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Sample records for reserpine

  1. Enantioselective Total Synthesis of (+)-Reserpine

    PubMed Central

    Rajapaksa, Naomi S.; McGowan, Meredeth A.; Rienzo, Matthew

    2013-01-01

    A catalytic, enantioselective synthesis of (+)-reserpine is reported. The route features a highly diastereoselective, chiral catalyst-controlled formal aza-Diels–Alder reaction between a 6-methoxytryptamine-derived dihydro-β-carboline and an enantioenriched α-substituted enone to form a key tetracyclic intermediate. This approach addresses the challenge of setting the C3 stereogenic center by using catalyst control. Elaboration of the tetracycle to (+)-reserpine includes an intramolecular aldol cyclization and a highly diastereoselective hydrogenation of a sterically hindered enoate. PMID:23331099

  2. The reserpine-treated cat

    PubMed Central

    Withrington, P.; Zaimis, Eleanor

    1961-01-01

    In cats, 24 hr after the administration of 1 mg/kg of reserpine, it was found that (a) the heart is in failure; (b) the sensitivity of the peripheral vessels to adrenaline, noradrenaline and isoprenaline, administered intravenously or close-arterially, is decreased; (c) any blood pressure changes are, as a rule, secondary to changes in heart contraction; and (d) the peripheral blood flow passively follows the blood pressure changes. Furthermore, any improvement of the circulation at this stage was found to be almost exclusively the result of an amelioration in the force of cardiac contraction. ImagesFig. 4Fig. 5Fig. 6Fig. 7Fig 8 PMID:14007730

  3. Reserpine

    MedlinePlus

    ... your blood pressure. These changes include eating a diet that is low in fat and salt, maintaining ... of the colon [large intestine] and rectum), a history of depression, or have received electric shock therapy. ...

  4. [Milestones of cardiovascular therapy. IV. Reserpine].

    PubMed

    Jerie, P

    2007-01-01

    Reserpine, the purified alkaloid of Rauwolfia serpentina, was the first potent drug widely used in the long-term treatment of hypertension. Rauwolfia serpentina is a tropical woody plant of the Apocyanaceae family ingenious to Asia, South America and Africa. Extracts of its different parts and of plants resembling to rauwolfia were used in Hindu medicine for snakebite, insomnia, insanity and many other diseases and complaints. In Europe, Georg Eberhard Rumpf first reported about rauwolfia in his Herbarium amboinense, 1755. The first modern paper about therapeutic applications of the whole root of rauwolfia was published in 1931 in the Indian Medical Journal by Sen and Bose, and many papers dealing with botanics, chemistry and pharmacology then appeared in Indian and European periodics. In 1949, Vakil published the first report of the antihypertensive effect of rauwolfia in the British Heart Journal. In the Ciba laboratories in Basel, Switzerland, Mueller, Schlittler and Bein analysed various rauwolfia alkaloids and published in 1952 the first complete report about their chemistry and pharmacology. In the same year, reserpine was introduced under the name Serpasil in the treatment of hypertension, tachycardia and thyreotoxicosis. The combination of reserpine, dihydroergocristine and a diuretic is still on the market (Brinerdin, Crystepin). In psychiatry, reserpine was prescribed as a tranqulizing agent until modem synthetic antidepressant and antipsychotic drugs were introduced. The author also briefly summarizes the chemistry, pharmacology and clinical use of reserpine.

  5. [Opsoclonus-polymyoclonia syndrome suppressed with reserpine].

    PubMed

    Harada, Y; Ishimitsu, H; Nishimoto, K; Miyata, I; Matsumi, N

    1986-04-01

    A 38-year-old man was admitted to Iwakuni National Hospital on July 6, 1978, with the complaints of difficulty seeing and walking. Two weeks before admission, he first experienced dizziness and it slowly progressed to uncontrollable tremor-like movements of the whole body. On admission, he was alert, oriented and afebrile. He had not experienced nausea, vomiting nor headache. He showed irregular horizontal oscillations of the eyes. Electronystagmographic study showed that this jerky eye movement appeared especially with changes of fixation of the eyes. It was also recorded during conjugate eye movement, and while he closed his eyes. He was ataxic, unable to walk, but no other abnormalities in cerebellar functions were observed. Spinal tap was performed and yielded watery clear cerebrospinal fluid containing 9/mm3 mononuclear cells. Clonazepam was given, 1.5 mg per day, for three days followed by doses of 3 mg per day. Improvement in walking was observed one week after starting the medication, when reserpine was started at a dose of 1 mg per day and increased to a dose of 1.5 mg per day in three days. One week after starting reserpine, opsoclonus improved markedly and he became able to read again. He was discharged home on September 3, 1978. Six months after admission, reserpine was decreased to 0.5 mg per day. Difficulty in reading developed within a month. Reserpine was given 1.0 mg per day and the doses was continuously given for next three months. One year after admission, he is back to his former occupation without medication. He complains of slight difficulty in reading for more than an hour, and in watching TV.(ABSTRACT TRUNCATED AT 250 WORDS)

  6. Green tea modulates reserpine toxicity in animal models.

    PubMed

    Al-Bloushi, Shaima; Safer, Abdel-Majeed; Afzal, Mohammed; Mousa, Shaker A

    2009-02-01

    Reserpine, a natural product extracted from Rauwolfia serpintina or Rauwolfia vomitoria, is a known dopamine depleter that inhibits several neurotransmitters. Reserpine has been used clinically to control hypertension, schizophrenia, insomnia and insanity. The use of this drug, however, has been limited because of its side effects which include oxidative damage to organs, including the liver. Green tea catechins are potent antioxidants that have the potential to counteract reserpine induced oxidative stress. This study investigated the merits of administering green tea concurrently with reserpine to prevent oxidative hepatic damage in Sprague-Dawely (SD) rats. Reserpine was found to cause hepatic damage, with elevated levels of oxidative stress markers, such as Thiobarbituric Acid Reactive Substances (TBARS), transaminases and cholesterol. Reserpine also induced hepatic ultra-structural damage in the cytoplasmic membrane, nuclear envelope, endoplasmic reticulum (rER), ribosomal stripping and mitochondria. Electron microscopy examination showed revival of liver cells as a result of green tea extract administration to experimental rats.

  7. The value of the reserpine test in psychopharmacology.

    PubMed

    Bourin, M; Poncelet, M; Chermat, R; Simon, P

    1983-01-01

    Numerous tests have been proposed to search for a possible antidepressive action. Many of these tests are based on a reversal of different reserpine effects, an approach justified mainly by the use of most the classic or new antidepressants. Three effects of reserpine were examined in mice: hypothermia, ptosis and akinesia. All tests were performed with reserpine 2.5 mg/kg, and the drugs were injected 4 h after reserpine administration. In these three models, we studied the relatively specific effects of 21 drugs known for their influence on the metabolism or action of norepinephrine (noradrenaline), serotonin and dopamine. Our results suggest that hypothermia antagonism is only obtained with drugs stimulating beta-adrenergic receptors directly or indirectly, ptosis antagonism with those stimulating alpha-adrenergic or serotonergic receptors, and akinesia antagonism with those stimulating dopaminergic receptors.

  8. Evidence for a reserpine-affected mechanism of resistance to tetracycline in Neisseria gonorrhoeae.

    PubMed

    Ruiz, Joaquim; Ribera, Anna; Jurado, Angels; Marco, Francesc; Vila, Jordi

    2005-10-01

    The presence of a reserpine-affected mechanism of tetracycline resistance was investigated in 17 Neisseria gonorrhoeae clinical isolates. To establish this fact the MIC of tetracycline in the presence and absence of reserpine was determined, and, in addition, mechanisms of tetracycline resistance were analyzed by PCR. The results showed that reserpine affects the MIC of tetracycline at least 4-fold in all isolates, including those containing the tetM gene. An inhibitory effect of reserpine against the MtrCDE efflux system was ruled out by using strains either with an inactive or with an unrepressed MtrCDE system. The results suggest the presence of a constitutive system of resistance to tetracycline, by a possible efflux pump, which may be inhibited by reserpine. Further studies are required to determine the exact nature of the action of reserpine on the MIC of tetracycline. PMID:16309425

  9. Histometric Analysis of the Effects of Reserpine on the Interstital Cells of the Rat Testis

    PubMed Central

    Dias, P. L. R.

