarian steroids, VCD acceleration of an analogous hormonal milieu in 1-mo-old Sprague–Dawley rats may be useful for probing the hormonal effects of perimenopause on age-related disease risk. PMID:22776052

  3. A New Model for Inducing Malignant Ovarian Tumours in Rats*

    PubMed Central

    Hilfrich, J.

    1973-01-01

    After the implantation of ovarian tissue into the spleen of gonadectomized female Sprague-Dawley rats (splenic ovary), luteomata and later benign granulosa or granulosa-theca cell tumours develop. Treatment of these rats with 7,12 dimethylbenz(a)anthracene (DMBA), given intravenously, 2 mg/kg body weight weekly, total dosage 40 mg/kg, immediately and especially 25 weeks after implantation of ovarian tissue into the spleen, led to malignant, partially metastasizing granulosa, and in one case theca cell tumours, 16-46 weeks after beginning the carcinogen treatment. No malignant neoplastic growth was seen when diethylnitrosamine (DEN), 20 mg/kg once weekly for life, was injected subcutaneously immediately or 25 weeks after implanting ovarian tissue. Since the normal, non-implanted rat ovary was not affected by DMBA treatment the malignant transformation of splenic ovaries in the respective experimental groups may be related to the increased stimulation by pituitary gonadotrophins and formation of luteomata or beginning granulosa and theca cell proliferations. ImagesFig. 1Fig. 2Fig. 3Fig. 4Fig. 5Fig. 6Fig. 7Fig. 8Fig. 9 PMID:4353388

  4. Oxidative Damage in the Aging Heart: an Experimental Rat Model

    PubMed Central

    Marques, Gustavo Lenci; Neto, Francisco Filipak; Ribeiro, Ciro Alberto de Oliveira; Liebel, Samuel; de Fraga, Rogério; Bueno, Ronaldo da Rocha Loures

    2015-01-01

    Introduction: Several theories have been proposed to explain the cause of ‘aging’; however, the factors that affect this complex process are still poorly understood. Of these theories, the accumulation of oxidative damage over time is among the most accepted. Particularly, the heart is one of the most affected organs by oxidative stress. The current study, therefore, aimed to investigate oxidative stress markers in myocardial tissue of rats at different ages. Methods: Seventy-two rats were distributed into 6 groups of 12 animals each and maintained for 3, 6, 9, 12, 18 and 24 months. After euthanasia, the heart was removed and the levels of non-protein thiols, lipid peroxidation, and protein carbonylation, as well as superoxide dismutase and catalase activities were determined. Results: Superoxide dismutase, catalase activity and lipid peroxidation were reduced in the older groups of animals, when compared with the younger group. However, protein carbonylation showed an increase in the 12-month group followed by a decrease in the older groups. In addition, the levels of non-protein thiols were increased in the 12-month group and not detected in the older groups. Conclusion: Our data showed that oxidative stress is not associated with aging in the heart. However, an increase in non-protein thiols may be an important factor that compensates for the decrease of superoxide dismutase and catalase activity in the oldest rats, to maintain appropriate antioxidant defenses against oxidative insults. PMID:27006709

  5. Auditory steady state responses in a schizophrenia rat model probed by excitatory/inhibitory receptor manipulation

    PubMed Central

    Vohs, Jenifer L.; Chambers, R. Andrew; O’Donnell, Brian F.; Krishnan, Giri P.; Morzorati, Sandra L.

    2012-01-01

    Alterations in neural synchrony and oscillations may contribute to the pathophysiology of schizophrenia and reflect aberrations in cortical glutamatergic and GABAergic neurotransmission. We tested the effects of a GABA agonist and a NMDA antagonist on auditory steady state responses (ASSRs) in awake rats with neonatal ventral hippocampal lesions (NVHLs) as a neurodevelopmental model of schizophrenia. NVHL vs. SHAM lesioned rats were injected with saline then either ketamine (NMDA antagonist) or muscimol (GABAA agonist). Time-frequency analyses examined alterations in phase locking (consistency) across trials and changes in total power (magnitude). ASSRs were compared at 5 stimulation frequencies (10, 20, 30, 40, and 50 Hz). In SHAM rats, phase locking and power generally increased with stimulation frequency. Both ketamine and muscimol also increased phase locking and power in SHAM rats, but mostly in the 20 to 40 Hz range. NVHL and ketamine altered the frequency dependence of phase locking, while only ketamine changed power frequency dependence. Muscimol affected power, but not phase locking, in the NVHL rats. NVHL and ketamine models of schizophrenia produce similar independent effects on ASSR, potentially representing similar forms of cortical network/glutamatergic dysfunction, albeit the effects of ketamine were more robust. Muscimol produced NVHL-dependent reductions in ASSR measures, suggesting that cortical networks in this model are intolerant to post-synaptic GABAergic stimulation. These findings suggest the utility of combining lesion, pharmacological, and ASSR approaches in understanding neural mechanisms underlying disturbed synchrony in schizophrenia. PMID:22504207

  6. Characterising bone material composition and structure in the ovariectomized (OVX) rat model of osteoporosis.

    PubMed

    Mathavan, Neashan; Turunen, Mikael J; Tägil, Magnus; Isaksson, Hanna

    2015-08-01

    The ovariectomized (OVX) rat model is well established in investigations of osteoporosis and osteoporotic therapies. Advent of techniques such as Fourier-transform infrared (FTIR) spectroscopy and small angle X-ray scattering (SAXS) facilitate characterization of bone composition and mineral structure, respectively, which are key determinants of bone strength. Limited publications exist on the implementation of these techniques in the OVX rat model. At 12 weeks of age, female Sprague-Dawley rats were either sham-operated (n = 6) or ovariectomized (n = 6) and sacrificed 18 weeks later. L2 lumbar vertebrae and proximal tibiae were assessed by µCT, FTIR and SAXS. Presence of extensive trabecular deterioration in the µCT data confirmed the onset of osteoporosis. FTIR compositional parameters were determined including measures of degree of mineralization, crystallinity, collagen maturity and acid phosphate content. Mineral crystal thickness was determined from the SAXS data using two approaches available in literature. Compositionally, a decline in the heterogeneity of acid phosphate content was observed while measures of crystallinity and collagen maturity remained unaltered. Using an iterative curve fitting method, OVX-induced increases in the mineral crystal thickness of 3.8 and 7.8 % (p < 0.05) were noted in the trabecular of the vertebra and tibia, respectively. In conclusion, implementation of FTIR and SAXS techniques in the OVX rat model, identified no significant compositional changes while substantiating thickening of the mineral crystals as a general structural feature of OVX-induced osteoporosis in rats. PMID:25894067

  7. Vagus nerve stimulation delivered during motor rehabilitation improves recovery in a rat model of stroke.

    PubMed

    Khodaparast, Navid; Hays, Seth A; Sloan, Andrew M; Fayyaz, Tabbassum; Hulsey, Daniel R; Rennaker, Robert L; Kilgard, Michael P

    2014-09-01

    Neural plasticity is widely believed to support functional recovery following brain damage. Vagus nerve stimulation paired with different forelimb movements causes long-lasting map plasticity in rat primary motor cortex that is specific to the paired movement. We tested the hypothesis that repeatedly pairing vagus nerve stimulation with upper forelimb movements would improve recovery of motor function in a rat model of stroke. Rats were separated into 3 groups: vagus nerve stimulation during rehabilitation (rehab), vagus nerve stimulation after rehab, and rehab alone. Animals underwent 4 training stages: shaping (motor skill learning), prelesion training, postlesion training, and therapeutic training. Rats were given a unilateral ischemic lesion within motor cortex and implanted with a left vagus nerve cuff. Animals were allowed 1 week of recovery before postlesion baseline training. During the therapeutic training stage, rats received vagus nerve stimulation paired with each successful trial. All 17 trained rats demonstrated significant contralateral forelimb impairment when performing a bradykinesia assessment task. Forelimb function was recovered completely to prelesion levels when vagus nerve stimulation was delivered during rehab training. Alternatively, intensive rehab training alone (without stimulation) failed to restore function to prelesion levels. Delivering the same amount of stimulation after rehab training did not yield improvements compared with rehab alone. These results demonstrate that vagus nerve stimulation repeatedly paired with successful forelimb movements can improve recovery after motor cortex ischemia and may be a viable option for stroke rehabilitation. PMID:24553102

  8. Metabolic acetate therapy improves phenotype in the tremor rat model of Canavan disease

    PubMed Central

    Arun, Peethambaran; Madhavarao, Chikkathur N.; Moffett, John R.; Hamilton, Kristen; Grunberg, Neil E.; Ariyannur, Prasanth S.; Gahl, William A.; Anikster, Yair; Mog, Steven; Hallows, William C.; Denu, John M.

    2010-01-01

    Genetic mutations that severely diminish the activity of aspartoacylase (ASPA) result in the fatal brain dysmyelinating disorder, Canavan disease. There is no effective treatment. ASPA produces free acetate from the concentrated brain metabolite, N-acetylaspartate (NAA). Because acetyl coenzyme A is a key building block for lipid synthesis, we postulated that the inability to catabolize NAA leads to a brain acetate deficiency during a critical period of CNS development, impairing myelination and possibly other aspects of brain development. We tested the hypothesis that acetate supplementation during postnatal myelination would ameliorate the severe phenotype associated with ASPA deficiency using the tremor rat model of Canavan disease. Glyceryltriacetate (GTA) was administered orally to tremor rats starting 7 days after birth, and was continued in food and water after weaning. Motor function, myelin lipids, and brain vacuolation were analyzed in GTA-treated and untreated tremor rats. Significant improvements were observed in motor performance and myelin galactocerebroside content in tremor rats treated with GTA. Further, brain vacuolation was modestly reduced, and these reductions were positively correlated with improved motor performance. We also examined the expression of the acetyl coenzyme A synthesizing enzyme acetyl coenzyme A synthase 1 and found upregulation of expression in tremor rats, with a return to near normal expression levels in GTA-treated tremor rats. These results confirm the critical role played by NAA-derived acetate in brain myelination and development, and demonstrate the potential usefulness of acetate therapy for the treatment of Canavan disease. PMID:20464498

  9. Progesterone Treatment Shows Benefit in Female Rats in a Pediatric Model of Controlled Cortical Impact Injury

    PubMed Central

    Geddes, Rastafa I.; Peterson, Bethany L.; Stein, Donald G.; Sayeed, Iqbal

    2016-01-01

    Purpose We recently showed that progesterone treatment can reduce lesion size and behavioral deficits after moderate-to-severe bilateral injury to the medial prefrontal cortex in immature male rats. Whether there are important sex differences in response to injury and progesterone treatment in very young subjects has not been given sufficient attention. Here we investigated progesterone’s effects in the same model of brain injury but with pre-pubescent females. Methods Twenty-eight-day-old female Sprague-Dawley rats received sham (n = 14) or controlled cortical impact (CCI) (n = 21) injury, were given progesterone (8 mg/kg body weight) or vehicle injections on post-injury days (PID) 1–7, and underwent behavioral testing from PID 9–27. Brains were evaluated for lesion size at PID 28. Results Lesion size in vehicle-treated female rats with CCI injury was smaller than that previously reported for similarly treated age-matched male rats. Treatment with progesterone reduced the effect of CCI on extent of damage and behavioral deficits. Conclusion Pre-pubescent female rats with midline CCI injury to the frontal cortex have reduced morphological and functional deficits following progesterone treatment. While gender differences in susceptibility to this injury were observed, progesterone treatment produced beneficial effects in young rats of both sexes following CCI. PMID:26799561

  10. Hyperglycemia inhibits complement-mediated immunological control of S. aureus in a rat model of peritonitis.

    PubMed

    Mauriello, Clifford T; Hair, Pamela S; Rohn, Reuben D; Rister, Nicholas S; Krishna, Neel K; Cunnion, Kenji M

    2014-01-01

    Hyperglycemia from diabetes is associated with increased risk of infection from S. aureus and increased severity of illness. Previous work in our laboratory demonstrated that elevated glucose (>6 mM) dramatically inhibited S. aureus-initiated complement-mediated immune effectors. Here we report in vivo studies evaluating the extent to which a hyperglycemic environment alters complement-mediated control of S. aureus infection in a rat peritonitis model. Rats were treated with streptozocin to induce diabetes or sham-treated and then inoculated i.p. with S. aureus. Rats were euthanized and had peritoneal lavage at 2 or 24 hours after infection to evaluate early and late complement-mediated effects. Hyperglycemia decreased the influx of IgG and complement components into the peritoneum in response to S. aureus infection and decreased anaphylatoxin generation. Hyperglycemia decreased C4-fragment and C3-fragment opsonization of S. aureus recovered in peritoneal fluids, compared with euglycemic or insulin-rescued rats. Hyperglycemic rats showed decreased phagocytosis efficiency compared with euglycemic rats, which correlated inversely with bacterial survival. These results suggest that hyperglycemia inhibited humoral effector recruitment, anaphylatoxin generation, and complement-mediated opsonization of S. aureus, suggesting that hyperglycemic inhibition of complement effectors may contribute to the increased risk and severity of S. aureus infections in diabetic patients. PMID:25610878

  11. Hyperglycemia Inhibits Complement-Mediated Immunological Control of S. aureus in a Rat Model of Peritonitis

    PubMed Central

    Mauriello, Clifford T.; Hair, Pamela S.; Rohn, Reuben D.; Rister, Nicholas S.; Krishna, Neel K.; Cunnion, Kenji M.

    2014-01-01

    Hyperglycemia from diabetes is associated with increased risk of infection from S. aureus and increased severity of illness. Previous work in our laboratory demonstrated that elevated glucose (>6 mM) dramatically inhibited S. aureus-initiated complement-mediated immune effectors. Here we report in vivo studies evaluating the extent to which a hyperglycemic environment alters complement-mediated control of S. aureus infection in a rat peritonitis model. Rats were treated with streptozocin to induce diabetes or sham-treated and then inoculated i.p. with S. aureus. Rats were euthanized and had peritoneal lavage at 2 or 24 hours after infection to evaluate early and late complement-mediated effects. Hyperglycemia decreased the influx of IgG and complement components into the peritoneum in response to S. aureus infection and decreased anaphylatoxin generation. Hyperglycemia decreased C4-fragment and C3-fragment opsonization of S. aureus recovered in peritoneal fluids, compared with euglycemic or insulin-rescued rats. Hyperglycemic rats showed decreased phagocytosis efficiency compared with euglycemic rats, which correlated inversely with bacterial survival. These results suggest that hyperglycemia inhibited humoral effector recruitment, anaphylatoxin generation, and complement-mediated opsonization of S. aureus, suggesting that hyperglycemic inhibition of complement effectors may contribute to the increased risk and severity of S. aureus infections in diabetic patients. PMID:25610878

  12. A genetic rat model of cholinergic hypersensitivity: implications for chemical intolerance, chronic fatigue, and asthma.