    1982-01-01

    Reserpine is known to block luteinizing hormone (LH) release and by this action to inhibit ovulation, delay implantation and cause abortion in rats. A histometric technique was applied to estimate quantitatively the changes in the density of rat testis interstitial cells after the injection of a fixed dose of reserpine over a varying period of time. A significant decrease in the density of the interstitial cell population was observed in relation to the duration of treatment with reserpine. Reserpine appears to produce atrophy of the interstitial cells of the testis possibly due to its LH-inhibiting action. PMID:7171476

  10. Reserpine-induced reduction in norepinephrine transporter function requires catecholamine storage vesicles.

    PubMed

    Mandela, Prashant; Chandley, Michelle; Xu, Yao-Yu; Zhu, Meng-Yang; Ordway, Gregory A

    2010-01-01

    Treatment of rats with reserpine, an inhibitor of the vesicular monoamine transporter (VMAT), depletes norepinephrine (NE) and regulates NE transporter (NET) expression. The present study examined the molecular mechanisms involved in regulation of the NET by reserpine using cultured cells. Exposure of rat PC12 cells to reserpine for a period as short as 5min decreased [(3)H]NE uptake capacity, an effect characterized by a robust decrease in the V(max) of the transport of [(3)H]NE. As expected, reserpine did not displace the binding of [(3)H]nisoxetine from the NET in membrane homogenates. The potency of reserpine for reducing [(3)H]NE uptake was dramatically lower in SK-N-SH cells that have reduced storage capacity for catecholamines. Reserpine had no effect on [(3)H]NE uptake in HEK-293 cells transfected with the rat NET (293-hNET), cells that lack catecholamine storage vesicles. NET regulation by reserpine was independent of trafficking of the NET from the cell surface. Pre-exposure of cells to inhibitors of several intracellular signaling cascades known to regulate the NET, including Ca(2+)/Ca(2+)-calmodulin dependent kinase and protein kinases A, C and G, did not affect the ability of reserpine to reduce [(3)H]NE uptake. Treatment of PC12 cells with the catecholamine depleting agent, alpha-methyl-p-tyrosine, increased [(3)H]NE uptake and eliminated the inhibitory effects of reserpine on [(3)H]NE uptake. Reserpine non-competitively inhibits NET activity through a Ca(2+)-independent process that requires catecholamine storage vesicles, revealing a novel pharmacological method to modify NET function. Further characterization of the molecular nature of reserpine's action could lead to the development of alternative therapeutic strategies for treating disorders known to be benefitted by treatment with traditional competitive NET inhibitors. PMID:20176067

  11. Analysis of the interaction of reserpine with actin by the photoaffinity labelling method.

    PubMed

    Ohmi, K; Nakamura, S

    1991-08-14

    The interaction of reserpine with one of the cytoskeletal proteins, actin, was analyzed by the photoaffinity labelling method using [3H]reserpine. Reserpine bound sufficiently to G- or oligomeric actin, but hardly to F-actin under the same experimental conditions. This result could be explained if reserpine binds to a specific region of the G-actin molecule that is responsible for actin-actin interactions. It is concordant with this idea that [3H]reserpine bound only to specific proteolytic fragments of actin. When reserpine was mixed with crude extracts of two kinds of tissues, chicken gizzard smooth muscle and bovine adrenal medulla, it bound to the 42 kDa protein of sodium dodecyl sulfate-polyacrylamide gel electrophoresis in both cases. Its molecular size and abundance suggest strongly that this 42 kDa protein is actin. The binding of reserpine to actin was inhibited by dopamine in a dose-dependent manner. These results suggest that actin could be one of the target molecules of reserpine.

  12. (-) Epigallocatechin-3-gallate attenuates reserpine-induced orofacial dyskinesia and oxidative stress in rat striatum.

    PubMed

    Wang, Mao-Hsien; Lin, Rui-Feng; Tseng, Hsiang-Chien; Soung, Hung-Sheng; Chang, Kuo-Chi; Tsai, Cheng-Chia

    2015-04-01

    Reserpine-induced orofacial dyskinesia (OD) has been used for decades as an animal model for human tardive dyskinesia (TD) because both of them have pathophysiology strongly associated with striatal oxidative stress. Green tea catechins, especially (-) epigallocatechin-3-gallate (EGCG), have potent antioxidative effects and are able to protect against various oxidative injuries. In this study, we examined the potential protective effects of EGCG on reserpine-induced behavioral and neurochemical dysfunction in rats. Reserpine treatment (1mg/kgs.c. one injection every other day, three injections total) induced significant increases (p<0.001) in the frequency of vacuous chewing movement (VCM) and tongue protrusion (TP) as well as the duration of facial twitching (FT). EGCG treatment (100mg/kgi.p. for 11days, starting 7days before the reserpine injections) was able to prevent most of the reserpine-induced OD. Also, EGCG treatment was able to reduce the reserpine-induced lipid peroxidation (LPO) production, and enhances the antioxidation power in the striatum of reserpine-treated rats. The above results indicate that EGCG has a protective role against reserpine-induced OD, probably via its powerful antioxidative properties. Thus, EGCG may possible have a clinically relevant therapeutic effect in preventing, delaying or even treating TD. PMID:25668129

  13. Different effects of 7-nitroindazole in reserpine-induced hypolocomotion in two strains of mice.

    PubMed

    Tadaiesky, Meigy T; Andreatini, Roberto; Vital, Maria A B F

    2006-03-27

    There are a number of reasons for believing that nitric oxide participates in motor control in the striatum. Therefore, effects of neuronal nitric oxide synthase inhibitor 7-nitroindazole (7-NI) were studied on the reserpine model of Parkinson's disease in Swiss and C57BL/6 mice using the open-field test. Mice received reserpine (1 mg/kg administered intraperitoneally). A significant hypolocomotion was observed 24 h and 48 h after reserpine injection. The treatment with 7-nitroindazole (25 mg/kg, administered intraperitoneally, 30 min after reserpine) attenuated reserpine-induced hypolocomotion 24 h and 48 h after the treatment in Swiss mice, but not completely in C57BL/6 mice. These results suggest that nitric oxide functions as an intercellular messenger in motor circuits in the brain. Moreover, our data suggests that the comparison of such mouse strains may provide information on genetic basis for strain differences in different sensitivity to these drugs.

  14. Effect of reserpine on salivary gland radioiodine uptake in thyroid cancer

    SciTech Connect

    Levy, H.A.; Park, C.H.

    1987-04-01

    Nine patients with thyroid cancer were treated with reserpine in an attempt to reduce radiation exposure to the salivary glands from 100-150 mCi doses of I-131 therapy to thyroid remnants or metastases. Three control patients were not treated with reserpine but did receive 100-150 mCi of I-131. Parotid/background ratios of activity after radioablative doses of I-131 in patients not treated with reserpine were significantly higher than the patients treated with reserpine, and this was also true seven days after the radioablative dose. Combined therapy with reserpine, chewing gum, lemon candies, and hydration is suggested for the prevention of sialadenitis and xerostomia due to large doses of radioiodine.

  15. Flow injection spectrofluorimetric determination of reserpine in tablets by on-line acetone sensitized photochemical reaction.

    PubMed

    Chen, H; He, Q

    2000-11-01

    On-line photochemical reaction of reserpine in the presence of acetone was investigated. Acetone was found to speed up the on-line photochemical conversion of reserpine into an intensively fluorescent compound. Not only reaction acidity but also the acetate buffer concentration affected the on-line photochemical induced fluorescence signal. Based on the observation an automated flow injection photochemical fluorimetric approach was developed. An injected sample zone was carried by a water stream to be merged with a acetate buffer (pH 3.4) solution containing 0.02% acetone in a knotted PTFE reactor (KR), which was freely coiled around a 6-W low pressure mercury lamp. While passing the KR, reserpine was transformed into an intensively fluorescent compound. It was on-line detected in a flow-through cell at the emission wavelength of 490 nm and excitation wavelength of 386 nm. At optimized conditions, a detection limit 0.45 mug l(-1) was achieved at a sampling rate of 90 h(-1). Eleven determinations of a 0.5 mg l(-1) reserpine standard solution gave a R.S.D. of 0.3%. The linear dynamic range of reserpine calibration curve was 0.01-0.75 mg l(-1). The proposed method was applied to assay the reserpine content in tablets and to monitor the dissolution profile of reserpine tablets. Satisfactory results were obtained for both the assays and dissolution studies. PMID:18968131

  16. The metabolism of histamine in rat hypothalamus and cortex after reserpine treatment.

    PubMed

    Maldonado, Martin; Maeyama, Kazutaka

    2015-01-01

    The effect of reserpine on histamine (HA) and tele-methylhistamine (N(τ)-MHA) in hypothalamus and cortex of rats was analyzed and compared to catecholamines. IP injection of reserpine (5 mg/kg) confirmed the effectiveness of reserpine treatment on noradrenaline and dopamine levels. Our in-vitro experiment with synaptosomal/crude mitochondrial fraction from hypothalamus and cortex confirmed that while mono amine oxidase (MAO) is an efficient metabolic enzyme for catecholamines, HA is not significantly affected by its enzymatic action. HMT activity after reserpine, pargyline and L-histidine treatment showed no differences compared to the control values. However HDC was significantly increased in both hypothalamus and cortex. In this study, Ws/Ws rats with deficiency of mast cells were used to clarify aspects of HA metabolism in HAergic neurons by eliminating the contribution of mast cells. The irreversible MAO-B inhibitor Pargyline (65 mg/kg) failed to accumulate N(τ)-MHA in the hypothalamus. However, when animals treated with reserpine and pargyline/reserpine were compared, the last group showed higher N(τ)-MHA values (p < 0.01). Moreover, the precursor of HA, L-histidine (1 g/kg), produced an increase of HA in the hypothalamus to 166% and the cortex to 348%. In conclusion, our results suggest that the effect of reserpine on the HA pools in the brain might be different. The neuronal HA pools are more resistant to reserpine as compared to those of catecholamine. Moreover, the HAergic pool appears to be more resistant to depletion than mast cells' pool, and thus HDC/HMT activity and its localization may play a key role in the understanding of HA metabolism in brain after reserpine treatment.

  17. Temperature dependence of catecholamine depletion by reserpine in the heat of the toad (Bufo marinus)

    PubMed Central

    Chang, P.; Rand, M. J.

    1971-01-01

    1. The catecholamines in toad ventricle were adrenaline (90%) and noradrenaline (10%); there was no dopamine. 2. Phenoxybenzamine and tyramine stimulated the isolated heart and reduced the catecholamine content. 3. Reserpine treatment of toads kept at 20° C did not affect the adrenaline but reduced the noradrenaline content of the ventricle. 4. At 37° C, reserpine caused depletion of both adrenaline and noradrenaline, and the stimulant actions of phenoxybenzamine and tyramine were lost. PMID:4104653

  18. Cannabidiol Prevents Motor and Cognitive Impairments Induced by Reserpine in Rats

    PubMed Central

    Peres, Fernanda F.; Levin, Raquel; Suiama, Mayra A.; Diana, Mariana C.; Gouvêa, Douglas A.; Almeida, Valéria; Santos, Camila M.; Lungato, Lisandro; Zuardi, Antônio W.; Hallak, Jaime E. C.; Crippa, José A.; Vânia, D’Almeida; Silva, Regina H.; Abílio, Vanessa C.

    2016-01-01

    Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa that presents antipsychotic, anxiolytic, anti-inflammatory, and neuroprotective effects. In Parkinson’s disease patients, CBD is able to attenuate the psychotic symptoms induced by L-DOPA and to improve quality of life. Repeated administration of reserpine in rodents induces motor impairments that are accompanied by cognitive deficits, and has been applied to model both tardive dyskinesia and Parkinson’s disease. The present study investigated whether CBD administration would attenuate reserpine-induced motor and cognitive impairments in rats. Male Wistar rats received four injections of CBD (0.5 or 5 mg/kg) or vehicle (days 2–5). On days 3 and 5, animals received also one injection of 1 mg/kg reserpine or vehicle. Locomotor activity, vacuous chewing movements, and catalepsy were assessed from day 1 to day 7. On days 8 and 9, we evaluated animals’ performance on the plus-maze discriminative avoidance task, for learning/memory assessment. CBD (0.5 and 5 mg/kg) attenuated the increase in catalepsy behavior and in oral movements – but not the decrease in locomotion – induced by reserpine. CBD (0.5 mg/kg) also ameliorated the reserpine-induced memory deficit in the discriminative avoidance task. Our data show that CBD is able to attenuate motor and cognitive impairments induced by reserpine, suggesting the use of this compound in the pharmacotherapy of Parkinson’s disease and tardive dyskinesia. PMID:27733830

  19. (-)Epigallocatechin-3-gallate prevents the reserpine-induced impairment of short-term social memory in rats.

    PubMed

    Tseng, Hsiang-Chien; Wang, Mao-Hsien; Soung, Hung-Sheng; Chang, Yi; Chang, Kuo-Chi

    2015-12-01

    Reserpine has been confirmed to induce cognitive dysfunction and increase brain neural oxidative stress. Green tea catechins, particularly (-)epigallocatechin-3-gallate (EGCG), have strong antioxidative properties and can protect against numerous oxidative damages. In this study, we examined the possible protective effects of EGCG on reserpine-induced impairment of short-term memory in rats. Reserpine (1 mg/kg, intraperitoneal)-induced memory impairment was assessed using the social recognition task method; locomotor activity and the olfactory discrimination ability were not altered as measured by an open-field test and an olfactory discrimination test, respectively. EGCG treatment (100 and 300 mg/kg, intraperitoneal, for 7 days, starting 6 days before the reserpine injection) could improve the worsened social memory of reserpine-treated rats. Also, EGCG treatment reduced reserpine-induced lipid peroxidation and enhanced the antioxidation power in the hippocampi of reserpine-treated rats. These results suggest a protective effect of EGCG in treating reserpine-induced impairment of memory, most probably through its powerful antioxidative activities. Accordingly, EGCG may hold a clinically relevant value in preventing reserpine-induced cognitive dysfunction. PMID:26196076

  20. Valeriana officinalis ameliorates vacuous chewing movements induced by reserpine in rats.

    PubMed

    Pereira, Romaiana Picada; Fachinetto, Roselei; de Souza Prestes, Alessandro; Wagner, Caroline; Sudati, Jéssie Haigert; Boligon, Aline Augusti; Athayde, Margareth Linde; Morsch, Vera Maria; Rocha, João Batista Teixeira

    2011-11-01

    Oral movements are associated with important neuropathologies as Parkinson's disease and tardive dyskinesia. However, until this time, there has been no known efficacious treatment, without side effects, for these disorders. Thus, the aim of the present study was to investigate the possible preventive effects of V. officinalis, a phytotherapic that has GABAergic and antioxidant properties, in vacuous chewing movements (VCMs) induced by reserpine in rats. Adult male rats were treated with reserpine (1 mg/kg, s.c.) and/or with V. officinalis (in the drinking water, starting 15 days before the administration of the reserpine). VCMs, locomotor activity and oxidative stress measurements were evaluated. Furthermore, we carried out the identification of valeric acid and gallic acid by HPLC in the V. officinalis tincture. Our findings demonstrated that reserpine caused a marked increase on VCMs and the co-treatment with V. officinalis was able to reduce the intensity of VCM. Reserpine did not induce oxidative stress in cerebral structures (cortex, hippocampus, striatum and substantia nigra). However, a significant positive correlation between DCF-oxidation (an estimation of oxidative stress) in the cortex and VCMs (p < 0.05) was observed. Moreover, a negative correlation between Na(+)K(+)-ATPase activity in substantia nigra and the number of VCMs was observed (p < 0.05). In conclusion, V. officinalis had behavioral protective effect against reserpine-induced VCMs in rats; however, the exact mechanisms that contributed to this effect have not been completely understood. PMID:21476069