    PubMed

    Overstreet, D H; Djuric, V

    2001-03-01

    The fact that only some individuals exposed to environmental chemicals develop chemical intolerance raises the possibility that genetic factors could be contributing factors. The present communication summarizes evidence from a genetic animal model of cholinergic supersensitivity that suggests that an abnormal cholinergic system could be one predisposing genetic factor. The Flinders Sensitive Line (FSL) rats were established by selective breeding for increased responses to an organophosphate. It was subsequently found that these FSL rats were also more sensitive to direct-acting muscarinic agonists and had elevated muscarinic receptors compared to the selectively bred parallel group, the Flinders Resistant Line (FRL) rats, or randomly bred control rats. Increased sensitivity to cholinergic agents has also been observed in several human populations, including individuals suffering from chemical intolerance. Indeed, the FSL rats exhibit certain behavioral characteristics such as abnormal sleep, activity, and appetite that are similar to those reported in these human populations. In addition, the FSL rats have been reported to exhibit increased sensitivity to a variety of other chemical agents. Peripheral tissues, such as intestinal and airway smooth muscle, appear to be more sensitive to both cholinergic agonists and an antigen, ovalbumin. Hypothermia, a centrally mediated response, is more pronounced in the FSL rats after nicotine and alcohol, as well as agents that are selective for the dopaminergic and serotonergic systems. In some cases, the increased sensitivity has been detected in the absence of any changes in the receptors with which the drugs interact (dopamine receptors), while receptor changes have been seen in other cases (nicotine receptors). Therefore, there may be multiple mechanisms underlying the multiple chemical sensitivity-chemical intolerance of the FSL rats. An elucidation of these mechanisms may provide useful clues to those involved in

  13. Genotypic and Phenotypic Characterization of P23H Line 1 Rat Model

    PubMed Central

    Orhan, Elise; Dalkara, Deniz; Neuillé, Marion; Lechauve, Christophe; Michiels, Christelle; Picaud, Serge; Léveillard, Thierry; Sahel, José-Alain; Naash, Muna I.; Lavail, Matthew M.; Zeitz, Christina; Audo, Isabelle

    2015-01-01

    Rod-cone dystrophy, also known as retinitis pigmentosa (RP), is the most common inherited degenerative photoreceptor disease, for which no therapy is currently available. The P23H rat is one of the most commonly used autosomal dominant RP models. It has been created by incorporation of a mutated mouse rhodopsin (Rho) transgene in the wild-type (WT) Sprague Dawley rat. Detailed genetic characterization of this transgenic animal has however never been fully reported. Here we filled this knowledge gap on P23H Line 1 rat (P23H-1) and provide additional phenotypic information applying non-invasive and state-of-the-art in vivo techniques that are relevant for preclinical therapeutic evaluations. Transgene sequence was analyzed by Sanger sequencing. Using quantitative PCR, transgene copy number was calculated and its expression measured in retinal tissue. Full field electroretinography (ERG) and spectral domain optical coherence tomography (SD-OCT) were performed at 1-, 2-, 3- and 6-months of age. Sanger sequencing revealed that P23H-1 rat carries the mutated mouse genomic Rho sequence from the promoter to the 3’ UTR. Transgene copy numbers were estimated at 9 and 18 copies in the hemizygous and homozygous rats respectively. In 1-month-old hemizygous P23H-1 rats, transgene expression represented 43% of all Rho expressed alleles. ERG showed a progressive rod-cone dysfunction peaking at 6 months-of-age. SD-OCT confirmed a progressive thinning of the photoreceptor cell layer leading to the disappearance of the outer retina by 6 months with additional morphological changes in the inner retinal cell layers in hemizygous P23H-1 rats. These results provide precise genotypic information of the P23H-1 rat with additional phenotypic characterization that will serve basis for therapeutic interventions, especially for those aiming at gene editing. PMID:26009893

  14. Hepatic drug metabolizing profile of Flinders Sensitive Line rat model of depression.

    PubMed

    Kotsovolou, Olga; Ingelman-Sundberg, Magnus; Lang, Matti A; Marselos, Marios; Overstreet, David H; Papadopoulou-Daifoti, Zoi; Johanson, Inger; Fotopoulos, Andrew; Konstandi, Maria

    2010-08-16

    The Flinders Sensitive Line (FSL) rat model of depression exhibits some behavioral, neurochemical, and pharmacological features that have been reported in depressed patients and has been very effective in screening antidepressants. Major factor that determines the effectiveness and toxicity of a drug is the drug metabolizing capacity of the liver. Therefore, in order to discriminate possible differentiation in the hepatic drug metabolism between FSL rats and Sprague-Dawley (SD) controls, their hepatic metabolic profile was investigated in this study. The data showed decreased glutathione (GSH) content and glutathione S-transferase (GST) activity and lower expression of certain major CYP enzymes, including the CYP2B1, CYP2C11 and CYP2D1 in FSL rats compared to SD controls. In contrast, p-nitrophenol hydroxylase (PNP), 7-ethoxyresorufin-O-dealkylase (EROD) and 16alpha-testosterone hydroxylase activities were higher in FSL rats. Interestingly, the wide spread environmental pollutant benzo(alpha)pyrene (B(alpha)P) induced CYP1A1, CYP1A2, CYP2B1/2 and ALDH3c at a lesser extend in FSL than in SD rats, whereas the antidepressant mirtazapine (MIRT) up-regulated CYP1A1/2, CYP2C11, CYP2D1, CYP2E1 and CYP3A1/2, mainly, in FSL rats. The drug also further increased ALDH3c whereas suppressed GSH content in B(alpha)P-exposed FSL rats. In conclusion, several key enzymes of the hepatic biotransformation machinery are differentially expressed in FSL than in SD rats, a condition that may influence the outcome of drug therapy. The MIRT-induced up-regulation of several drug-metabolizing enzymes indicates the critical role of antidepressant treatment that should be always taken into account in the designing of treatment and interpretation of insufficient pharmacotherapy or drug toxicity. PMID:20595028

  15. Analgesic effect of minocycline in rat model of inflammation-induced visceral pain.

    PubMed

    Kannampalli, Pradeep; Pochiraju, Soumya; Bruckert, Mitchell; Shaker, Reza; Banerjee, Banani; Sengupta, Jyoti N

    2014-03-15

    The present study investigates the analgesic effect of minocycline, a semi-synthetic tetracycline antibiotic, in a rat model of inflammation-induced visceral pain. Inflammation was induced in male rats by intracolonic administration of tri-nitrobenzenesulphonic acid (TNBS). Visceral hyperalgesia was assessed by comparing the viscero-motor response (VMR) to graded colorectal distension (CRD) prior and post 7 days after TNBS treatment. Electrophysiology recordings from CRD-sensitive pelvic nerve afferents (PNA) and lumbo-sacral (LS) spinal neurons were performed in naïve and inflamed rats. Colonic inflammation produced visceral hyperalgesia characterized by increase in the VMRs to CRD accompanied with simultaneous activation of microglia in the spinal cord and satellite glial cells (SGCs) in the dorsal root ganglions (DRGs). Selectively inhibiting the glial activation following inflammation by araC (Arabinofuranosyl Cytidine) prevented the development of visceral hyperalgesia. Intrathecal minocycline significantly attenuated the VMR to CRD in inflamed rats, whereas systemic minocycline produced a delayed effect. In electrophysiology experiments, minocycline significantly attenuated the mechanotransduction of CRD-sensitive PNAs and the responses of CRD-sensitive LS spinal neurons in TNBS-treated rats. While the spinal effect of minocycline was observed within 5min of administration, systemic injection of the drug produced a delayed effect (60min) in inflamed rats. Interestingly, minocycline did not exhibit analgesic effect in naïve, non-inflamed rats. The results demonstrate that intrathecal injection of minocycline can effectively attenuate inflammation-induced visceral hyperalgesia. Minocycline might as well act on neuronal targets in the spinal cord of inflamed rats, in addition to the widely reported glial inhibitory action to produce analgesia. PMID:24485889

  16. Analgesic effect of Minocycline in rat model of inflammation-induced visceral pain

    PubMed Central

    Kannampalli, Pradeep; Pochiraju, Soumya; Bruckert, Mitchell; Shaker, Reza; Banerjee, Banani; Sengupta, Jyoti N.

    2014-01-01

    The present study investigates the analgesic effect of minocycline, a semi-synthetic tetracycline antibiotic, in a rat model of inflammation-induced visceral pain. Inflammation was induced in male rats by intracolonic administration of tri-nitrobenzenesulphonic acid (TNBS). Visceral hyperalgesia was assessed by comparing the viscero-motor response (VMR) to graded colorectal distension (CRD) prior and post 7 days after TNBS treatment. Electrophysiology recordings from CRD-sensitive pelvic nerve afferents (PNA) and lumbo-sacral (LS) spinal neurons were performed in naïve and inflamed rats. Colonic inflammation produced visceral hyperalgesia characterized by increase in the VMRs to CRD accompanied with simultaneous activation of microglia in the spinal cord and satellite glial cells (SGCs) in the dorsal root ganglions (DRGs). Selectively inhibiting the glial activation following inflammation by araC (Arabinofuranosyl Cytidine) prevented the development of visceral hyperalgesia. Intrathecal minocycline significantly attenuated the VMR to CRD in inflamed rats, whereas systemic minocycline produced a delayed effect. In electrophysiology experiments, minocycline significantly attenuated the mechanotransduction of CRD-sensitive PNAs and the responses of CRD-sensitive LS spinal neurons in TNBS-treated rats. While the spinal effect of minocycline was observed within 5 min of administration, systemic injection of the drug produced a delayed effect (60 min) in inflamed rats. Interestingly, minocycline did not exhibit analgesic effect in naïve, non-inflamed rats. The results demonstrate that intrathecal injection of minocycline can effectively attenuate inflammation-induced visceral hyperalgesia. Minocycline might as well act on neuronal targets in the spinal cord of inflamed rats, in addition to the widely reported glial inhibitory action to produce analgesia. PMID:24485889

  17. Transgenesis and neuroendocrine physiology: a transgenic rat model expressing growth hormone in vasopressin neurones

    PubMed Central

    Wells, Sara E; Flavell, David M; Bisset, Gordon W; Houston, Pamela A; Christian, Helen; Fairhall, Keith M; Robinson, Iain C A F

    2003-01-01

    Human growth hormone (hGH) and bovine neurophysin (bNP) DNA reporter fragments were inserted into the rat vasopressin (VP) and oxytocin (OT) genes in a 44 kb cosmid construct used to generate two lines of transgenic rats, termed JP17 and JP59. Both lines showed specific hGH expression in magnocellular VP cells in the hypothalamic paraventricular (PVN) and supraoptic nuclei (SON). hGH was also expressed in parvocellular neurones in suprachiasmatic nuclei (SCN), medial amygdala and habenular nuclei in JP17 rats; the rat OT-bNP (rOT-bNP) transgene was not expressed in either line. Immunohistochemistry and radioimmunoassay showed hGH protein in the hypothalamus from where it was transported in varicose fibres via the median eminence to the posterior pituitary gland. Immunogold electron microscopy showed hGH co-stored with VP-NP in the same granules. The VP-hGH transgene did not affect water balance, VP storage or release in vivo. Drinking 2 % saline for 72 h increased hypothalamic transgene hGH mRNA expression, and depleted posterior pituitary hGH and VP stores in parallel. In anaesthetised, water-loaded JP17 rats, hGH was released with VP in response to an acute hypovolumic stimulus (sodium nitrosopentacyano, 400 μg I.V.). JP17 rats had a reduced growth rate, lower anterior pituitary rGH contents, and a reduced amplitude of endogenous pulsatile rGH secretion assessed by automated blood microsampling in conscious rats, consistent with a short-loop feedback of the VP-hGH on the endogenous GH axis. This transgenic rat model enables us to study physiological regulation of hypothalamic transgene protein production, transport and secretion, as well as its effects on other neuroendocrine systems in vivo. PMID:12813157

  18. A BBDR-HPT Axis Model for the Lactating Rat and Nursing Pup: Evaluation of Iodide Deficiency

    EPA Science Inventory

    A biologically based dose response (BBDR) model for the lactating rat and pup hypothalamic-pituitary-thyroid (HPT) axis is being developed to advance understanding of thyroid hormone disruptions and developmental neurotoxicity (DNT). The model for the lactating rat and pup quanti...

  19. Evaluation of survival and neurological deficit in rats in the new model of global transient cerebral ischemia.

    PubMed

    Chernysheva, G A; Smol'yakova, V I; Osipenko, A N; Plotnikov, M B

    2014-12-01

    We propose a modification to rat model of transient global cerebral ischemia with four-vessel occlusion avoiding pneumothorax and minimizing the consequences of surgery. Survival and neurological deficit in rats in this model was studied over 5 days. PMID:25430646

  20. Cardiovascular and hormonal (aldosterone) responses in a rat model which mimics responses to weightlessness

    NASA Technical Reports Server (NTRS)

    Musacchia, X. J.; Steffen, J. M.

    1984-01-01

    Cardiovascular responses and fluid/electrolyte shifts seen during spaceflight have been attributed to cephalad redistribution of vascular fluid. The antiorthostatic (AO) rat (suspended, head-down tilt of 15-20 deg) is used to model these responses. This study documents that elevated blood pressures in AO rats are sustained for periods of up to seven days, compared with presuspension values. Increased blood pressures in AO rats suggests a specific response to AO positioning, potentially relatable to a cephalad fluid shift. To assess a role for hormonal regulation of sodium excretion, serum aldosterone levels were measured. Circulating aldosterone concentrations were seen to increase approximately 100 percent during seven days of AO suspension, concurrently with a pronounced natriuresis. These results suggest that aldosterone may not be involved in the long term regulation of increased Na(+) excretion in AO animals. These studies continue to show the usefulness of models for the development of animal protocols for space flight.

  1. Simultaneous measurement of hemorheological and hemodynamic properties using a rat extracorporeal model

    NASA Astrophysics Data System (ADS)

    Yeom, Eunseop; Lee, Sang Joon; CenterBiofluid; Biomimetics Research Team

    2015-11-01

    It is well known that cardiovascular diseases (CVDs) are closely related with the variations of hemorheological and hemodynamic properties. Accurate measurement of these properties is essential for early diagnosis of CVDs. However, in vitro measurements have technical limitation for the accurate measurement because in vitro exposure can change hemorheological properties. To resolve this problem, a rat extracorporeal model which connects the artery and vein in a rat was employed in this study. Blood flows in the rat extracorporeal model were visualized by an ultrasound imaging system and microfluidic devices for monitoring hemorheological and hemodynamic properties. As a result, the system can be effectively used to measure blood viscosity, red blood cell aggregation and flow rate under ex vivo conditions. The present results would be helpful to develop a diagnostic modality for monitoring the variations in hemorheological and hemodynamic parameters. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea Government (MSIP) (No. 2008-0061991).

  2. Development of an FE model of the rat head subjected to air shock loading.

    PubMed

    Zhu, Feng; Mao, Haojie; Dal Cengio Leonardi, Alessandra; Wagner, Christina; Chou, Clifford; Jin, Xin; Bir, Cynthia; Vandevord, Pamela; Yang, King H; King, Albert I

    2010-11-01

    As early as the 1950's, Gurdjian and colleagues (Gurdjian et al. 1955) observed that brain injuries could occur by direct pressure loading without any global head accelerations. This pressure-induced injury mechanism was "forgotten" for some time and is being rekindled due to the many mild traumatic brain injuries attributed to blast overpressure. The aim of the current study was to develop a finite element (FE) model to predict the biomechanical response of rat brain under a shock tube environment. The rat head model, including more than 530,000 hexahedral elements with a typical element size of 100 to 300 microns was developed based on a previous rat brain model for simulating a blunt controlled cortical impact. An FE model, which represents gas flow in a 0.305-m diameter shock tube, was formulated to provide input (incident) blast overpressures to the rat model. It used an Eulerian approach and the predicted pressures were verified with experimental data. These two models were integrated and an arbitrary Lagrangian-Eulerian (ALE) fluid-structure coupling algorithm was then utilized to simulate the interaction of the shock wave with the rat head. The FE model-predicted pressure-time histories at the cortex and in the lateral ventricle were in reasonable agreement with those obtained experimentally. Further examination of the FE model predictions revealed that pressure amplification, caused by shock wave reflection at the interface of the materials with distinct wave impedances, was found in the skull. The overpressures in the anterior and posterior regions were 50% higher than those at the vertex and central regions, indicating a higher possibility of injuries in the coup and contrecoup sites. At an incident pressure of 85 kPa, the shear stress and principal strain in the brain remained at a low level, implying that they are not the main mechanism causing injury in the current scenario. PMID:21512910

  3. Role of group 3 innate lymphoid cells during experimental otitis media in a rat model.

    PubMed

    Cho, Chang Gun; Gong, Sung Ho; Kim, Hee-Bok; Song, Jae-Jun; Park, Joo Hyun; Lim, Yun-Sung; Park, Seok-Won

    2016-09-01

    The objective of this study was to evaluate the role of group 3 innate lymphoid cells (ILC3) in the middle ear (ME) mucosal response to bacterial infection in a rat model. To confirm the role of ILC3 in bacterially induced otitis media (OM), the serum concentrations of IL-17 and IL-22 were determined by ELISA, and the tissue expression of IL-17 and IL-22 in infected ME mucosa was assessed by immunohistochemical staining. Immunohistochemical staining of specific cell surface markers was also assessed to confirm the origin of the cells expressing IL-17 and IL-22. Twenty Sprague-Dawley rats were used in the surgically-induced animal model of OM. OM was induced by inoculation of non-typeable Haemophilus influenzae into the ME cavity of the rats. The rats were divided into four experimental groups: three infected groups and one control group. Infected groups were subdivided into sets of 5 rats, one for each of the three time points (1, 4 and 7 days post-inoculation). For determination of rat IL-17 and IL-22 levels in infected rats and control rats, infected or control ME mucosa sections were analyzed by immunohistochemistry with specific antibodies directed against IL-17 and IL-22. Immunohistochemical staining for CD3, RORγt, and NKp46 were also conducted on the samples to confirm the origin of cells expressing IL-17 and IL-22. IL-17 and IL-22 serum concentrations were significantly increased in the infected rats compared to control rats. Immunohistochemical staining revealed increased IL-17 and IL-22 expressions in all infected ME mucosae from the first day after inoculation. In addition, the results of tissue staining for the specific surface markers were negative for CD3 and NKp46, but were highly positive for RORγt. IL-17 and IL-22 revealed their association with the bacterially induced proliferative and hyperplastic responses of ME mucosa, which are characteristic features in pathogenesis of OM. Surface marker examination showed that the source cells for IL-17

  4. Left and right 6-hydroxydopamine lesions of the medial prefrontal cortex differentially affect voluntary ethanol consumption.

    PubMed

    Nielsen, D M; Crosley, K J; Keller, R W; Glick, S D; Carlson, J N

    1999-03-27

    Dopaminergic projections to the medial prefrontal cortex (mPFC) were unilaterally lesioned with 6-hydroxydopamine (6-OHDA) to examine how dopamine (DA) asymmetry in the mPFC influences voluntary ethanol consumption. Differences in nucleus accumbens (NAS) DA neurotransmission have been related to individual differences in locomotor activity and in the rewarding efficacy of ethanol. Therefore, differences in locomotor activity were used to further characterize the effects of unilateral mPFC 6-OHDA lesions on ethanol consumption. Male Long Evans rats were assessed for high versus low levels of spontaneous locomotor activity. DA terminals in the left or right mPFC were unilaterally lesioned with 6-OHDA, resulting in an average DA depletion of 54% and 50%, respectively. After a minimum seven-day recovery period, preference for a 10% ethanol solution vs. water was determined in a 24-h 2-bottle home-cage free-choice paradigm. Left mPFC 6-OHDA lesions increased and right lesions decreased ethanol consumption. These differential effects of left and right lesions were primarily attributable to rats exhibiting low locomotor activity prior to surgery. The present data suggest that right greater than left cortical DA asymmetry in combination with low endogenous NAS DA (predicted by low locomotor activity levels) may increase the vulnerability to abuse ethanol. PMID:10095012

  5. Particulate matter inhalation exacerbates cardiopulmonary injury in a rat model of isoproterenol-induced cardiomyopathy.

    PubMed

    Carll, Alex P; Haykal-Coates, Najwa; Winsett, Darrell W; Rowan, William H; Hazari, Mehdi S; Ledbetter, Allen D; Nyska, Abraham; Cascio, Wayne E; Watkinson, William P; Costa, Daniel L; Farraj, Aimen K

    2010-04-01

    Ambient particulate matter (PM) exposure is linked to cardiovascular events and death, especially among individuals with heart disease. A model of toxic cardiomyopathy was developed in Spontaneously Hypertensive Heart Failure (SHHF) rats to explore potential mechanisms. Rats were infused with isoproterenol (ISO; 2.5 mg/kg/day subcutaneous [sc]), a beta-adrenergic agonist, for 28 days and subsequently exposed to PM by inhalation. ISO induced tachycardia and hypotension throughout treatment followed by postinfusion decrements in heart rate, contractility, and blood pressures (systolic, diastolic, pulse), and fibrotic cardiomyopathy. Changes in heart rate and heart rate variability (HRV) 17 days after ISO cessation indicated parasympathetic dominance with concomitantly altered ventilation. Rats were subsequently exposed to filtered air or Harvard Particle 12 (HP12) (12 mg/m(3))--a metal-rich oil combustion-derived PM--at 18 and 19 days (4 h/day) after ISO infusion via nose-only inhalation to determine if cardio-impaired rats were more responsive to the effects of PM exposure. Inhalation of PM among ISO-pretreated rats significantly increased pulmonary lactate dehydrogenase, serum high-density lipoprotein (HDL) cholesterol, and heart-to-body mass ratio. PM exposure increased the number of ISO-pretreated rats that experienced bradyarrhythmic events, which occurred concomitantly with acute alterations of HRV. PM, however, did not significantly affect mean HRV in the ISO- or saline-pretreated groups. In summary, subchronic ISO treatment elicited some pathophysiologic and histopathological features of heart failure, including cardiomyopathy. The enhanced sensitivity to PM exposure in SHHF rats with ISO-accelerated cardiomyopathy suggests that this model may be useful for elucidating the mechanisms by which PM exposure exacerbates heart disease. PMID:20121584

  6. Modeling habituation in rat EEG-evoked responses via a neural mass model with feedback

    PubMed Central

    Tadmor, Gilead; Diamond, Solomon G.; Miller, Eric; Franceschini, Maria Angela; Brooks, Dana H.

    2012-01-01

    Habituation is a generic property of the neural response to repeated stimuli. Its strength often increases as inter-stimuli relaxation periods decrease. We propose a simple, broadly applicable control structure that enables a neural mass model of the evoked EEG response to exhibit habituated behavior. A key motivation for this investigation is the ongoing effort to develop model-based reconstruction of multimodal functional neuroimaging data. The control structure proposed here is illustrated and validated in the context of a biophysical neural mass model, developed by Riera et al. (Hum Brain Mapp 27(11):896–914, 2006; 28(4):335–354, 2007), and of simplifications thereof, using data from rat EEG response to medial nerve stimuli presented at frequencies from 1 to 8 Hz. Performance was tested by predictions of both the response to the next stimulus based on the current one, and also of continued stimuli trains over 4-s time intervals based on the first stimulus in the interval, with similar success statistics. These tests demonstrate the ability of simple generative models to capture key features of the evoked response, including habituation. PMID:22282292

  7. A new experimental model of acid- and endotoxin-induced acute lung injury in rats.

    PubMed

    Puig, F; Herrero, R; Guillamat-Prats, R; Gómez, M N; Tijero, J; Chimenti, L; Stelmakh, O; Blanch, L; Serrano-Mollar, A; Matthay, M A; Artigas, A

    2016-08-01

    The majority of the animal models of acute lung injury (ALI) are focused on the acute phase. This limits the studies of the mechanisms involved in later phases and the effects of long-term treatments. Thus the goal of this study was to develop an experimental ALI model of aspiration pneumonia, in which diffuse alveolar damage continues for 72 h. Rats were intratracheally instilled with one dose of HCl (0.1 mol/l) followed by another instillation of one dose of LPS (0, 10, 20, 30, or 40 μg/g body weight) 2 h later, which models aspiration of gastric contents that progresses to secondary lung injury from bacteria or bacterial products. The rats were euthanized at 24, 48, and 72 h after the last instillation. The results showed that HCl and LPS at all doses caused activation of inflammatory responses, increased protein permeability and apoptosis, and induced mild hypoxemia in rat lungs at 24 h postinstillation. However, this lung damage was present at 72 h only in rats receiving HCl and LPS at the doses of 30 and 40 μg/g body wt. Mortality (∼50%) occurred in the first 48 h and only in the rats treated with HCl and LPS at the highest dose (40 μg/g body wt). In conclusion, intratracheal instillation of HCl followed by LPS at the dose of 30 μg/g body wt results in severe diffuse alveolar damage that continues at least 72 h. This rat model of aspiration pneumonia-induced ALI will be useful for testing long-term effects of new therapeutic strategies in ALI. PMID:27317688

  8. Generation of a novel transgenic rat model for tracing extracellular vesicles in body fluids

    PubMed Central

    Yoshimura, Aya; Kawamata, Masaki; Yoshioka, Yusuke; Katsuda, Takeshi; Kikuchi, Hisae; Nagai, Yoshitaka; Adachi, Naoki; Numakawa, Tadahiro; Kunugi, Hiroshi; Ochiya, Takahiro; Tamai, Yoshitaka

    2016-01-01

    Extracellular vesicles (EVs) play an important role in the transfer of biomolecules between cells. To elucidate the intercellular transfer fate of EVs in vivo, we generated a new transgenic (Tg) rat model using green fluorescent protein (GFP)-tagged human CD63. CD63 protein is highly enriched on EV membranes via trafficking into late endosomes and is often used as an EV marker. The new Tg rat line in which human CD63-GFP is under control of the CAG promoter exhibited high expression of GFP in various body tissues. Exogenous human CD63-GFP was detected on EVs isolated from three body fluids of the Tg rats: blood serum, breast milk and amniotic fluid. In vitro culture allowed transfer of serum-derived CD63-GFP EVs into recipient rat embryonic fibroblasts, where the EVs localized in endocytic organelles. These results suggested that this Tg rat model should provide significant information for understanding the intercellular transfer and/or mother-child transfer of EVs in vivo. PMID:27539050

  9. Partial gene deletion in LEC rat: An animal model for Wilson disease

    SciTech Connect

    Wu, J.; Forbes, J.R.; Cox, D.W.

    1994-09-01

    Wilson disease is an inherited disorder of copper transport in which incorporation of copper into ceruloplasmin and excretion of copper into bile are greatly reduced. Copper accumulates to a toxic level in the liver and also in the brain and kidney, causing a spectrum of hepatic and neurological abnormalities. We have recently cloned the gene for Wilson disease (designated ATP7B), which encodes a putative copper-transporting P-type ATPase. The inbred mutant Long-Evans Cinnamon (LEC) rat strain shows similarity to Wilson disease in many clinical and biochemical features. We have cloned cDNAs for the rat homologue (Atp7b) of the human Wilson disease gene (ATP7B) and have shown that the two genes have {approximately}82% identity at the amino acid sequence level. Rat cDNA sequences were used to identify a partial deletion in the Atp7b gene in the LEC rat. The deletion removes at least 750 bp of the coding region at the 3{prime} end, which includes the crucial ATP binding domain and extends downstream of the gene. The proximal breakpoint has been precisely localized at the cDNA level. Our results provide convincing evidence that the LEC rat is an animal model for Wilson disease. This model will be important for studying liver pathophysiology, for developing therapy for Wilson disease, and for studying the pathway of copper transport and its possible interaction with other heavy metals.

  10. Development of a standardized laparoscopic caecum resection model to simulate laparoscopic appendectomy in rats

    PubMed Central

    2014-01-01

    Background Laparoscopic appendectomy (LA) has become one of the most common surgical procedures to date. To improve and standardize this technique further, cost-effective and reliable animal models are needed. Methods In a pilot study, 30 Wistar rats underwent laparoscopic caecum resection (as rats do not have an appendix vermiformis), to optimize the instrumental and surgical parameters. A subsequent test study was performed in another 30 rats to compare three different techniques for caecum resection and bowel closure. Results Bipolar coagulation led to an insufficiency of caecal stump closure in all operated rats (Group 1, n = 10). Endoloop ligation followed by bipolar coagulation and resection (Group 2, n = 10) or resection with a LigaSure™ device (Group 3, n = 10) resulted in sufficient caecal stump closure. Conclusions We developed a LA model enabling us to compare three different caecum resection techniques in rats. In conclusion, only endoloop closure followed by bipolar coagulation proved to be a secure and cost-effective surgical approach. PMID:24934381

  11. Zinc supplementation provides behavioral resiliency in a rat model of traumatic brain injury

    PubMed Central

    Cope, Elise C.; Morris, Deborah R.; Scrimgeour, Angus G.; VanLandingham, Jacob W.; Levenson, Cathy W.