  1. Behavioral and neurochemical effects of chronic administration of reserpine and SKF-38393 in rats

    SciTech Connect

    Neisewander, J.L.; Lucki, I.; McGonigle, P. )

    1991-05-01

    Alterations in the density of dopamine receptor subtypes and behaviors mediated by the D1-selective agonist SKF-38393 were examined in rats treated chronically with reserpine, SKF-38393 or the combination of these drugs. Animals received either vehicle or reserpine (1 mg/kg s.c.) on days 1 to 28 and, in addition, half of each of these groups were treated with vehicle and half were treated with SKF-38393 (5-10 mg/kg s.c.) on days 15 to 29. Quantitative autoradiographic measurement of D1 receptors labeled with ({sup 3}H)SCH-23390 and D2 receptors labeled with ({sup 3}H)spiroperidol revealed that chronic administration of reserpine increased the density of both receptor subtypes in the nucleus accumbens and caudate-putamen, but not in the substantia nigra. Chronic administration of SKF-38393 alone did not alter D1 receptor density in any of these regions. However, chronic administration of the agonist in reserpinized animals decreased D1 receptor density in the nucleus accumbens, but not in the caudate-putamen or substantia nigra, demonstrating that this partial agonist can selectively down-regulate D1 receptors when endogenous dopaminergic tone is removed. The chronic drug treatments also altered behavioral responses. Chronic administration of SKF-38393 alone produced sensitization of the oral dyskinesia response elicited by a challenge injection of the agonist, but no significant change in the grooming response. Acute administration of SKF-38393 in rats treated with reserpine for 14 days produced stereotypy which was not altered after chronic administration of the agonist. Surprisingly, chronic administration of reserpine alone produced a spontaneous oral dyskinesia, which was blocked dose-dependently by the D2-selective antagonist spiroperidol. These findings are discussed in terms of their relevance to Parkinson's disease and tardive dyskinesia.

  2. Effects of reserpine on reproduction and serotonin immunoreactivity in the stable fly Stomoxys calcitrans (L.) ✩

    PubMed Central

    Liu, Samuel S.; Li, Andrew Y.; Witt, Colleen M.; Pérez de León, Adalberto A.

    2014-01-01

    Biogenic amines are known to play critical roles in key insect behaviors such as feeding and reproduction. This study documents the effects of reserpine on mating and egg-laying behaviors of the stable fly, Stomoxys calcitrans (L.) (Diptera: Muscidae), which is one of the most significant biting fly pests affecting cattle. Two sperm staining techniques were adapted successfully to reveal the morphology of stable fly sperm, for the first time, and determine successful mating in females through the assessment of sperm transfer. This approach was also applied to assess sperm transfer by males treated with different doses of reserpine. Mating or sperm transfer did not occur in flies during the first 3 days after emergence. Thereafter, the percentage of females that mated increased with age. Reserpine treatment of males reduced sperm transfer in a dose-dependent manner. Older males were more sensitive to reserpine treatment than younger flies. Reserpine treatment of 5 days old females reduced the number of eggs laid, but had no effect on egg-hatching rates. Results of immunoreactivity (IR) experiments indicated that serotonin in the neuronal processes innervating male testes was completely depleted by reserpine within 5 h after treatment. This effect was transient as the serotonin immunoreactive signal was recovered in 33.3% of the males at 1 day post-treatment and in 94.4% of the flies at 3 days post-treatment. The results of this study concur with previous findings in other insect species and extend our knowledge of the critical roles biogenic amines play in mating and oviposition behaviors of the stable fly. The work could provide a foundation to further characterize the specific roles of individual biogenic amines and their receptors in stable fly reproduction. PMID:23321479

  3. [Haloperidol, reserpine, l-dopa and amantidine in the treatment of Huntington chorea (author's transl)].

    PubMed

    Candelise, L

    1976-01-01

    Two drugs that should reduce striatal dopamine activity (haloperidol and reserpine) and two other drugs that should increase it (L-Dopa and amantadine) have been successively adminstered to six patients suffering from Huntington's Chorea. The most effective treatment in reducing hyperkinesis was haloperidol, followed by reserpine. Treatment with L-Dopa did not have appreciable effect, on this type of involuntary movements. Against some theoretical expectations administration of amantadine was followed by a slight improvement in the control of involuntary activity. PMID:134449

  4. Effects of Reserpine on Reproduction and Serotonin Immunoreactivity in the Stable Fly Stomoxys Calcitrans (L.)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Biogenic amines are known to play critical roles in key insect behaviors such as feeding and reproduction. This study documents the effects of reserpine on mating and egg-laying behaviors of the stable fly, Stomoxys calcitrans (L.) (Diptera: Muscidae), which is one of the most economically significa...

  5. Effect of reserpine on the histochemical and biochemical properties of rat intestinal mucin

    SciTech Connect

    Forstner, J.; Roomi, N.; Khorasani, R.; Kuhns, W.; Forstner, G. )

    1991-04-01

    Biochemical and histochemical parameters of intestinal mucins were examined in control and reserpine-treated rats. An assay for intestinal mucin sulfotransferase was developed and the activity shown to increase 3.4 times over control levels in rats given intraperitonal reserpine (0.5 mg/kg body wt) daily for 7 days. Histochemical staining of intestinal sections revealed an increase in sulfomucins in goblet cells of reserpine-treated rats. The effects were prominent as early as 1 day following injection, particularly in the distal third of the small intestine, and during the next 6 days these changes spread progressively to the middle and proximal thirds. After 3 days of treatment mucins were purified from each intestinal segment and compared to control mucins with respect to composition and (35S)NaSO{sub 4} incorporation. Although individual amino acid and carbohydrate molar ratios were unchanged, the total carbohydrate and sulfate content of mucins in treated animals was elevated (two to three times above control) in the middle and distal thirds of the intestine. In vivo ({sup 35}S)SO{sub 4} incorporation into these mucins was also proportionaltely elevated, and was targetted to O-linked oligosaccharide side chains. These findings are consistent with an action of reserpine causing an increased production of mucin which is enriched in glycoprotein components bearing sulfated oligosaccharide chains. The relevance of these findings to the production of hypersulfated and hyperglycosylated mucins in cystic fibrosis is discussed.

  6. Kinetics and Thermodynamics of Reserpine Adsorption onto Strong Acidic Cationic Exchange Fiber

    PubMed Central

    Guo, Zhanjing; Liu, Xiongmin; Huang, Hongmiao

    2015-01-01

    The kinetics and thermodynamics of the adsorption process of reserpine adsorbed onto the strong acidic cationic exchange fiber (SACEF) were studied by batch adsorption experiments. The adsorption capacity strongly depended on pH values, and the optimum reserpine adsorption onto the SACEF occurred at pH = 5 of reserpine solution. With the increase of temperature and initial concentration, the adsorption capacity increased. The equilibrium was attained within 20 mins. The adsorption process could be better described by the pseudo-second-order model and the Freundlich isotherm model. The calculated activation energy Ea was 4.35 kJ/mol. And the thermodynamic parameters were: 4.97<ΔH<7.44 kJ/mol, -15.29<ΔG<-11.87 kJ/mol and 41.97<ΔS<47.35 J/mol·K. The thermodynamic parameters demonstrated that the adsorption was an endothermic, spontaneous and feasible process of physisorption within the temperature range between 283 K and 323 K and the initial concentration range between 100 mg/L and 300 mg/L. All the results showed that the SACEF had a good adsorption performance for the adsorption of reserpine from alcoholic solution. PMID:26422265

  7. The effects of posture changes on blood pressure and heart rate of anesthetized and reserpinized sloths.

    PubMed

    Duarte, D P; Huggins, S E; Da Costa, C P; Leal, A M

    1989-01-01

    1. Tilting sloths anesthetized with chloralose from erect to supine or supine to erect produced little or no effect on heart rate. 2. Tilting anesthetized sloths from erect to supine increased both systolic and diastolic pressures significantly and by about the same amounts. The maximum effect was produced in 20 sec. 3. Pressures stabilized at a higher level than in the erect posture but below the maximum reached in tilting. 4. Tilting these sloths from the supine to the erect posture resulted in a rapid (20 sec) and dramatic fall in pressures to below the initial erect pressure levels. Return to initial erect levels took place slowly. 5. Tilting reserpinized sloths from erect to supine or supine to erect produced little or no effect on heart rate. 6. Tilting reserpinized sloths from erect to supine increased both systolic and diastolic pressures materially and by similar amounts. The maximum effect took 50 sec. 7. Pressures stabilized at higher levels than in the erect posture but less than maximum reached with tilting. 8. Tilting these sloths from supine to erect caused significant falls in pressure to slightly below the initial erect pressure, with maximum effect reached in 30 sec and eventual return to control level. 9. Pressure changes were almost entirely the result of altered venous return. 10. Neither chloralose nor reserpine completely blocked vascular control but reduced it materially.