    2011-01-01

    Depression, anxiety, and impairments in learning and memory are all associated with traumatic brain injury (TBI). Because of the strong link between zinc deficiency, depression, and anxiety, in both humans and rodent models, we hypothesized that dietary zinc supplementation prior to injury could provide behavioral resiliency to lessen the severity of these outcomes after TBI. Rats were fed a marginal zinc deficient (5 ppm), zinc adequate (30 ppm), or zinc supplemented (180 ppm) diet for 4 weeks followed by a moderately-severe TBI using the well-established model of controlled cortical impact (CCI). Following CCI, rats displayed depression-like behaviors as measured by the 2-bottle saccharin preference test for anhedonia. Injury also resulted in evidence of stress and impairments in Morris water maze (MWM) performance compared to sham-injured controls. While moderate zinc deficiency did not worsen outcomes following TBI, rats that were fed the zinc supplemented diet for 4 weeks showed significantly attenuated increases in adrenal weight (p<0.05) as well as reduced depression-like behaviors (p<0.001). Supplementation prior to injury improved resilience such that there was not only significant improvements in cognitive behavior compared to injured rats fed an adequate diet (p<0.01), there were no significant differences between supplemented and sham-operated rats in MWM performance at any point in the 10-day trial. These data suggest a role for supplemental zinc in preventing cognitive and behavioral deficits associated with TBI. PMID:21699908

  12. Small Animal Models for Human Metapneumovirus: Cotton Rat is More Permissive than Hamster and Mouse

    PubMed Central

    Zhang, Yu; Niewiesk, Stefan; Li, Jianrong

    2014-01-01

    Human metapneumovirus (hMPV) is the second most prevalent causative agent of pediatric respiratory infections worldwide. Currently, there are no vaccines or antiviral drugs against this virus. One of the major hurdles in hMPV research is the difficulty to identify a robust small animal model to accurately evaluate the efficacy and safety of vaccines and therapeutics. In this study, we compared the replication and pathogenesis of hMPV in BALB/c mice, Syrian golden hamsters, and cotton rats. It was found that BALB/c mice are not permissive for hMPV infection despite the use of a high dose (6.5 log10 PFU) of virus for intranasal inoculation. In hamsters, hMPV replicated efficiently in nasal turbinates but demonstrated only limited replication in lungs. In cotton rats, hMPV replicated efficiently in both nasal turbinate and lung when intranasally administered with three different doses (4, 5, and 6 log10 PFU) of hMPV. Lungs of cotton rats infected by hMPV developed interstitial pneumonia with mononuclear cells infiltrates and increased lumen exudation. By immunohistochemistry, viral antigens were detected at the luminal surfaces of the bronchial epithelial cells in lungs. Vaccination of cotton rats with hMPV completely protected upper and lower respiratory tract from wildtype challenge. The immunization also elicited elevated serum neutralizing antibody. Collectively, these results demonstrated that cotton rat is a robust small animal model for hMPV infection. PMID:25438015

  13. Porphyromonas gingivalis and Treponema denticola Mixed Microbial Infection in a Rat Model of Periodontal Disease

    PubMed Central

    Verma, Raj K.; Rajapakse, Sunethra; Meka, Archana; Hamrick, Clayton; Pola, Sheela; Bhattacharyya, Indraneel; Nair, Madhu; Wallet, Shannon M.; Aukhil, Ikramuddin; Kesavalu, Lakshmyya

    2010-01-01

    Porphyromonas gingivalis and Treponema denticola are periodontal pathogens that express virulence factors associated with the pathogenesis of periodontitis. In this paper we tested the hypothesis that P. gingivalis and T. denticola are synergistic in terms of virulence; using a model of mixed microbial infection in rats. Groups of rats were orally infected with either P. gingivalis or T. denticola or mixed microbial infections for 7 and 12 weeks. P. gingivalis genomic DNA was detected more frequently by PCR than T. denticola. Both bacteria induced significantly high IgG, IgG2b, IgG1, IgG2a antibody levels indicating a stimulation of Th1 and Th2 immune response. Radiographic and morphometric measurements demonstrated that rats infected with the mixed infection exhibited significantly more alveolar bone loss than shaminfected control rats. Histology revealed apical migration of junctional epithelium, rete ridge elongation, and crestal alveolar bone resorption; resembling periodontal disease lesion. These results showed that P. gingivalis and T. denticola exhibit no synergistic virulence in a rat model of periodontal disease. PMID:20592756

  14. Generation of a novel transgenic rat model for tracing extracellular vesicles in body fluids.

    PubMed

    Yoshimura, Aya; Kawamata, Masaki; Yoshioka, Yusuke; Katsuda, Takeshi; Kikuchi, Hisae; Nagai, Yoshitaka; Adachi, Naoki; Numakawa, Tadahiro; Kunugi, Hiroshi; Ochiya, Takahiro; Tamai, Yoshitaka

    2016-01-01

    Extracellular vesicles (EVs) play an important role in the transfer of biomolecules between cells. To elucidate the intercellular transfer fate of EVs in vivo, we generated a new transgenic (Tg) rat model using green fluorescent protein (GFP)-tagged human CD63. CD63 protein is highly enriched on EV membranes via trafficking into late endosomes and is often used as an EV marker. The new Tg rat line in which human CD63-GFP is under control of the CAG promoter exhibited high expression of GFP in various body tissues. Exogenous human CD63-GFP was detected on EVs isolated from three body fluids of the Tg rats: blood serum, breast milk and amniotic fluid. In vitro culture allowed transfer of serum-derived CD63-GFP EVs into recipient rat embryonic fibroblasts, where the EVs localized in endocytic organelles. These results suggested that this Tg rat model should provide significant information for understanding the intercellular transfer and/or mother-child transfer of EVs in vivo. PMID:27539050

  15. Bamboo leaf extract improves spatial learning ability in a rat model with senile dementia.

    PubMed

    Liu, Jian-xiang; Zhu, Min-ying; Feng, Ci-yuan; Ding, Hai-bin; Zhan, Ying; Zhao, Zhan; Ding, Yue-min

    2015-07-01

    Senile dementia (SD) is a syndrome characterized by progressive neurological deterioration. Treatment for the disease is still under investigation. Bamboo leaf extract (B-extract) has been known for its biological efficacy in anti-oxidant and anti-cancer activities. However, study on B-extract for its protection against dementia is very limited. The effect of B-extract on a rat model with SD was examined. B-extract improved spatial learning ability of the dementia rats. The hippocampus of dementia model rats showed reduced levels of acetylcholine (ACh), epinephrine (E), norepinephrine (NE), and dopamine (DA), and increased activities of acetylcholine esterase (AChE) and monoamine oxidase (MAO). Treatment with B-extract 20 mg/(kg·d) for 7 weeks significantly inhibited the enzyme activity compared with untreated dementia rats, and raised the levels of ACh, E, and DA in the hippocampus. In addition, treatment with B-extract elevated the level of γ-aminobutyric acid (GABA), but reduced the level of glutamate (Glu) in the brain. These data suggest that B-extract might be a potential drug in treating impairment of spatial memory in dementia rats by regulating the central neurotransmitter function. PMID:26160717

  16. The Establishment of Metabolic Syndrome Model by Induction of Fructose Drinking Water in Male Wistar Rats

    PubMed Central

    Thent, Zar Chi; Sapri, Shaiful Ridzwan; Sahruddin, Natasya Nadia; Mohd Yusof, Mohd Rafizul; Haji Suhaimi, Farihah

    2014-01-01

    Background. Metabolic syndrome can be caused by modification of diet by means of consumption of high carbohydrate and high fat diet such as fructose. Aims. To develop a metabolic syndrome rat model by induction of fructose drinking water (FDW) in male Wistar rats. Methods. Eighteen male Wistar rats were fed with FDW 20% and FDW 25% for a duration of eight weeks. The physiological changes with regard to food and fluid intake, as well as calorie intake, were measured. The metabolic changes such as obesity, dyslipidaemia, hypertension, and hyperglycaemia were determined. Data was presented in mean ± SEM subjected to one-way ANOVA. Results. Male Wistar rats fed with FDW 20% for eight weeks developed significant higher obesity parameters compared to those fed with FDW 25%. There was hypertrophy of adipocytes in F20 and F25. There were also systolic hypertension, hypertriglyceridemia, and hyperglycemia in both groups. Conclusion. We conclude that the metabolic syndrome rat model is best established with the induction of FDW 20% for eight weeks. This was evident in the form of higher obesity parameter which caused the development of the metabolic syndrome. PMID:25045660

  17. New Wistar Kyoto and spontaneously hypertensive rat transgenic models with ubiquitous expression of green fluorescent protein

    PubMed Central

    Garcia Diaz, Ana Isabel; Moyon, Ben; Coan, Philip M.; Alfazema, Neza; Venda, Lara; Woollard, Kevin; Aitman, Tim

    2016-01-01

    ABSTRACT The Wistar Kyoto (WKY) rat and the spontaneously hypertensive (SHR) rat inbred strains are well-established models for human crescentic glomerulonephritis (CRGN) and metabolic syndrome, respectively. Novel transgenic (Tg) strains add research opportunities and increase scientific value to well-established rat models. We have created two novel Tg strains using Sleeping Beauty transposon germline transgenesis, ubiquitously expressing green fluorescent protein (GFP) under the rat elongation factor 1 alpha (EF1a) promoter on the WKY and SHR genetic backgrounds. The Sleeping Beauty system functioned with high transgenesis efficiency; 75% of new rats born after embryo microinjections were transgene positive. By ligation-mediated PCR, we located the genome integration sites, confirming no exonic disruption and defining a single or low copy number of the transgenes in the new WKY-GFP and SHR-GFP Tg lines. We report GFP-bright expression in embryos, tissues and organs in both lines and show preliminary in vitro and in vivo imaging data that demonstrate the utility of the new GFP-expressing lines for adoptive transfer, transplantation and fate mapping studies of CRGN, metabolic syndrome and other traits for which these strains have been extensively studied over the past four decades. PMID:26769799

  18. Manifestation of Hyperandrogenism in the Continuous Light Exposure-Induced PCOS Rat Model

    PubMed Central

    Kang, Xuezhi; Jia, Lina; Shen, Xueyong

    2015-01-01

    Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder, and its pathogenesis has yet to be completely clarified. A fully convincing animal model has not been established for PCOS. In earlier studies, researchers have shown that the exposure of rats to continuous light can induce PCOS; nevertheless, hyperandrogenism, a key characteristic observed in human PCOS, has not been reported previously. In the present study, we found that (1) body weights decreased in female rats in a continuous light environment with both ovarian and uterine augmentation; (2) the estrous cycle in rats under continuous light environment was disordered, and polycystic ovary-like changes occurred, accompanied with fur loss and lethargy; and (3) serum testosterone levels in rats in a continuous light environment significantly increased. Our data suggest that continuous light can lead to the occurrence of PCOS in female rats without the need for drugs; this is a reasonable PCOS animal model that is more consistent with the natural disease state in humans; and poor sleep habits or negligence of sleep hygiene may be an important lifestyle factor in pathogenesis of PCOS. PMID:26064969

  19. Zinc supplementation provides behavioral resiliency in a rat model of traumatic brain injury.

    PubMed

    Cope, Elise C; Morris, Deborah R; Scrimgeour, Angus G; VanLandingham, Jacob W; Levenson, Cathy W

    2011-10-24

    Depression, anxiety, and impairments in learning and memory are all associated with traumatic brain injury (TBI). Because of the strong link between zinc deficiency, depression, and anxiety, in both humans and rodent models, we hypothesized that dietary zinc supplementation prior to injury could provide behavioral resiliency to lessen the severity of these outcomes after TBI. Rats were fed a marginal zinc deficient (5 ppm), zinc adequate (30 ppm), or zinc supplemented (180 ppm) diet for 4 weeks followed by a moderately-severe TBI using the well-established model of controlled cortical impact (CCI). Following CCI, rats displayed depression-like behaviors as measured by the 2-bottle saccharin preference test for anhedonia. Injury also resulted in evidence of stress and impairments in Morris water maze (MWM) performance compared to sham-injured controls. While moderate zinc deficiency did not worsen outcomes following TBI, rats that were fed the zinc supplemented diet for 4 weeks showed significantly attenuated increases in adrenal weight (p<0.05) as well as reduced depression-like behaviors (p<0.001). Supplementation prior to injury improved resilience such that there was not only significant improvements in cognitive behavior compared to injured rats fed an adequate diet (p<0.01), there were no significant differences between supplemented and sham-operated rats in MWM performance at any point in the 10-day trial. These data suggest a role for supplemental zinc in preventing cognitive and behavioral deficits associated with TBI. PMID:21699908

  20. New Wistar Kyoto and spontaneously hypertensive rat transgenic models with ubiquitous expression of green fluorescent protein.

    PubMed

    Garcia Diaz, Ana Isabel; Moyon, Ben; Coan, Philip M; Alfazema, Neza; Venda, Lara; Woollard, Kevin; Aitman, Tim

    2016-04-01

    The Wistar Kyoto (WKY) rat and the spontaneously hypertensive (SHR) rat inbred strains are well-established models for human crescentic glomerulonephritis (CRGN) and metabolic syndrome, respectively. Novel transgenic (Tg) strains add research opportunities and increase scientific value to well-established rat models. We have created two novel Tg strains using Sleeping Beauty transposon germline transgenesis, ubiquitously expressing green fluorescent protein (GFP) under the rat elongation factor 1 alpha (EF1a) promoter on the WKY and SHR genetic backgrounds. The Sleeping Beauty system functioned with high transgenesis efficiency; 75% of new rats born after embryo microinjections were transgene positive. By ligation-mediated PCR, we located the genome integration sites, confirming no exonic disruption and defining a single or low copy number of the transgenes in the new WKY-GFP and SHR-GFP Tg lines. We report GFP-bright expression in embryos, tissues and organs in both lines and show preliminaryin vitroandin vivoimaging data that demonstrate the utility of the new GFP-expressing lines for adoptive transfer, transplantation and fate mapping studies of CRGN, metabolic syndrome and other traits for which these strains have been extensively studied over the past four decades. PMID:26769799

  1. Functional MRI and neural responses in a rat model of Alzheimer’s disease

    PubMed Central

    Sanganahalli, Basavaraju G.; Herman, Peter; Behar, Kevin L.; Blumenfeld, Hal; Rothman, Douglas L.; Hyder, Fahmeed

    2013-01-01

    Based on the hypothesis that brain plaques and tangles can affect cortical functions in Alzheimer's disease (AD) and thus modify functional activity, we investigated functional responses in an AD rat model (called the Samaritan Alzheimer’s rat achieved by ventricular infusion of amyloid peptide) and age-matched healthy control. High-field functional magnetic resonance imaging (fMRI) and extracellular neural activity measurements were applied to characterize sensory-evoked responses. Electrical stimulation of the forepaw led to BOLD and neural responses in the contralateral somatosensory cortex and thalamus. In AD brain we noted much smaller BOLD activation patterns in the somatosensory cortex (i.e., about 50% less activated voxels compared to normal brain). While magnitudes of BOLD and neural responses in the cerebral cortex were markedly attenuated in AD rats compared to normal rats (by about 50%), the dynamic coupling between the BOLD and neural responses in the cerebral cortex, as assessed by transfer function analysis, remained unaltered between the groups. However thalamic BOLD and neural responses were unaltered in AD brain compared to controls. Thus cortical responses in the AD model were indeed diminished compared to controls, but the thalamic responses in the AD and control rats were quite similar. Therefore these results suggest that Alzheimer’s disease may affect cortical function more than subcortical function, which may have implications for interpreting altered human brain functional responses in fMRI studies of Alzheimer’s disease. PMID:23648961