  8. Depressive-like symptoms in a reserpine-induced model of fibromyalgia in rats.

    PubMed

    Blasco-Serra, Arantxa; Escrihuela-Vidal, Francesc; González-Soler, Eva M; Martínez-Expósito, Fernando; Blasco-Ausina, M Carmen; Martínez-Bellver, Sergio; Cervera-Ferri, Ana; Teruel-Martí, Vicent; Valverde-Navarro, Alfonso A

    2015-11-01

    Since the pathogenesis of fibromyalgia is unknown, treatment options are limited, ineffective and in fact based on symptom relief. A recently proposed rat model of fibromyalgia is based on central depletion of monamines caused by reserpine administration. This model showed widespread musculoskeletal pain and depressive-like symptoms, but the methodology used to measure such symptoms has been criticized. Evidence relates the high prevalence of pain and depression in fibromyalgia to common pathogenic pathways, most probably focused on the monoaminergic system. The present study aims at a validation of the reserpine model of fibromyalgia. For this purpose, rats undergoing this model have been tested for depressive-like symptoms with a Novelty-Suppressed Feeding Test adaptation. Animals administered with reserpine and subjected to forced food deprivation performed a smaller number of incursions to the center of the open field, evidenced by a decrease in the per-minute rate of the rats' approaching, smelling or touching the food. They also took more time to eat from the central food than control rats. These NSFT findings suggest the presence of depressive-like disorders in this animal model of fibromyalgia.

  9. Effects of kainic acid on hypothermia induced by reserpine, oxotremorine and apomorphine in mice.

    PubMed

    Bourin, M; Poisson, L; Larousse, C

    1987-03-01

    Antagonists of the norepinephrine reuptake and beta-adrenoreceptor agonists are potent, at once, on the three following tests: antagonism of hypothermia induced by reserpine, oxotremorine and apomorphine. 2-Carboxy-4-isopropenyl-3-pyrrolidine-acetic acid (kainic acid), which is a powerful stimulant of the neurons and a destroyer of the dopaminergic neurons, has been used in these tests to show if it is possible to antagonize hypothermia induced by different substances. The results obtained show that kainic acid is potent on these three tests, thus providing evidence that it is a stimulant of norepinephrine neurons as well as serotoninergic neurons, even if it is peripherically injected.

  10. Effects of denervation and reserpine on nexuses in the rat vas deferens.

    PubMed

    Westfall, D P; Millecchia, L L; Lee, T J; Corey, S P; Smith, D J; Fleming, W W

    1977-01-21

    Permanganate-fixed vasa deferentia from rats were examined for the presence of nexal-like contacts by electron microscopy. There was a significantly greater incidence of nexuses (2X) in chronically denervated tissues (5-7 days) but not in tissues from reserpine-pretreated animals (1.0 mg/kg/day for 5-7 days). The results suggest that an increase in nexal regions may not be a general feature of postjunctional supersensitivity but rather may contribute to other denervation-induced changes in contractile response. PMID:832678

  11. Agmatine attenuates reserpine-induced oral dyskinesia in mice: Role of oxidative stress, nitric oxide and glutamate NMDA receptors.

    PubMed

    Cunha, Andréia S; Matheus, Filipe C; Moretti, Morgana; Sampaio, Tuane B; Poli, Anicleto; Santos, Danúbia B; Colle, Dirleise; Cunha, Mauricio P; Blum-Silva, Carlos H; Sandjo, Louis P; Reginatto, Flávio H; Rodrigues, Ana Lúcia S; Farina, Marcelo; Prediger, Rui D

    2016-10-01

    Dyskinesia consists in a series of trunk, limbs and orofacial involuntary movements that can be observed following long-term pharmacological treatment in some psychotic and neurological disorders such as schizophrenia and Parkinson's disease, respectively. Agmatine is an endogenous arginine metabolite that emerges as neuromodulator and a promising agent to manage diverse central nervous system disorders by modulating nitric oxide (NO) pathway, glutamate NMDA receptors and oxidative stress. Herein, we investigated the effects of a single intraperitoneal (i.p.) administration of different agmatine doses (10, 30 or 100mg/kg) against the orofacial dyskinesia induced by reserpine (1mg/kg,s.c.) in mice by measuring the vacuous chewing movements and tongue protusion frequencies, and the duration of facial twitching. The results showed an orofacial antidyskinetic effect of agmatine (30mg/kg, i.p.) or the combined administration of sub-effective doses of agmatine (10mg/kg, i.p.) with the NMDA receptor antagonists amantadine (1mg/kg, i.p.) and MK801 (0.01mg/kg, i.p.) or the neuronal nitric oxide synthase (NOS) inhibitor 7-nitroindazole (7-NI; 0.1mg/kg, i.p.). Reserpine-treated mice displayed locomotor activity deficits in the open field and agmatine had no effect on this response. Reserpine increased nitrite and nitrate levels in cerebral cortex, but agmatine did not reverse it. Remarkably, agmatine reversed the decrease of dopamine and non-protein thiols (NPSH) levels caused by reserpine in the striatum. However, no changes were observed in striatal immunocontent of proteins related to the dopaminergic system including tyrosine hydroxylase, dopamine transporter, vesicular monoamine transporter type 2, pDARPP-32[Thr75], dopamine D1 and D2 receptors. These results indicate that the blockade of NO pathway, NMDAR and oxidative stress are possible mechanisms associated with the protective effects of agmatine against the orofacial dyskinesia induced by reserpine in mice.

  12. Effects of centrally of peripherally injected adrenomedullin on reserpine-induced gastric lesions.

    PubMed

    Clementi, G; Caruso, A; Cutuli, V M; de Bernardis, E; Prato, A; Mangano, N G; Amico-Roxas, M

    1998-10-30

    Adrenomedullin intracerebroventricularly administered (0.1 to 20 ng/rat i.c.v.), showed significant gastroprotective activity in a dose-dependent manner. When the peptide was intravenously administered (1 to 1000 ng/kg i.v.) it did not show significant gastroprotective activity in the same test. The gastroprotective effect of the peptide (10 ng/rat) was abolished by bilateral adrenalectomy, by pretreatment with the beta-adrenoceptor antagonist, propranolol (1 mg/kg i.p.), or by a calcitonin gene-related peptide (CGRP) receptor antagonist, CGRP-(8-37) fragment (1 or 10 ng/rat i.c.v.). This study showed that adrenomedullin is protective against reserpine-induced gastric lesions, that the action involves sympathetic nerve activity, and moreover interferes with CGRP receptors.