  2. Analgesic Effect of Intrathecal Gabapentin in a Rat Model of Persistent Muscle Pain

    PubMed Central

    Kang, Tae-Wook; Sohn, Min Kyun; Park, Noh Kyoung; Ko, Sang Hyung; Cho, Kyoung Jin; Beom, Jaewon

    2014-01-01

    Objective To evaluate the analgesic effect of intrathecal gabapentin therapy on secondary hyperalgesia in a rat model of persistent muscle pain. Methods Intrathecal catheters were implanted into rats. Mechanical secondary hyperalgesia was induced by repeated intramuscular injections of acidic solution into the gastrocnemius muscle. Gabapentin was administrated intrathecally. Rats were allocated to control and experimental (gabapentin 30, 100, 300, and 1,000 µg) group. After gabapentin administration, mechanical withdrawal threshold was measured every 15 minutes and the motor function was measured 30 minutes later. Results Mechanical hyperalgesia was evoked after the second acidic buffer injection. There was a significant improvement on the mechanical threshold after administration of 100, 300, and 1,000 µg gabapentin compared to pre-injection and the control group. The analgesic effect continued for 105, 135, and 210 minutes, respectively. To discern side effects, motor function was measured. Motor function was preserved in both groups after gabapentin administration, except for rats who received 1,000 µg gabapentin. Conclusion Intrathecal gabapentin administration produces dose-dependent improvements in mechanical hyperalgesia in a persistent muscle pain rat model. This implicates the central nervous system as having a strong influence on the development of persistent mechanical hyperalgesia. These results are helpful in understanding the pathophysiology of secondary hyperalgesia and in the treatment of patients with chronic muscle pain. PMID:25379498

  3. Evaluation of the response of rat skeletal muscle to a model of weightlessness

    NASA Technical Reports Server (NTRS)

    Templeton, G. H.; Padalino, M.; Glasberg, M.; Manton, J.; Silver, P.; Sutko, J.

    1982-01-01

    Suspension of rats in a head-down tilt position such that their hind limbs are non-load bearing has been proposed as a model for weightlessness. Changes observed in metabolism, bone formation (Morey et al., 1979), and muscle catabolism (Mussachia et al., 1980) support the validity of the model. To further document this model, the effects of suspension on the mechanical, biochemical and histochemical characteristics of two hind limb skeletal muscles, the gastrocnemius and the soleus, are investigated.

  4. Effects of Astragalus polysaccharides on memory impairment in a diabetic rat model

    PubMed Central

    Dun, Changping; Liu, Junqian; Qiu, Fucheng; Wu, Xueda; Wang, Yakun; Zhao, Yongyan; Gu, Ping

    2016-01-01

    Objective Astragalus polysaccharides (APS) are active constituents of Astragalus membranaceus. In this study, we aimed to investigate the effects of APS on memory impairment in a diabetic rat model and their mechanisms. Methods A diabetic model was established in 50 male Wistar rats with streptozotocin intra-peritoneal injection. A blood glucose level higher than 16.7 mmol/L obtained 72 hours after the injection was regarded as a successful diabetic model. The modeled rats were divided into model group, high, medium, and low doses of APS, and piracetam groups (positive control). A group of ten rats without streptozotocin-induced diabetes were used as a normal control. After respective consecutive 8-week treatments, the levels of blood fasting plasma glucose, insulin, hemoglobin A1c, memory performance, hippocampal malondialdehyde, and superoxide dismutase were determined. Results After the 8-week APS treatment, serum fasting plasma glucose, hemoglobin A1c, and insulin levels were decreased compared with those of the model group (P<0.05). Importantly, memory impairment in the diabetic model was reversed by APS treatments. In addition, hippocampal malondialdehyde concentration was lowered, whereas that of superoxide dismutase was higher after APS treatments. Conclusion APS are important active components responsible for memory improvement in rats with streptozotocin-induced diabetes. The potential mechanism of action is associated with the effects of APS on glucose and lipid metabolism, and antioxidative and insulin resistance. APS are constituents of A. membranaceus that are potential candidate therapeutic agents for the treatment of memory deficit in diabetes. PMID:27445477

  5. Pathogenicity of enterococci in a rat model of fecal peritonitis.

    PubMed

    Matlow, A G; Bohnen, J M; Nohr, C; Christou, N; Meakins, J

    1989-07-01

    The pathogenicity of enterococci in intraabdominal sepsis has not been clarified. Therefore, fecal-type peritonitis was induced in rats by intraperitoneal injection of barium sulfate along with a bacterial inoculum consisting of Escherichia coli, Bacteroides fragilis, and Clostridium perfringens with or without Streptococcus faecalis. Mortality at 19 d and characteristics of intraabdominal abscesses in survivors at 19 d were analyzed. The presence of S. faecalis in the original inoculum was significantly associated with death or large (greater than 20 mm) abscess formation when these two end points were examined together. S. faecalis may synergize with other bacteria in intraabdominal sepsis to augment morbidity and possibly mortality. PMID:2543707

  6. Beneficial effect of farnesoid X receptor activation on metabolism in a diabetic rat model.

    PubMed

    Zhang, Hong-Mei; Wang, Xuan; Wu, Zhao-Hong; Liu, Hui-Ling; Chen, Wei; Zhang, Zhong-Zhi; Chen, Dan; Zeng, Tian-Shu

    2016-03-01

    Farnesoid X receptor (FXR) is an important regulator of glucose and lipid homeostasis. However, the exact role of FXR in diabetes remains to be fully elucidated. The present study examined the effects of chenodeoxycholic acid (CDCA), an agonist of FXR, on metabolism profile in a rat model of type 2 diabetes mellitus (T2DM). Male Wistar rats (8‑week‑old; n=40) were randomized into the following four groups (n=10): Untreated control, CDCA‑treated, T2DM, and CDCA‑treated T2DM. To establish the T2DM model, the rats were fed a high‑fat diet (HFD) for 4 weeks and received a single low‑dose intraperitoneal injection of streptozotocin (30 mg/kg), followed by an additional 4 weeks of HFD feeding. CDCA was administrated (10 mg/kg/d) intraperitoneally for 10 days. Reverse transcription‑quantitative polymerase chain reaction and western blotting assays were performed to determine the RNA and protein expression of FXR, phosphoenolpyruvate carboxykinase, G6Pase, proliferator‑activated receptor‑γ coactivator‑1 and short heterodimer partner in rat liver tissue. The results revealed that FXR activation by CDCA did not reduce body weight, but it lowered the plasma levels of fasting glucose, insulin and triglycerides in the T2DM rats. CDCA administration reversed the downregulation of the mRNA and protein expression of FXR in the T2DM rat liver tissue samples. Furthermore, treatment with CDCA reduced the mRNA and protein expression levels of phosphoenolpyruvate carboxykinase, glucose 6‑phosphatase and peroxisome proliferator‑activated receptor‑γ coactivator‑1 in the liver tissue samples of the T2DM rats. By contrast, CDCA treatment increased the mRNA and protein expression levels of short heterodimer partner in the liver tissue samples of the T2DM rats. In conclusion, FXR agonist treatment induces beneficial effects on metabolism in the rat T2DM model. In conclusion, the present study indicated that the FXR agonist may be useful for the treatment

  7. Berberine ameliorates cartilage degeneration in interleukin-1β-stimulated rat chondrocytes and in a rat model of osteoarthritis via Akt signalling

    PubMed Central

    Zhao, Honghai; Zhang, Tongen; Xia, Chun; Shi, Lei; Wang, Shaojie; Zheng, Xinpeng; Hu, Tianhui; Zhang, Bing

    2014-01-01

    Berberine, a plant alkaloid used in Chinese medicine, has broad cell-protective functions in a variety of cell lines. Chondrocyte apoptosis contributes to the pathogenesis of cartilage degeneration in osteoarthritis (OA). However, little is known about the effect and underlying mechanism of berberine on OA chondrocytes. Here, we assessed the effects of berberine on cartilage degeneration in interleukin-1β (IL-1β)-stimulated rat chondrocytes and in a rat model of OA. The results of an MTT assay and western blotting analysis showed that berberine attenuated the inhibitory effect of IL-1β on the cell viability and proliferating cell nuclear antigen expression in rat chondrocytes. Furthermore, berberine activated Akt, which triggered p70S6K/S6 pathway and up-regulated the levels of aggrecan and Col II expression in IL-1β-stimulated rat chondrocytes. In addition, berberine increased the level of proteoglycans in cartilage matrix and the thickness of articular cartilage, with the elevated levels of Col II, p-Akt and p-S6 expression in a rat OA model, as demonstrated by histopathological and immunohistochemistry techniques. The data thus strongly suggest that berberine may ameliorate cartilage degeneration from OA by promoting cell survival and matrix production of chondrocytes, which was partly attributed to the activation of Akt in IL-1β-stimulated articular chondrocytes and in a rat OA model. The resultant chondroprotective effects indicate that berberine merits consideration as a therapeutic agent in OA. PMID:24286347

  8. Bisphenol A Induces Hepatotoxicity through Oxidative Stress in Rat Model

    PubMed Central

    Hassan, Zeinab K.; Elobeid, Mai A.; Virk, Promy; Omer, Sawsan A.; ElAmin, Maha; Daghestani, Maha H.; AlOlayan, Ebtisam M.

    2012-01-01

    Reactive oxygen species (ROS) are cytotoxic agents that lead to significant oxidative damage. Bisphenol A (BPA) is a contaminant with increasing exposure to it and exerts both toxic and estrogenic effects on mammalian cells. Due to limited information concerning the effect of BPA on liver, this study investigates whether BPA causes hepatotoxicity by induction of oxidative stress in liver. Rats were divided into five groups: The first four groups, BPA (0.1, 1, 10, 50 mg/kg/day) were administrated orally to rats for four weeks. The fifth group was taken water with vehicle. The final body weights in the 0.1 mg group showed a significant decrease compared to control group. Significant decreased levels of reduced glutathione, superoxide dismutase, glutathione peroxidase, glutathione-S-transferase, glutathione reductase and catalase activity were found in the 50 mg BPA group compared to control groups. High dose of BPA (50 mg/kg) significantly increased the biochemical levels of ALT, ALP and total bilirubin. BPA effect on the activity of antioxidant genes was confirmed by real time PCR in which the expression levels of these genes in liver tissue were significantly decrease compared to control. Data from this study demonstrate that BPA generate ROS and reduce the antioxidant gene expression that causes hepatotoxicity. PMID:22888396

  9. Hyperbilirubinemia Diminishes Respiratory Drive in a Rat Pup Model

    PubMed Central

    Mesner, Oded; Miller, Martha J.; Iben, Sabine C.; Kc, Prabha; Mayer, Catherine A.; A. Haxhiu, Musa; Martin, Richard J.

    2008-01-01

    Although apnea is common in premature babies, there is a paucity of information concerning the pathophysiologic basis of these episodes and their relationship to other perinatal conditions such as hyperbilirubinemia. Unconjugated hyperbilirubinemia in premature infants, even in moderately high levels, may cause encephalopathy affecting brainstem functions and has been linked to increased incidence of apnea in these infants. Thus, there is a need to clarify mechanisms by which bilirubin may alter respiratory control and induce apnea of prematurity. In this study, bilirubin or placebo was infused intravenously in 9 day-old rat pups, n=36. Serum hyperbilirubinemia peaked in the first hours after bilirubin infusion. Twenty four hours after bilirubin infusion, respiration was recorded by plethysmography at rest and under hypercapnic and hypoxic conditions. In treated pups, minute ventilation on room air was significantly reduced, hyperventilatory response to CO2 was blunted and hypoxic ventilatory depression was increased, as compared to placebo injected rat pups. Brainstem bilirubin deposition and immunoreactivity to bilirubin was detected in the brainstem on histologic analysis. We speculate that high serum bilirubin levels may cause prolonged inhibition of brainstem autonomic function and that this could underlie the exacerbation of apnea noted in premature babies who have experienced jaundice. PMID:18458654

  10. Microglial Activation in Rat Experimental Spinal Cord Injury Model

    PubMed Central

    Abdanipour, Alireza; Tiraihi, Taki; Taheri, Taher; Kazemi, Hadi

    2013-01-01

    Background: The present study was designed to evaluate the secondary microglial activation processes after spinal cord injury (SCI). Methods: A quantitative histological study was performed to determine ED-1 positive cells, glial cell density, and cavitation size in untreated SCI rats at days 1, 2, and 4, and weeks 1, 2, 3, and 4. Results: The results of glial cell quantification along the 4900-µm long injured spinal cord showed a significant increase in glial cell density percentage at day 2 as compared to other days. Whereas the highest increase in ED-1 immunoreactive cells (monocyte/phagocyte marker in rats) was observed at day 2 (23.15%) post-injury. Evaluation of cavity percentage showed a significant difference between weeks 3 and 4 post-injury groups. Conclusions: This study provides a new insight into the multiphase immune response to SCI, including cellular inflammation, macrophages/microglia activation, glial cell density, and cavitation. Better understanding of the inflammatory processes associated with acute SCI would permit the development of better therapeutic strategies. PMID:23999718

  11. Apricot ameliorates alcohol induced testicular damage in rat model.

    PubMed

    Kurus, Meltem; Ugras, Murat; Ates, Burhan; Otlu, Ali

    2009-10-01

    In this study, we intended to determine the possible preventive effects of dietary apricot on oxidative stress due to ethanol usage in rat testes. The animals were divided into six groups as follows: Group 1 was control. Group 2 received ethanol. Group 3 were fed with apricot diet for 3 months. Group 4 were fed with apricot diet for 6 months. Group 5 received ethanol and apricot diet for 3 months. Group 6 were fed apricot diet for 3 months, and then ethanol+apricot diet for 3 months. Following sacrification, the testes were treated for morphological (tubular and germ cell histology, Sertoli and Leydig cell counts) and biochemical (superoxide dismutase, glutathion peroxidase, catalase, malondialdehyde) analyses. In Group 2, severe histopathological changes in seminiferous tubules and germ cells were determined as well as tubular degeneration and atrophy. Sertoli and Leydig cell counts in the interstitial tissue were decreased. Biochemical parameters revealed tissue oxidative stress. Similar alterations existed in Group 5, although to a lesser extent. In Groups 1, 3 and 4, no histopathological alterations were noted. Results of Group 6 were similar to the controls. Apricot rich diet may have a preventive role on histopathological changes caused by alcohol in rat testes. PMID:19651185