  13. Peripheral and spinal mechanisms of nociception in a rat reserpine-induced pain model.

    PubMed

    Taguchi, Toru; Katanosaka, Kimiaki; Yasui, Masaya; Hayashi, Koei; Yamashita, Mai; Wakatsuki, Koji; Kiyama, Hiroshi; Yamanaka, Akihiro; Mizumura, Kazue

    2015-03-01

    Chronic widespread pain is a serious medical problem, yet the mechanisms of nociception and pain are poorly understood. Using a reserpine-induced pain model originally reported as a putative animal model for fibromyalgia, this study was undertaken to examine the following: (1) expression of several ion channels responsible for pain, mechanotransduction, and generation/propagation of action potentials in the dorsal root ganglion (DRG), (2) activities of peripheral nociceptive afferents, and (3) alterations in spinal microglial cells. A significant increase in mRNA expression of the acid-sensing ion channel (ASIC)-3 was detected in the DRG, and the behavioral mechanical hyperalgesia was significantly reversed by subcutaneous injection of APETx2, a selective blocker of ASIC3. Single-fiber recordings in vitro revealed facilitated mechanical responses of mechanoresponsive C-fibers both in the skin and muscle although the proportion of mechanoresponsive C-nociceptors was paradoxically decreased. In the spinal dorsal horn, microglial cells labeled with Iba1 immunoreactivity was activated, especially in laminae I-II where the nociceptive input is mainly processed compared with the other laminae. The activated microglia and behavioral hyperalgesia were significantly tranquilized by intraperitoneal injection of minocycline. These results suggest that the increase in ASIC3 in the DRG facilitated mechanical response of the remaining C-nociceptors and that activated spinal microglia may direct to intensify pain in this model. Pain may be further amplified by reserpine-induced dysfunction of the descending pain inhibitory system and by the decrease in peripheral drive to this system resulting from a reduced proportion of mechanoresponsive C-nociceptors.

  14. Serum glucose, serum free fatty acids and adipose tissue lipids after fatal hypothermia of cold acclimatized, reserpine or propranolol treated guinea-pigs.

    PubMed

    Hirvonen, J; Huttunen, P; Vapaatalo, H

    1976-03-24

    Surviving ability in frost (-20 degree C) was studied in cold acclimatized guinea-pigs given either reserpine, propranolol or saline. Survival time, rectal temperature at death, serum glucose, serum FFA and triglycerides in the interscapular adipose tissue were determined. Rectal temperature was highest in the reserpine group, in the same animals that endured the frost the shortest time. The survival time had decreased by about a half of that in the controls. Propranolol treatment decreased the living time only slightly. The fact that serum glucose remained high in the reserpine treated animals was obviously related to the short survival time. In the propranolol group glucose values were somewhat higher than in the control group (saline-animals). Reserpine seemed to have inhibited the release of FFA in the warm-acclimatized animals as interpreted from the low serum values. On the other hand, FFA were rather high in the cold-acclimatized reserpine animals. The blocking effect of reserpine reflected also in the higher contents of triglycerides in the adipose tissue both in cold-acclimatized and warm-acclimatized animals. Propranolol prevented slightly the depletion of the triglycerides. Amount of total lipids in the adipose tissue was lower in the cold-acclimatized animals than in the warm-acclimatized ones because of the change of the type of the adipocytes from unilocular to multilocular. The results corroborated the importance of FFA for longer survival in severe cold. Sensitization to reserpine seems to develop during cold-acclimatization. It calls attention to a possible hazard of reserpine treatment in cold environment. PMID:961065

  15. The Efflux Pump Inhibitor Reserpine Selects Multidrug-Resistant Streptococcus pneumoniae Strains That Overexpress the ABC Transporters PatA and PatB▿ †

    PubMed Central

    Garvey, Mark I.; Piddock, Laura J. V.

    2008-01-01

    One way to combat multidrug-resistant microorganisms is the use of efflux pump inhibitors (EPIs). Spontaneous mutants resistant to the EPI reserpine selected from Streptococcus pneumoniae NCTC 7465 and R6 at a frequency suggestive of a single mutational event were also multidrug resistant. No mutations in pmrA (which encodes the efflux protein PmrA) were detected, and the expression of pmrA was unaltered in all mutants. In the reserpine-resistant multidrug-resistant mutants, the overexpression of both patA and patB, which encode ABC transporters, was associated with accumulation of low concentrations of antibiotics and dyes. The addition of sodium orthovanadate, an inhibitor of ABC efflux pumps, or the insertional inactivation of either gene restored wild-type antibiotic susceptibility and wild-type levels of accumulation. Only when patA was insertionally inactivated were both multidrug resistance and reserpine resistance lost. Strains in which patA was insertionally inactivated grew significantly more slowly than the wild type. These data indicate that the overexpression of both patA and patB confers multidrug resistance in S. pneumoniae but that only patA is involved in reserpine resistance. The selection of reserpine-resistant multidrug-resistant pneumococci has implications for analogous systems in other bacteria or in cancer. PMID:18362193

  16. Attenuation of reserpine-induced pain/depression dyad by gentiopicroside through downregulation of GluN2B receptors in the amygdala of mice.

    PubMed

    Liu, Shui-bing; Zhao, Rong; Li, Xu-sheng; Guo, Hong-ju; Tian, Zhen; Zhang, Nan; Gao, Guo-dong; Zhao, Ming-gao

    2014-06-01

    Epidemiological studies demonstrate that pain frequently occurs comorbid with depression. Gentiopicroside (Gent) is a secoiridoid compound isolated from Gentiana lutea that exhibits analgesic properties and inhibits the expression of GluN2B-containing N-methyl-D-aspartate (NMDA) receptors in the anterior cingulate cortex of mice. However, the effects of Gent on the reserpine-induced pain/depression dyad and its underlying mechanisms are unclear. Reserpine administration (1 mg/kg subcutaneous daily for 3 days) caused a significant decrease in the nociceptive threshold as evidenced by the reduced paw withdrawal latency in response to a radiant heat source and mechanical allodynia. Behavioral detection indicated a significant increase in immobility time during a forced swim test, as well as decreased time in the central area and total travel distance in an open field test. Furthermore, reserpinized animals exhibited increased oxidative stress. Systemic Gent administration dose-dependently ameliorated the behavioral deficits associated with reserpine-induced pain/depression dyad. At the same time, the decrease in biogenic amine levels (norepinephrine, dopamine, and serotonin) was integrated with the increase in caspase-3 levels and GluN2B-containing NMDA receptors in the amygdala of the reserpine-injected mice. Gent significantly reversed the changes in the levels of biogenic amines, caspase-3, and GluN2B-containing NMDA receptors in amygdala. However, Gent did not affect the expression of GluN2A-containing NMDA receptors. The inhibitory effects of Gent on oxidative stress were occluded by simultaneous treatment of GluN2B receptors antagonist Ro25-6981. Our study provides strong evidence that Gent inhibits reserpine-induced pain/depression dyad by downregulating GluN2B receptors in the amygdala.

  17. Attenuation of reserpine-induced pain/depression dyad by gentiopicroside through downregulation of GluN2B receptors in the amygdala of mice.

    PubMed

    Liu, Shui-bing; Zhao, Rong; Li, Xu-sheng; Guo, Hong-ju; Tian, Zhen; Zhang, Nan; Gao, Guo-dong; Zhao, Ming-gao

    2014-06-01

    Epidemiological studies demonstrate that pain frequently occurs comorbid with depression. Gentiopicroside (Gent) is a secoiridoid compound isolated from Gentiana lutea that exhibits analgesic properties and inhibits the expression of GluN2B-containing N-methyl-D-aspartate (NMDA) receptors in the anterior cingulate cortex of mice. However, the effects of Gent on the reserpine-induced pain/depression dyad and its underlying mechanisms are unclear. Reserpine administration (1 mg/kg subcutaneous daily for 3 days) caused a significant decrease in the nociceptive threshold as evidenced by the reduced paw withdrawal latency in response to a radiant heat source and mechanical allodynia. Behavioral detection indicated a significant increase in immobility time during a forced swim test, as well as decreased time in the central area and total travel distance in an open field test. Furthermore, reserpinized animals exhibited increased oxidative stress. Systemic Gent administration dose-dependently ameliorated the behavioral deficits associated with reserpine-induced pain/depression dyad. At the same time, the decrease in biogenic amine levels (norepinephrine, dopamine, and serotonin) was integrated with the increase in caspase-3 levels and GluN2B-containing NMDA receptors in the amygdala of the reserpine-injected mice. Gent significantly reversed the changes in the levels of biogenic amines, caspase-3, and GluN2B-containing NMDA receptors in amygdala. However, Gent did not affect the expression of GluN2A-containing NMDA receptors. The inhibitory effects of Gent on oxidative stress were occluded by simultaneous treatment of GluN2B receptors antagonist Ro25-6981. Our study provides strong evidence that Gent inhibits reserpine-induced pain/depression dyad by downregulating GluN2B receptors in the amygdala. PMID:24584520

  18. Acute treatment with bis selenide, an organic compound containing the trace element selenium, prevents memory deficits induced by reserpine in rats.

    PubMed

    Bortolatto, Cristiani Folharini; Guerra Souza, Ana Cristina; Wilhelm, Ethel Antunes; Nogueira, Cristina Wayne

    2013-01-01

    Taking into account the promising pharmacological actions of (Z)-2,3-bis(4-chlorophenylselanyl) prop-2-en-1-ol) (bis selenide), an organic compound containing the trace element selenium, and the constant search for drugs that improve the cognitive performance, the objective of the present study was to investigate whether bis selenide treatment ameliorates memory deficits induced by reserpine in rats. For this aim, male adult rats received a single subcutaneous injection of reserpine (1 mg/kg), a biogenic amine-depleting agent used to induce memory deficit. After 24 h, bis selenide at doses of 25 and 50 mg/kg was administered to rats by intragastric route, and 1 h later, the animals were submitted to behavior tasks. The effects of acute administration of bis selenide on memory were evaluated by social recognition, step-down passive avoidance, and object recognition paradigms. Exploratory and locomotor activities of rats were determined using the open-field test. Analysis of data revealed that the social memory disruption caused by reserpine was reversed by bis selenide at both doses. In addition, bis selenide, at the highest dose, prevented the memory deficit resulting from reserpine administration to rats in step-down passive avoidance and object recognition tasks. No significant alterations in locomotor and exploratory behaviors were found in animals treated with reserpine and/or bis selenide. Results obtained from distinct memory behavioral paradigms revealed that an acute treatment with bis selenide attenuated memory deficits induced by reserpine in rats.

  19. Effect of the enzymatic inhibitor of Kunitz on the gastric lesions from reserpine, from phenylbutazone, from pyloric ligation and by restraint in the rat

    NASA Technical Reports Server (NTRS)

    Guerrin, F.; Demaille, A.; Merveille, P.; Bel, C.

    1980-01-01

    The protective effects of certain polypeptides on gastric ulcerations caused from reserpine and phenylbutazone in the rate were studied. It was found that the Kunitz enzymatic inhibitor exerts a protective action in regard to gastric lesions. However, the inhibitor did not change the development of Shay ulcers and stress ulcers from restraint.

  20. Antioxidant-mediated preventative effect of Dragon-pearl tea crude polyphenol extract on reserpine-induced gastric ulcers

    PubMed Central

    YI, RUOKUN; WANG, RUI; SUN, PENG; ZHAO, XIN

    2015-01-01

    Dragon-pearl tea is a type of green tea commonly consumed in Southwest China. In the present study, the antioxidative and anti-gastric ulcer effects of Dragon-pearl tea crude polyphenols (DTCP) were determined in vitro and in vivo. Treatment with 25, 50 or 100 µg/ml DTCP resulted in notable antioxidant effects in vitro, which manifested as 2,2-diphenyl-1-picrylhydrazyl and OH radical-scavenging activity. Furthermore, using an in vivo mouse model, DTCP was shown to reduce the gastric ulcer area in the stomach, in which the 200 mg/kg DTCP dose exhibited the most marked effect, with a gastric ulcer index inhibitory rate of 72.63%. In addition, DTCP was demonstrated to improve stomach acidity conditions in vivo by increasing the pH and reducing the level of gastric juice, as compared with the reserpine-induced gastric ulcer control mice. Furthermore, DTCP altered the serum levels of a number of oxidation-related biomolecules, including superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), malondialdehyde (MDA), lipid peroxidation (LPO) and catalase (CAT), to subsequently exert an anti-gastric ulcer effect. Treatment with 50, 100 and 200 mg/kg DTCP increased the SOD, GSH-Px and CAT levels and reduced the MDA and LPO levels in the mouse model of gastric ulcers. These serum level alterations resulted in the modified serum levels of prostaglandin E2 (PGE2) and nitric oxide (NO), which are associated with gastric mucosal protection. A reverse transcription-quantitative polymerase chain reaction (RT-PCR) assay is a molecular biology experiment which could determine the changes of mRNA in tissues. Using the RT-PCR assay, DTCP was observed to increase the mRNA expression levels of certain genes associated with gastric ulcers: Epidermal growth factor, epidermal growth factor receptor, vascular endothelial growth factor and vascular endothelial growth factor receptor 1, while reducing gastrin expression levels. Therefore, the results indicated that DTCP induced a marked

  1. Scale-Up of Agrobacterium rhizogenes-Mediated Hairy Root Cultures of Rauwolfia serpentina: A Persuasive Approach for Stable Reserpine Production.

    PubMed

    Mehrotra, Shakti; Srivastava, Vikas; Goel, Manoj K; Kukreja, Arun K

    2016-01-01

    Roots of Rauwolfia serpentina, also known as "Sarpagandha" possess high pharmaceutical value due to the presence of reserpine and other medicinally important terpene indole alkaloids. Ever increasing commercial demand of R. serpentina roots is the major reason behind the unsystematic harvesting and fast decline of the species from its natural environment. Considering Agrobacterium rhizogenes-mediated hairy root cultures as an alternative source for the production of plant-based secondary metabolites, the present optimized protocol offers a commercially feasible method for the production of reserpine, the most potent alkaloid from R. serpentina roots. This end-to-end protocol presents the establishment of hairy root culture from the leaf explants of R. serpentina through the infection of A. rhizogenes strain A4 in liquid B5 culture medium and its up-scaling in a 5 L bench top, mechanically agitated bioreactor. The transformed nature of roots was confirmed through PCR-based rol A gene amplification in genomic DNA of putative hairy roots. The extraction and quantification of reserpine in bioreactor grown roots has been done using monolithic reverse phase high-performance liquid chromatography (HPLC). PMID:27108322

  2. Evaluation of the face validity of reserpine administration as an animal model of depression--Parkinson's disease association.

    PubMed

    Skalisz, Luana L; Beijamini, Vanessa; Joca, Samia L; Vital, Maria A B F; Da Cunha, Claudio; Andreatini, Roberto

    2002-06-01

    The aim of the present study was to develop an animal model for the study of depressive symptoms associated with Parkinson's disease (PD). Mice treated intraperitoneally with reserpine (RES), 2.0 and 1.0 mg/kg, or its vehicle (VEHIC) were submitted to the sucrose solution (2%) consumption test (a model employed to mimic the depressive symptoms found in PD) and to the spontaneous locomotor activity test (a model employed to mimic the motor impairment found in PD). All animals were submitted to both tests. Twenty-four hours after treatment, only RES 2.0-treated animals showed a significantly decreased preference for the sucrose solution (mean +/- S.E.M. RES 2.0 = 54.4 +/- 4.1%, RES 1.0 = 68.5 +/- 2.5%, VEHIC = 62.3 +/- 4.1%). There was no significant difference among groups in water, sucrose or total fluid consumption. Locomotor activity was significantly decreased by both RES doses (number of beam interruptions: RES 2.0 = 59.9 +/- 11.4, RES 1.0 = 82.2 +/- 9.7, VEHIC = 116.8 +/- 8.2). Thus, RES 2.0 administration to mice induced depressive (anhedonia) and motor (decreased locomotor activity) symptoms of depression-PD association. This suggests that the RES model shows an important aspect of face validity for the depressive state associated with PD, i.e., phenomenological similarities between the model and the situation being modeled.