  12. Aspergillus infection monitored by multimodal imaging in a rat model.

    PubMed

    Pluhacek, Tomas; Petrik, Milos; Luptakova, Dominika; Benada, Oldrich; Palyzova, Andrea; Lemr, Karel; Havlicek, Vladimir

    2016-06-01

    Although myriads of experimental approaches have been published in the field of fungal infection diagnostics, interestingly, in 21st century there is no satisfactory early noninvasive tool for Aspergillus diagnostics with good sensitivity and specificity. In this work, we for the first time described the fungal burden in rat lungs by multimodal imaging approach. The Aspergillus infection was monitored by positron emission tomography and light microscopy employing modified Grocott's methenamine silver staining and eosin counterstaining. Laser ablation inductively coupled plasma mass spectrometry imaging has revealed a dramatic iron increase in fungi-affected areas, which can be presumably attributed to microbial siderophores. Quantitative elemental data were inferred from matrix-matched standards prepared from rat lungs. The iron, silver, and gold MS images collected with variable laser foci revealed that particularly silver or gold can be used as excellent elements useful for sensitively tracking the Aspergillus infection. The limit of detection was determined for both (107) Ag and (197) Au as 0.03 μg/g (5 μm laser focus). The selective incorporation of (107) Ag and (197) Au into fungal cell bodies and low background noise from both elements were confirmed by energy dispersive X-ray scattering utilizing the submicron lateral resolving power of scanning electron microscopy. The low limits of detection and quantitation of both gold and silver make ICP-MS imaging monitoring a viable alternative to standard optical evaluation used in current clinical settings. PMID:27060291

  13. Phospholipase A2 in Experimental Allergic Bronchitis: A Lesson from Mouse and Rat Models

    PubMed Central

    Mruwat, Rufayda; Yedgar, Saul; Lavon, Iris; Ariel, Amiram; Krimsky, Miron; Shoseyov, David

    2013-01-01

    Background Phospholipases A2 (PLA2) hydrolyzes phospholipids, initiating the production of inflammatory lipid mediators. We have previously shown that in rats, sPLA2 and cPLA2 play opposing roles in the pathophysiology of ovalbumin (OVA)-induced experimental allergic bronchitis (OVA-EAB), an asthma model: Upon disease induction sPLA2 expression and production of the broncho-constricting CysLTs are elevated, whereas cPLA2 expression and the broncho-dilating PGE2 production are suppressed. These were reversed upon disease amelioration by treatment with an sPLA2 inhibitor. However, studies in mice reported the involvement of both sPLA2 and cPLA2 in EAB induction. Objectives To examine the relevance of mouse and rat models to understanding asthma pathophysiology. Methods OVA-EAB was induced in mice using the same methodology applied in rats. Disease and biochemical markers in mice were compared with those in rats. Results As in rats, EAB in mice was associated with increased mRNA of sPLA2, specifically sPLA2gX, in the lungs, and production of the broncho-constricting eicosanoids CysLTs, PGD2 and TBX2 in bronchoalveolar lavage (BAL). In contrast, EAB in mice was associated also with elevated cPLA2 mRNA and PGE2 production. Yet, treatment with an sPLA2 inhibitor ameliorated the EAB concomitantly with reverting the expression of both cPLA2 and sPLA2, and eicosanoid production. Conclusions In both mice and rats sPLA2 is pivotal in OVA-induced EAB. Yet, amelioration of asthma markers in mouse models, and human tissues, was observed also upon cPLA2 inhibition. It is plausible that airway conditions, involving multiple cell types and organs, require the combined action of more than one, essential, PLA2s. PMID:24204651

  14. Establishment of a rat model for osteoarthritis resulting from anterior cruciate ligament rupture and its significance

    PubMed Central

    OUYANG, XIAO; WANG, JIAN; HONG, SHI DONG; XIN, FENG; WANG, LIN; YANG, XIAO WEI; WANG, JING RONG; WANG, LI MING; WEI, BO; WANG, QING; CUI, WEI DING

    2015-01-01

    The purpose of this study was to examine the establishment of a model concerned with osteoarthritis resulting from the anterior cruciate ligament rupture of rats and investigate the associated mechanism, as well as provide a theoretical basis for clinical treatment of the disease. Forty Sprague-Dawley male rats were randomly divided into two groups of 20 rats each and the anterior cruciate ligament transaction model and knee joint brake model were successfully established. Two rats in the anterior cruciate ligament transection group (10%) and 3 rats in the knee joint brake group (15.0%) died. The survival rate of the two groups was not statistically significant (χ2<0.001, P=1.000). Swelling of the knee joint and synovium of rats in the two experimental groups was aggravated. The Mankin score was significantly higher in the anterior cruciate ligament transection group than that in the experimental group and the difference was statistically significant (P<0.05). By contrast, no significant difference was observed for osteoarthritis severity for the two experimental groups (P>0.05). Analysis of the subgroups showed that the proportion of the anterior cruciate ligament in the experimental group was significantly higher than that of the knee joint brake group, and the difference was statistically significant (P<0.05). By contrast, the difference was not statistically significant in the comparison of the medium and early proportion (P>0.05). The content of protein polysaccharide and II collagen fiber in the experimental group of the anterior cruciate ligament transection was lower than that of the knee joint brake group, and this difference was statistically significant (P<0.05). Thus the mechanism of osteoarthritis may be associated with the decrease in the content of protein and II collagen fibers. PMID:26668592

  15. DEVELOPMENT OF A PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL FOR DELTAMETHRIN IN DEVELOPING SPRAGUE-DAWLEY RATS

    EPA Science Inventory

    This work describes the development of a physiologically based pharmacokinetic (PBPK) model of deltamethrin, a type II pyrethroid, in the developing male Sprague-Dawley rat. Generalized Michaelis-Menten equations were used to calculate metabolic rate constants and organ weights ...

  16. ESTIMATING CHLOROFORM BIOTRANSFORMATION IN F-344 RAT LIVER USING IN VITRO TECHNIQUES AND PHARMACOKINETIC MODELING

    EPA Science Inventory

    ESTIMATING CHLOROFORM BIOTRANSFORMATION IN F-344 RAT LIVER USING IN VITRO TECHNIQUES AND PHARMACOKINETIC MODELING

    Linskey, C.F.1, Harrison, R.A.2., Zhao, G.3., Barton, H.A., Lipscomb, J.C4., and Evans, M.V2., 1UNC, ESE, Chapel Hill, NC ; 2USEPA, ORD, NHEERL, RTP, NC; 3 UN...

  17. [Effect and mechanism of icariin on myocardial ischemia-reperfusion injury model in diabetes rats].

    PubMed

    Hu, Yan-wu; Liu, Kai; Yan, Meng-tong

    2015-11-01

    To study the therapeutic effect and possible mechanism of icariin on myocardial ischemia-reperfusion injury ( MIRI) model in diabetes rats. The model of diabetic rats were induced by Streptozotocin (STZ), then the model of MIRI was established by ligating the reversible left anterior descending coronary artery for 30 min, and then reperfusing for 120 min. totally 40 male SD were randomly divided into five groups: the control group (NS), the ischemia reperfusion group (NIR), the diabetes control group (MS), the diabetic ischemia reperfusion group (MIR) and the diabetic ischemia reperfusion with icariin group (MIRI). The changes in blood glucose, body weight and living status were observed; the enzyme activity of serum CK-MB, LDH, GSH-Px and myocardium SOD and the content MDA and NO in myocardium were detected; the myocardial pathological changes were observed by HE staining; the myocardial Caspase-3, the Bcl-2, Bax protein expressions were detected by Western blot. The result showed that the diabetes model was successfully replicated; myocardial ischemia-reperfusion injury was more serious in diabetes rats; icariin can increase NO, SOD, GSH-Px, Bcl-2 protein expression, decrease MDA formation, CK-MB and LDH activities and Caspase-3 and Bcl-2 protein expressions and myocardial damage. The result suggested that icariin may play a protective role against ischemia reperfusion myocardial injury in diabetes rats by resisting oxidative stress and inhibiting cell apoptosis. PMID:27071263

  18. Strain Differences in Antioxidants in Rat Models of Cardiovascular Disease Exposed to Ozone

    EPA Science Inventory

    We examined the hypothesis that antioxidant substances and enzymes in lung, heart and in bronchoalveolar lavage fluid (BALF) are altered in response to 03 in cardiovascular disease and/or metabolic syndrome (CVD)-prone rat models. CVD strains [spontaneously hypertensive (SH), SH ...

  19. Variability in Ozone-Induced Pulmonary Injury and Inflammation in Healthy and Cardiovascular Compromised Rat Models

    EPA Science Inventory

    The molecular bases for variability in air pollutant-induced pulmonary injury due to underlying cardiovascular (CVD) and/or metabolic diseases are unknown. We hypothesized that healthy and genetic CVD-prone rat models will exhibit exacerbated response to acute ozone exposure depe...

  20. ASSESSMENT OF ESTROGENICITY BY USING THE DELAYED IMPLANTING RAT MODEL AND EXAMPLES

    EPA Science Inventory

    Assessment of estrogenicity by using the delayed implanting rat model and examples.

    Cummings AM, Laws SC.

    Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, N...

  1. Procaine Attenuates Pain Behaviors of Neuropathic Pain Model Rats Possibly via Inhibiting JAK2/STAT3

    PubMed Central

    Li, Donghua; Yan, Yurong; Yu, Lingzhi; Duan, Yong

    2016-01-01

    Neuropathic pain (NPP) is the main culprit among chronic pains affecting the normal life of patients. Procaine is a frequently-used local anesthesia with multiple efficacies in various diseases. However, its role in modulating NPP has not been reported yet. This study aims at uncovering the role of procaine in NPP. Rats were pretreated with procaine by intrathecal injection. Then NPP rat model was induced by sciatic nerve chronic compression injury (CCI) and behavior tests were performed to analyze the pain behaviors upon mechanical, thermal and cold stimulations. Spinal expression of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) was detected by qRT-PCR and western blot. JAK2 was also overexpressed in procaine treated model rats for behavior tests. Results showed that procaine pretreatment improved the pain behaviors of model rats upon mechanical, thermal and cold stimulations, with the best effect occurring on the 15th day post model construction (p<0.05). Procaine also inhibited JAK2 and STAT3 expression in both mRNA (p<0.05) and protein levels. Overexpression of JAK2 increased STAT3 level and reversed the improvement effects of procaine in pain behaviors (p<0.01). These findings indicate that procaine is capable of attenuating NPP, suggesting procaine is a potential therapeutic strategy for treating NPP. Its role may be associated with the inhibition on JAK2/STAT3 signaling. PMID:27530113

  2. Application of Mathematical Modelling as a Tool to Analyze the EEG Signals in Rat Model of Focal Cerebral Ischemia

    NASA Astrophysics Data System (ADS)

    Paul, S.; Bhattacharya, P.; Pandey, A. K.; Patnaik, R.

    2014-01-01

    The present paper envisages the application of mathematical modelling with the autoregressive (AR) model method as a tool to analyze electroencephalogram data in rat subjects of transient focal cerebral ischemia. This modelling method was used to determine the frequencies and characteristic changes in brain waveforms which occur as a result of disorders or fluctuating physiological states. This method of analysis was utilized to ensure actual correlation of the different mathematical paradigms. The EEG data was obtained from different regions of the rat brain and was modelled by AR method in a MATLAB platform. AR modelling was utilized to study the long-term functional outcomes of a stroke and also is preferable for EEG signal analysis because the signals consist of discrete frequency intervals. Modern spectral analysis, namely AR spectrum analysis, was used to correlate the conditional and prevalent changes in brain function in response to a stroke.

  3. Comparative Metabolism of Carbon Tetrachloride in Rats, Mice and Hamsters Using Gas Uptake and PBPK Modeling

    SciTech Connect

    Thrall, Karla D. ); Vucelick, Mark E.; Gies, Richard A. ); Zangar, Richard C. ); Weitz, Karl K. ); Poet, Torka S. ); Springer, David L. ); Grant, Donna M. ); Benson, Janet M.

    2000-08-25

    No study has comprehensively compared the rate of metabolism of carbon tetrachloride (CCl4) across species. Therefore, the in vivo metabolism of CCl4 was evaluated using groups of male animals (F344 rats, B6C3F1 mice, and Syrian hamsters) exposed to 40-1800 ppm CCl4 in a closed, recirculating gas-uptake system. For each species, an optimal fit of the family of uptake curves was obtained by adjusting Michaelis-Menten metabolic constants Km (affinity) and Vmax (capacity) using a physiologically based pharmacokinetic (PBPK) model. The results show that the mouse has a slightly higher capacity and lower affinity for metabolizing CCl4 compared to the rat, while the hamster has a higher capacity and lower affinity than either rat or mouse. A comparison of the Vmax to Km ratio, normalized for mg of liver protein (L/hr/mg) across species indicates that hamsters metabolize more CCl4 than either rats or mice, and should be more susceptible to CCl4-induced hepatotoxicity. These species comparisons were evaluated against toxicokinetic studies conducted in animals exposed by nose-only inhalation to 20 ppm 14C-labeled CCl4 for 4 hours. The toxicokinetic study results are consistent with the in vivo rates of metabolism, with rats eliminating less radioactivity associated with metabolism (14CO2 and urine/feces) and more radioactivity associated with the parent compound (radioactivity trapped on charcoal) compared to either hamsters or mice. The in vivo metabolic constants determined here, together with in vitro constants determined using rat, mouse, hamster and human liver microsomes, were used to estimate human in vivo metabolic rates of 1.49 mg/hr/kg body weight and 0.25 mg/L for Vmax and Km, respectively. Normalizing the rate of metabolism (Vmax/Km) by mg liver protein, the rate of metabolism of CCl4 differs across species, with hamster > mouse& > rat > human.

  4. Formoterol decreases muscle wasting as well as inflammation in the rat model of rheumatoid arthritis.

    PubMed

    Gómez-SanMiguel, Ana Belén; Gomez-Moreira, Carolina; Nieto-Bona, María Paz; Fernández-Galaz, Carmen; Villanúa, Maria Ángeles; Martín, Ana Isabel; López-Calderón, Asunción

    2016-06-01

    Adjuvant-induced arthritis is an experimental model of rheumatoid arthritis that is associated with body weight loss and muscle wasting. β2-adrenergic receptor agonists are powerful anabolic agents that trigger skeletal muscle hypertrophy and have been proposed as a promising treatment for muscle wasting in human patients. The aim of this work was to determine whether formoterol, a selective β2-adrenoreceptor agonist, is able to ameliorate muscle wasting in arthritic rats. Arthritis was induced in male Wistar rats by intradermal injection of Freund's adjuvant. Control and arthritic rats were injected daily with 50 μg/kg sc formoterol or saline for 12 days. Body weight change, food intake, and arthritis index were analyzed. After euthanasia, in the gastrocnemius mRNA was analyzed by PCR, and proteins were analyzed by Western blotting. Arthritis decreased gastrocnemius weight, cross-sectional area, and myofiber size, whereas formoterol increased those variables in both arthritic and control rats. Formoterol decreased the external signs of arthritis as well as NF-κB(p65) activation, TNFα, and COX-2 levels in the gastrocnemius of arthritic and control rats. Those effects of formoterol were associated with a decreased expression of myostatin, atrogin-1, and MuRF1 and in LC3b lipidation. Arthritis increased the expression of MyoD, myogenin, IGF-I, and IGFBP-3 and -5 in the gastrocnemius. In control and in arthritic rats, treatment with formoterol increased Akt phosphorylation and myogenin levels, whereas it decreased IGFBP-3 expression in the gastrocnemius. These data suggest that formoterol has an anti-inflammatory effect and decreases muscle wasting in arthritic rats through increasing Akt activity and myogenin and decreasing myostatin, the p-NF-κB(p65)/TNF pathway, and IGFBP-3. PMID:27245339

  5. Increased VGLUT3 involved in visceral hyperalgesia in a rat model of irritable bowel syndrome

    PubMed Central

    Yang, Chang-Qing; Duan, Li-Ping; Qiao, Pei-Tang; Zhao, Li; Guo, Li-Li

    2015-01-01

    AIM: To investigate the activity of vesicular glutamate transporter-3 (VGLUT3) in a visceral hyperalgesia rat model of irritable bowel syndrome, and the role of mast cells (MCs). METHODS: Transient intestinal infection was induced by oral administration of Trichinella spiralis larvae in rats. On the 100th day post-infection (PI), the rats were divided into an acute cold restraint stress (ACRS) group and a non-stressed group. Age-matched untreated rats served as controls. The abdominal withdrawal reflex was used to measure the visceromotor response to colorectal distension (CRD). The expression levels of VGLUT3 in peripheral and central neurons were analyzed by immunofluorescence and western blotting. RESULTS: VGLUT3 expression in the L6S1 dorsal root ganglion cells was significantly higher in the PI group than in the control group (0.32 ± 0.009 vs 0.22 ± 0.008, P < 0.01), and there was no significant difference in the expression of VGLUT3 between MC-deficient rats and their normal wild-type littermates. Immunofluorescence showed that the expression levels of VGLUT3 in PI + ACRS rats were enhanced in the prefrontal cortex of the brain compared with the control group. CONCLUSION: VGLUT3 is involved in the pathogenesis of visceral hyperalgesia. Coexpression of c-fos, 5-hydroxytryptamine and VGLUT3 after CRD was observed in associated neuronal pathways. Increased VGLUT3 induced by transient intestinal infection was found in peripheral nerves, and was independent of MCs. Moreover, the expression of VGLUT3 was enhanced in the prefrontal cortex in rats with induced infection and stress. PMID:25780293

  6. Chronic NOS inhibition accelerates NAFLD progression in an obese rat model.

    PubMed

    Sheldon, Ryan D; Padilla, Jaume; Jenkins, Nathan T; Laughlin, M Harold; Rector, R Scott

    2015-03-15

    The progression in nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis is a serious health concern, but the underlying mechanisms remain unclear. We hypothesized that chronic inhibition of nitric oxide (NO) synthase (NOS) via N(ω)-nitro-L-arginine methyl ester (L-NAME) would intensify liver injury in a rat model of obesity, insulin resistance, and NAFLD. Obese Otsuka Long-Evans Tokushima fatty (OLETF) and lean Long-Evans Tokushima Otsuka (LETO) rats received control or L-NAME (65-70 mg·kg(-1)·day(-1))-containing drinking water for 4 wk. L-NAME treatment significantly (P < 0.05) reduced serum NO metabolites and food intake in both groups. Remarkably, despite no increase in body weight, L-NAME treatment increased hepatic triacylglycerol content (+40%, P < 0.05) vs. control OLETF rats. This increase was associated with impaired (P < 0.05) hepatic mitochondrial state 3 respiration. Interestingly, the opposite effect was found in LETO rats, where L-NAME increased (P < 0.05) hepatic mitochondrial state 3 respiration. In addition, L-NAME induced a shift toward proinflammatory M1 macrophage polarity, as indicated by elevated hepatic CD11c (P < 0.05) and IL-1β (P = 0.07) mRNA in OLETF rats and reduced expression of the anti-inflammatory M2 markers CD163 and CD206 (P < 0.05) in LETO rats. Markers of total macrophage content (CD68 and F4/80) mRNA were unaffected by L-NAME in either group. In conclusion, systemic NOS inhibition in the obese OLETF rats reduced hepatic mitochondrial respiration, increased hepatic triacylglycerol accumulation, and increased hepatic inflammation. These findings suggest an important role for proper NO metabolism in the hepatic adaptation to obesity. PMID:25573175

  7. Increase in osteoclastogenesis in an obese Otsuka Long-Evans Tokushima fatty rat model.

    PubMed

    Ootsuka, Tomoyo; Nakanishi, Atsuko; Tsukamoto, Ikuyo

    2015-09-01

    In the present study, the effects of obesity on bone metabolism were investigated using a hyperphagic and obese rat model, the Otsuka Long‑Evans Tokushima fatty (OLETF) rat, which exhibits normal glycemic control at 8 weeks of age. Body weight, food intake, fat mass, markers of bone resorption, the activities of tartrate‑resistant acid phosphatase (TRAP) and cathepsin K, the number of osteoclasts in the proximal tibia, and the serum C‑terminal crosslinking telopeptide level were higher in OLETF rats than those in control rats (Long‑Evans Tokushima Otsuka; LETO). However, no differences in markers of bone formation, alkaline phosphatase activity, the number of osteoblasts in the proximal tibia or the serum osteocalcin level were observed. mRNA and protein levels of c‑fms, receptor for activation of nuclear factor‑κB (RANK), RANK ligand (RANKL), TRAP and cathepsin K were significantly increased in OLETF rats, although those levels of macrophage colony‑stimulating factor (M‑CSF) and osteoprotegerin (OPG) were similar to those in LETO rats. The level of serum tumor necrosis factor α (TNFα), and that of TNFα mRNA in bone, increased in association with the activation of NFκB. Furthermore, a frequency analysis and a colony formation assay respectively showed that the number of osteoclast precursors and the number of colony‑forming cells induced by M‑CSF each increased in OLETF rats compared with the control group. These results suggested that hyperphagia‑induced obesity with normal glycemic control induces the upregulation of osteoclastogenesis that is associated with an increase in the expression of c‑fms, RANK and RANKL, which is induced by TNFα, via the activation of NFκB. PMID:25997439

  8. Therapeutic effect of organoselenium dietary supplementation in a sporadic dementia of Alzheimer's type model in rats.

    PubMed

    Pinton, Simone; Brüning, César A; Sartori Oliveira, Carla E; Prigol, Marina; Nogueira, Cristina Wayne

    2013-01-01

    It is known that selenium (Se) might play different roles in the progression of Alzheimer's disease (AD), but there is a lack of evidence that proves whether supplementation with Se is beneficial or not for the treatment of AD. Thus, the aim of the current study was to investigate the therapeutic effect of p,p'-methoxyl-diphenyl diselenide [(MeOPhSe)(2)], an organoselenium compound, against streptozotocin (STZ)-induced sporadic dementia of Alzheimer's type (SDAT) in rats. Male Wistar rats received STZ twice daily (1.0 mg/8 μl; 4 μl/ventricle) for 21 days. After 21 days of STZ injection, regular-diet-fed rats were supplemented with 10 ppm of (MeOPhSe)(2) during 30 days. At the end of this period, the rats were challenged in the Morris water maze and step-down passive avoidance tasks. The activity of acetylcholinesterase (AChE), deficit in cerebral energy metabolism (measurement of adenosine 5-triphosphate and adenosine 5-diphosphate levels), and oxidative and nitrosative stress were determined in the cortex and hippocampus of rats. The results demonstrated that (MeOPhSe)(2) dietary supplementation reverted STZ-induced memory impairment of rats in both cognitive tasks. The findings also indicated that (MeOPhSe)(2) dietary supplementation reverted oxidative stress in the STZ group (decreased reactive species and tyrosine nitration levels and enhanced nonprotein thiol levels). Moreover, (MeOPhSe)(2) dietary supplementation normalized AChE activity, which was enhanced by STZ injection, but did not revert the deficit in cerebral energy metabolism caused by STZ. The results of the present study indicated the therapeutic effect of the (MeOPhSe)(2)-supplemented diet in a rat model of SDAT. PMID:22959057

  9. Decreased exposure of simvastatin and simvastatin acid in a rat model of type 2 diabetes

    PubMed Central

    Xu, Dan; Li, Feng; Zhang, Mian; Zhang, Ji; Liu, Can; Hu, Meng-yue; Zhong, Ze-yu; Jia, Ling-ling; Wang, Da-wei; Wu, Jie; Liu, Li; Liu, Xiao-dong

    2014-01-01

    Aim: Simvastatin is frequently administered to diabetic patients with hypercholesterolemia. The aim of the study was to investigate the pharmacokinetics of simvastatin and its hydrolysate simvastatin acid in a rat model of type 2 diabetes. Methods: Diabetes was induced in 4-week-old rats by a treatment of high-fat diet combined with streptozotocin. After the rats received a single dose of simvastatin (20 mg/kg, po, or 2 mg/kg, iv), the plasma concentrations of simvastatin and simvastatin acid were determined. Simvastatin metabolism and cytochrome P4503A (Cyp3a) activity were assessed in hepatic microsomes, and its uptake was studied in freshly isolated hepatocytes. The expression of Cyp3a1, organic anion transporting polypeptide 2 (Oatp2), multidrug resistance-associated protein 2 (Mrp2) and breast cancer resistance protein (Bcrp) in livers was measured using qRT-PCR. Results: After oral or intravenous administration, the plasma concentrations and areas under concentrations of simvastatin and simvastatin acid were markedly decreased in diabetic rats. Both simvastatin metabolism and Cyp3a activity were markedly increased in hepatocytes of diabetic rats, accompanied by increased expression of hepatic Cyp3a1 mRNA. Furthermore, the uptake of simvastatin by hepatocytes of diabetic rats was markedly increased, which was associated with increased expression of the influx transporter Oatp2, and decreased expression of the efflux transporters Mrp2 and Bcrp. Conclusion: Diabetes enhances the metabolism of simvastatin and simvastatin acid in rats via up-regulating hepatic Cyp3a activity and expression and increasing hepatic uptake. PMID:25152023

  10. Neuroprotective effect of 4-(Phenylsulfanyl)butan-2-one on optic nerve crush model in rats.

    PubMed

    Chien, Jia-Ying; Sheu, Jyh-Horng; Wen, Zhi-Hong; Tsai, Rong-Kung; Huang, Shun-Ping

    2016-02-01

    This study is to investigate the effect of coral-related compound, 4-(phenylsulfanyl)butan-2-one (4-PSB-2) on optic nerves (ON) and retinal ganglion cells (RGC) in a rat model subjected to ON crush. The ONs of adult male Wistar rat (150-180 g) were crushed by a standardized method. The control eyes received a sham operation. 4-PSB-2 (5 mg/kg in 0.2 mL phosphate-buffered saline) or phosphate-buffered saline (PBS control) was immediately administered after ON crush once by subcutaneous injection. Rats were euthanized at 2 weeks after the crush injury. RGC density was counted by retrograde labeling with FluoroGold (FG) application to the superior colliculus, and visual function was assessed by flash visual evoked potentials (FVEP). TUNEL assay, immunoblotting analysis of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX2) in the retinas, and immunohistochemistry of ED1 in the ON were evaluated. Two weeks after the insult, the RGC densities in the central and mid-peripheral retinas in ON-crushed, 4-PSB-2-treated rats were significantly higher than that of the corresponding ON-crushed, PBS-treated rats FVEP measurements showed a significantly better preserved latency of the P1 wave in the ON-crushed, 4-PSB-2-treated rats than the ON-crushed, PBS treated rats. TUNEL assays showed fewer TUNEL positive cells in the ON-crushed, 4-PSB-2-treated rats. The number of ED1 positive cells was reduced at the lesion site of the optic nerve in the ON-crushed, 4-PSB-2-treated group. Furthermore, administration of 4-PSB-2 significantly attenuated ON crush insult-stimulated iNOS and COX2 expression in the retinas. These results demonstrated that 4-PSB-2 protects RGCs and helps preserve the visual function in the rat model of optic nerve crush. 4-PSB-2 may work by being anti-apoptotic and by attenuation of the inflammatory responses involving less ED1 positive cells infiltration in ON as well as suppression of iNOS/COX-2 signaling pathway in the retinas to rescue RGCs

  11. Vitamin D supplementation improves pathophysiology in a rat model of preeclampsia.

    PubMed

    Faulkner, Jessica L; Cornelius, Denise C; Amaral, Lorena M; Harmon, Ashlyn C; Cunningham, Mark W; Darby, Marie M; Ibrahim, Tarek; Thomas, D'Andrea S; Herse, Florian; Wallukat, Gerd; Dechend, Ralf; LaMarca, Babbette

    2016-02-15

    Deficiency of vitamin D (VD) is associated with preeclampsia (PE), a hypertensive disorder of pregnancy characterized by proinflammatory immune activation. We sought to determine whether VD supplementation would reduce the pathophysiology and hypertension associated with the reduced uterine perfusion pressure (RUPP) rat model of PE. Normal pregnant (NP) and RUPP rats were supplemented with VD2 or VD3 (270 IU and 15 IU/day, respectively) on gestation days 14-18 and mean arterial pressures (MAPs) measured on day 19. MAP increased in RUPP to 123 ± 2 mmHg compared with 102 ± 3 mmHg in NP and decreased to 113 ± 3 mmHg with VD2 and 115 ± 3 mmHg with VD3 in RUPP rats. Circulating CD4+ T cells increased in RUPP to 7.90 ± 1.36% lymphocytes compared with 2.04 ± 0.67% in NP but was lowered to 0.90 ± 0.19% with VD2 and 4.26 ± 1.55% with VD3 in RUPP rats. AT1-AA, measured by chronotropic assay, decreased from 19.5 ± 0.4 bpm in RUPPs to 8.3 ± 0.5 bpm with VD2 and to 15.4 ± 0.7 bpm with VD3. Renal cortex endothelin-1 (ET-1) expression was increased in RUPP rats (11.6 ± 2.1-fold change from NP) and decreased with both VD2 (3.3 ± 1.1-fold) and VD3 (3.1 ± 0.6-fold) supplementation in RUPP rats. Plasma-soluble FMS-like tyrosine kinase-1 (sFlt-1) was also reduced to 74.2 ± 6.6 pg/ml in VD2-treated and 91.0 ± 16.1 pg/ml in VD3-treated RUPP rats compared with 132.7 ± 19.9 pg/ml in RUPP rats. VD treatment reduced CD4+ T cells, AT1-AA, ET-1, sFlt-1, and blood pressure in the RUPP rat model of PE and could be an avenue to improve treatment of hypertension in response to placental ischemia. PMID:26676250

  12. Dual restoring effects of gastrodin on dopamine in rat models of Tourette's syndrome.

    PubMed

    Zhang, Feng; Li, Anyuan

    2015-02-19

    Tourette's syndrome (TS) occurs commonly in children, and dysfunction of dopaminergic system has long been postulated to underlie the disorder. Here, we used two TS rat models induced by 3,3'-iminodipropionitrile (IDPN) and Apomorphine (Apo) to assess an unique dopamine (DA) modulating property of gastrodin (GAS), the main bioactive component isolated from Gastrodia elata Blume, which has been widely used for treating various neurological disorders. By using high-performance liquid chromatography (HPLC), the dual restoring effects of gastrodin, at least partially, has been observed: on the one hand, gastrodin increased the down-regulated striatal DA content in IDPN-induced rats; on the other hand, gastrodin decreased the up-regulated striatal DA content in Apo-induced rats. Taken together, our data corroborated that gastrodin could restore the abnormal striatal DA dually, and this therapeutic potential might be meaningful for the anti-tic treatment. PMID:25549540

  13. The Protective Effects of Shen-Fu Injection on Experimental Acute Pancreatitis in a Rat Model

    PubMed Central

    Huang, Lei; Cao, Jun

    2014-01-01

    Objectives. In the present study, we investigated the protective effects of Shen-Fu injection (SFI) on a caerulein-induced rat pancreatitis (AP) model. Methods. SFI was given to rats in the SFI treated group through intraperitoneal injection. Blood and pancreas samples were collected for serological and histopathological studies. Results. Our results showed that AP caused significant decrease in tissue glutathione (GSH) and serum IL-4 and IL-10, while pancreatic malondialdehyde (MDA) and myeloperoxidase (MPO) were increased. Furthermore, TNF-α, IL-1β, amylase, and lipase levels were also significantly increased. On the other hand, SFI treatment reserved all these biochemical indices as well as histopathologic alterations that were induced by caerulein. Conclusion. Our findings suggest that the SFI protects against caerulein-induced AP in rats via modulation of cytokines, oxidative stress, and Nuclear Factor-kappa B (NF-κB) activity. PMID:24738018

  14. Cardiac Motion Analysis Using High-Speed Video Images in a Rat Model for Myocardial Infarction

    NASA Astrophysics Data System (ADS)

    Ishii, Idaku; Okuda, Toshikazu; Nie, Yuman; Takaki, Takeshi; Orito, Kensuke; Tanaka, Akane; Matsuda, Hiroshi

    In this study, we performed a cardiac motion analysis by using 1000-frames per second (fps) stereo images to capture the three-dimensional motion of small color markers in a rat heart. This method of recording cardiac motion could quantify the rate of change in the myocardial area, which indicated localized myocardial activity of rhythmic expansion and contraction. We analyzed the three-dimensional motion distributions in a rat model for myocardial infarction, in which the heart rate was 4 times/s or more. In the analysis, we spatiotemporally quantified the characteristic cardiac motion in ischemic heart diseases and found that infarction due to ischemia in the rat heart was spread around the left ventricle.

  15. Interleukin-1β induces the upregulation of caveolin-1 expression in a rat brain tumor model

    PubMed Central

    QIN, LI-JUAN; JIA, YONG-SEN; ZHANG, YI-BING; WANG, YIN-HUAN

    2016-01-01

    The aim of the present study was to investigate the expression of caveolin-1 in rat brain glioma tissue, and to determine whether interleukin-1β (IL-1β) has a role in this process. Using glioma cells, a tumor-burdened rat model was established, and the expression of caveolin-1 protein in the tumor sites was significantly increased following intracarotid infusion of IL-1β (3.7 ng/kg/min), as indicated by western blot analysis. The maximum value of the caveolin-1 expression was observed in tumor-burdened rats after 60 min of IL-1β perfusion, and which was significantly enhanced by vascular endothelial growth factor (VEGF). In addition, VEGF also significantly increased IL-1β-induced blood tumor barrier (BTB) permeability. The results suggest that the IL-1β-induced BTB permeability increase may be associated with the expression of caveolin-1 protein, and VEGF may be involved in this process. PMID:27073627

  16. Protective effects of sivelestat in a caerulein-induced rat acute pancreatitis model.

    PubMed

    Cao, Jun; Liu, Quanyan

    2013-12-01

    In the present study, we investigated the protective effects of sivelestat on acute pancreatitis (AP) in a rat model. Sivelestat is a specific neutrophil elastase inhibitor, which has been developed in Japan in 1991. Varying doses of sivelestat in normal saline were infused continuously in sivelestat-treated groups through osmotic pumps. Blood and pancreas samples were collected for serological and histopathological studies, and ten rats in each group were taken for survival observation. Increasing doses of sivelestat inhibits the expression of lipase, amylase, corticosterone, IL-1β, TNF-α, and nuclear factor-κB. Furthermore, sivelestat reduces the inflammatory cells infiltration, histological damage, and mortality rate. Meanwhile, the total antioxidant power and serum level of IL-4 in high-dose sivelestat-treated groups were increased. Our findings suggest that the increasing doses of sivelestat protect against caerulein-induced AP in rats, and this protection is possibly associated with the anti-inflammatory ability of sivelestat. PMID:23794035

  17. Regulation of hematopoiesis in rats exposed to antiorthostatic, hypokinetic/hypodynamia. I - Model description

    NASA Technical Reports Server (NTRS)

    Dunn, C. D. R.; Johnson, P. C.; Lange, R. D.; Perez, L.; Nessel, R.

    1985-01-01

    The effect of a 7-day suspension in a jacket and harness with 20-deg head-down tilt on body weight, food and water consumption, and hematological parameters is investigated experimentally in male Sprague-Dawley rats weighing 150-175 g. The results are presented in graphs and compared with those for unsuspended controls and with published data on rats and humans exposed to microgravity in space flight. Suspended rats are found to have reduced red-blood-cell mass, erythropoiesis, plasma volume (leading to temporarily increased hematocrit), body weight, and food and water consumption; rightward-shifted oxyhemoglobin-dissociation curves; and unchanged platelet count, leucocyte count or PHA reactivity, and red-blood-cell shape distribution. Since many of these effects are also seen in space flight, the present experimental model is considered a promising technique for simulating the hematopoietic effects of microgravity at 1 g.

  18. A rat model of liver transplantation with a steatotic donor liver after cardiac death

    PubMed Central

    Cai, Qiucheng; Fan, Hongkai; Xiong, Rihui; Jiang, Yi

    2015-01-01

    This study aimed to establish a rat liver transplantation model with a steatotic donor liver after cardiac death, reflecting clinical conditions. Rats were fed a high-fat diet for 8 weeks to establish the fatty liver model. This model simulates liver steatosis caused by various factors before clinical donation after cardiac death. A pneumothorax was created in the donor rat to induce hypoxia and cardiac arrest before incising the liver. This simulated the processes of hypoxia and cardiac arrest caused by withdrawal of treatment in actual clinical situations. The harvested cardiac death donor liver was then transplanted using the Kamada technique. Donor operative time was 45.7 ± 4.2 min; cardiac arrest time, 9 ± 0.8 min; recipient surgery time, 40.3 ± 4.9 min; and no-liver time, 15 ± 2.5 min. Of 40 liver-transplanted rats, 2 died within 24 h, with a surgical success rate of 95%. The transaminase levels on post-transplantation days 1, 3, 5, and 7 were 835.4 ± 71.33 U/L, 1334.5 ± 102.13 U/L, 536.4 ± 65.52 U/L, and 218.2 ± 36.77 U/L, respectively. This rat liver transplantation model with a steatotic donor liver after cardiac death could improve the simulation of the pathophysiological processes of clinical donation after cardiac death, and could be used as a reliable and stable animal model. PMID:26629068

  19. Selective binding of lectins to normal and neoplastic urothelium in rat and mouse bladder carcinogenesis models.

    PubMed

    Zupančič, Daša; Kreft, Mateja Erdani; Romih, Rok

    2014-01-01

    Bladder cancer adjuvant intravesical therapy could be optimized by more selective targeting of neoplastic tissue via specific binding of lectins to plasma membrane carbohydrates. Our aim was to establish rat and mouse models of bladder carcinogenesis to investigate in vivo and ex vivo binding of selected lectins to the luminal surface of normal and neoplastic urothelium. Male rats and mice were treated with 0.05 % N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in drinking water and used for ex vivo and in vivo lectin binding experiments. Urinary bladder samples were also used for paraffin embedding, scanning electron microscopy and immunofluorescence labelling of uroplakins. During carcinogenesis, the structure of the urinary bladder luminal surface changed from microridges to microvilli and ropy ridges and the expression of urothelial-specific glycoproteins uroplakins was decreased. Ex vivo and in vivo lectin binding experiments gave comparable results. Jacalin (lectin from Artocarpus integrifolia) exhibited the highest selectivity for neoplastic compared to normal urothelium of rats and mice. The binding of lectin from Amaranthus caudatus decreased in rat model and increased in mouse carcinogenesis model, indicating interspecies variations of plasma membrane glycosylation. Lectin from Datura stramonium showed higher affinity for neoplastic urothelium compared to the normal in rat and mouse model. The BBN-induced animal models of bladder carcinogenesis offer a promising approach for lectin binding experiments and further lectin-mediated targeted drug delivery research. Moreover, in vivo lectin binding experiments are comparable to ex vivo experiments, which should be considered when planning and optimizing future research. PMID:23828036

  20. An immunohistochemical study of the sciatic nerve in a rat knee immobilization model.

    PubMed

    Yoshida, Shinya; Matsuzaki, Taro; Hoso, Masahiro

    2016-04-01

    [Purpose] This study was performed to immunohistochemically evaluate changes in the periphery of the sciatic nerve in a rat model of knee immobilization, and to assess the effects of range of motion exercise. [Subjects and Methods] Twenty-one male rats were divided randomly into three groups: control (C), immobilized (I), and exercise (E group). Rats in the I and E groups had the right knee joint immobilized for 2 weeks. In the E group, range of motion exercise was also performed. After the experimental period, the periphery of the sciatic nerve was immunohistochemically observed. [Results] Immunohistochemical staining revealed that the myelin sheath and the perineurium in all groups were laminin positive. In the C and E groups, all rats showed normal staining. In contrast, 4 rats in the I group exhibited weak labeling. [Conclusion] Our results suggest that immobilization alters the perineurium at a molecular level and the range of motion exercise is essential for maintaining the environment of the perineurium. PMID:27190437

  1. Inflammation and Atrophy Precede Prostate Neoplasia in PhIP Induced Rat Model

    SciTech Connect

    Borowsky, A D; Dingley, K; Ubick, E; Turteltaub, K; Cardiff, R D; DeVere-White, R

    2006-06-01

    2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP) has been implicated as a major mutagenic heterocyclic amine in the human diet and is carcinogenic in the rat prostate. In order to validate PhIP induced rat prostate neoplasia as a model of human prostate cancer progression, we sought to study the earliest histologic and morphologic changes in the prostate and to follow the progressive changes over time. We fed 67 male Fischer F344 5 week old rats with PhIP (400 PPM) or control diets for 20 weeks, and then sacrificed animals for histomorphologic examination at age 25 weeks, 45 weeks, and 65 weeks. Animals treated with PhIP showed significantly more inflammation (P=.002 (25wk), >.001(45wk), .016(65wk)) and atrophy (P=.003(25wk), >.001(45wk), .006 (65wk)) in their prostate glands relative to controls. Prostatic intraepithelial neoplasia (PIN) occurred only in PhIP treated rats. PIN lesions arose in areas of glandular atrophy, most often in the ventral prostate. Atypical cells in areas of atrophy show loss of glutathione S-transferase pi immunostaining preceding development of PIN. None of the animals in this study developed invasive carcinomas differing from previous reports. Overall, these findings suggest that the pathogenesis of prostatic neoplasia in the PhIP treated rat prostate proceeds from inflammation to post-inflammatory proliferative atrophy to PIN.

  2. Weight loss and brown adipose tissue reduction in rat model of sleep apnea

    PubMed Central

    Martinez, Denis; Vasconcellos, Luiz FT; de Oliveira, Patricia G; Konrad, Signorá P

    2008-01-01

    Background - Obesity is related to obstructive sleep apnea-hypopnea syndrome (OSAHS), but its roles in OSAHS as cause or consequence are not fully clarified. Isocapnic intermittent hypoxia (IIH) is a model of OSAHS. We verified the effect of IIH on body weight and brown adipose tissue (BAT) of Wistar rats. Methods Nine-month-old male breeders Wistar rats of two groups were studied: 8 rats submitted to IIH and 5 control rats submitted to sham IIH. The rats were weighed at the baseline and at the end of three weeks, after being placed in the IIH apparatus seven days per week, eight hours a day, in the lights on period, simulating an apnea index of 30/hour. After experimental period, the animals were weighed and measured as well as the BAT, abdominal, perirenal, and epididymal fat, the heart, and the gastrocnemius muscle. Results Body weight of the hypoxia group decreased 17 ± 7 grams, significantly different from the variation observed in the control group (p = 0,001). The BAT was 15% lighter in the hypoxia group and reached marginally the alpha error probability (p = 0.054). Conclusion Our preliminary results justify a larger study for a longer time in order to confirm the effect of isocapnic intermittent hypoxia on body weight and BAT. PMID:18671859

  3. Therapeutic Effects of Melatonin On Liver And Kidney Damages In Intensive Exercise Model of Rats.

    PubMed

    Gedikli, Semin; Gelen, Volkan; Sengul, Emin; Ozkanlar, Seckin; Gur, Cihan; Agırbas, Ozturk; Cakmak, Fatih; Kara, Adem

    2015-01-01

    Extensive exercise induces inflammatory reactions together with high production of free radicals and subsequent liver and kidney tissues damage. This study was designed to investigate for effects of melatonin on liver and kidney tissues in the extensive exercise exposed rats and non-exercised rats. In this research, 24-male Sprague-Dawley rats were divided into four groups. For exercise rat model, the rats were exposed to slow pace running with the velocity of 10 m/min for 5 minutes for five days just before the study. And for last ten days after adaptation period, the exercise was improved as 15 min with the speed of 20 m/min and intra-peritoneal melatonin injection has been performed to the melatonin treated groups with the dose of 10 mg/kg. Biochemical results revealed a decrease in the parameters of kidney and liver enzymes in exercise-group and an increase in the parameters of serum, liver and kidney enzymes in the group that melatonin-exercise-group. As for histological analysis, while it is observed that there are cellular degenerations in the liver and kidney tissues with exercise application, a decrease has been observed in these degenerations in the group that melatonin was applied. At the end of the research, it has been determined that exercise application causes some damages on liver and kidney, and these damages were ameliorated with melatonin treatment. PMID:26310355