  3. Influence of cocaine and sodium on bretylium uptake by reserpine-treated guinea-pig left atrium.

    PubMed Central

    García, A G; Sánchez-García, P

    1975-01-01

    1 The effects of cocaine and sodium on bretylium uptake into sympathetic nerve terminals were investigated in the reserpine-treated guinea-pig left atrium. The ability of bretylium pretreatment to increase the retention of noradrenaline was used as an index of bretylium uptake. Such increased retention has been assessed both by direct measurement and by the ability of tyramine to produce an inotropic response. 2 The restoration of the response to tyramine after incubation with noradrenaline was abolished when the atrium was pretreated with bretylium in the presence of cocaine. When bretylium was added before cocaine, or when alpha-methyl-noradrenaline (not a substrate for monoamine oxidase) was used for incubation, the responses to tyramine were restored in the normal way. 3 Bretylium greatly enhanced the retention of [3-H]-noradrenaline; when bretylium was added in the presence of cocaine, [3-H]-noradrenaline retention was severely impaired. 4 Pretreatment with bretylium in a low-sodium (25 mM) or sodium-free medium significantly decreased the retention of [3-H]-noradrenaline, as compared with the control. 5 Potassium deprivation did not modify the enhanced retention of [3-H]-noradrenaline induced by bretylium pretreatment. 6 Bretylium was released from the nerve terminals by exposure of the preparation to a sodium-free medium or to a solution containing calcium 50 mM, leading to a considerable decrease in [3-H]-noradrenaline retention. 7 The results are consistent with the view that both cocaine and sodium deprivation block the uptake of bretylium by the adrenergic nerve terminals, and that bretylium is probably taken up by a mechanism similar to or identical with the uptake system for noradrenaline and other amines. PMID:1148485

  4. Evaluation of the Xpa-deficient transgenic mouse model for short-term carcinogenicity testing: 9-month studies with haloperidol, reserpine, phenacetin, and D-mannitol.

    PubMed

    Lina, Ben A R; Woutersen, Ruud A; Bruijntjes, Joost P; van Benthem, Jan; van den Berg, Jolanda A H; Monbaliu, Johan; Thoolen, Bob J J M; Beems, Rudolf B; van Kreijl, Coen F

    2004-01-01

    As part of the international evaluation program coordinated by ILSI/HESI, the potential of DNA repair deficient Xpa-/- mice and the double knockout Xpa-/-.p53+/- mice for short term carcinogenicity assays was evaluated. For comparison also wild-type C57BL/6 mice (WT) were included in these studies. Four test compounds were administered to groups of 15 male and 15 female Xpa-/- mice, Xpa-/-.p53+/- mice and WT mice for 39 weeks. The model compounds investigated were haloperidol, reserpine (nongenotoxic rodent carcinogens, putative human noncarcinogens), phenacetin (genotoxic rodent carcinogen, suspected human carcinogen), and D-mannitol (noncarcinogen in rodents and humans). The test compounds were administered as admixture to rodent diet at levels up to 25 mg/kg diet for haloperidol, 7.5 mg/kg diet for reserpine, 0.75% for phenacetin, and 10% for D-mannitol. These levels included the maximum tolerable dose (MTD). Survival was not affected with any of the test compounds. Haloperidol, reserpine and D-mannitol were negative in the carcinogenicity assay with Xpa-/- and Xpa-/-.p53+/- mice, showing low and comparable tumor incidences in controls and high-dose animals. The results obtained with phenacetin may be designated equivocal in Xpa-/-.p53+/- mice, based on the occurrence of a single rare tumor in the target organ (kidney) accompanied by a low incidence of hyperplastic renal lesions and a high incidence of karyomegaly. These results are in agreement with the currently known carcinogenic potential of the 4 test compounds in humans. PMID:15200157

  5. Evaluation of the Xpa-deficient transgenic mouse model for short-term carcinogenicity testing: 9-month studies with haloperidol, reserpine, phenacetin, and D-mannitol.

    PubMed

    Lina, Ben A R; Woutersen, Ruud A; Bruijntjes, Joost P; van Benthem, Jan; van den Berg, Jolanda A H; Monbaliu, Johan; Thoolen, Bob J J M; Beems, Rudolf B; van Kreijl, Coen F

    2004-01-01

    As part of the international evaluation program coordinated by ILSI/HESI, the potential of DNA repair deficient Xpa-/- mice and the double knockout Xpa-/-.p53+/- mice for short term carcinogenicity assays was evaluated. For comparison also wild-type C57BL/6 mice (WT) were included in these studies. Four test compounds were administered to groups of 15 male and 15 female Xpa-/- mice, Xpa-/-.p53+/- mice and WT mice for 39 weeks. The model compounds investigated were haloperidol, reserpine (nongenotoxic rodent carcinogens, putative human noncarcinogens), phenacetin (genotoxic rodent carcinogen, suspected human carcinogen), and D-mannitol (noncarcinogen in rodents and humans). The test compounds were administered as admixture to rodent diet at levels up to 25 mg/kg diet for haloperidol, 7.5 mg/kg diet for reserpine, 0.75% for phenacetin, and 10% for D-mannitol. These levels included the maximum tolerable dose (MTD). Survival was not affected with any of the test compounds. Haloperidol, reserpine and D-mannitol were negative in the carcinogenicity assay with Xpa-/- and Xpa-/-.p53+/- mice, showing low and comparable tumor incidences in controls and high-dose animals. The results obtained with phenacetin may be designated equivocal in Xpa-/-.p53+/- mice, based on the occurrence of a single rare tumor in the target organ (kidney) accompanied by a low incidence of hyperplastic renal lesions and a high incidence of karyomegaly. These results are in agreement with the currently known carcinogenic potential of the 4 test compounds in humans.

  6. Time course of the changes of TH mRNA in rat brain and adrenal medulla after a single injection of reserpine.

    PubMed Central

    Biguet, N F; Buda, M; Lamouroux, A; Samolyk, D; Mallet, J

    1986-01-01

    A single injection of reserpine causes a long lasting enhancement of the activity of tyrosine hydroxylase (TH), the enzyme catalyzing the rate-limiting step in the biosynthesis of catecholamines. A sensitive method has been developed to assay both TH mRNA level and enzyme activity in tissue from a single rat. The time course of the induction was analysed in adrenals, locus coeruleus and substantia nigra. In both locus coeruleus and adrenals reserpine caused respectively 4.2- and 4.5-fold increase of TH mRNA which was maximal 2 days after drug injection. This increase is about twice that of the enzyme activity. No change was observed in substantia nigra. The effect lasted longer in locus coeruleus than in adrenal. In the latter, TH mRNA had almost returned to initial values at day 4 whereas at this time it is 3-fold higher in locus coeruleus and still significant at day 18. This result suggests that induction of TH results from an enhanced transcription of the TH gene. The time course difference between locus coeruleus and adrenals is most likely to result from a difference in the stability of TH mRNA in the two structures. Images Fig. 1. Fig. 2. Fig. 3. Fig. 4. PMID:2872048

  7. The Sea Urchin Embryo, an Invertebrate Model for Mammalian Developmental Neurotoxicity, Reveals Multiple Neurotransmitter Mechanisms for Effects of Chlorpyrifos: Therapeutic Interventions and a Comparison with the Monoamine Depleter, Reserpine

    PubMed Central

    Buznikov, Gennady A.; Nikitina, Lyudmila A.; Rakić, Ljubiša M.; Miloševi, Ivan; Bezuglov, Vladimir V.; Lauder, Jean M.; Slotkin, Theodore A.

    2007-01-01

    Lower organisms show promise for the screening of neurotoxicants that might target mammalian brain development. Sea urchins use neurotransmitters as embryonic growth regulatory signals, so that adverse effects on neural substrates for mammalian brain development can be studied in this simple organism. We compared the effects of the organophosphate insecticide, chlorpyrifos in sea urchin embryos with those of the monoamine depleter, reserpine, so as to investigate multiple neurotransmitter mechanisms involved in developmental toxicity and to evaluate different therapeutic interventions corresponding to each neurotransmitter system. Whereas reserpine interfered with all stages of embryonic development, the effects of chlorpyrifos did not emerge until the mid-blastula stage. After that point, the effects of the two agents were similar. Treatment with membrane permeable analogs of the monoamine neurotransmitters, serotonin and dopamine, prevented the adverse effects of either chlorpyrifos or reserpine, despite the fact that chlorpyrifos works simultaneously through actions on acetylcholine, monoamines and other neurotransmitter pathways. This suggests that different neurotransmitters, converging on the same downstream signaling events, could work together or in parallel to offset the developmental disruption caused by exposure to disparate agents. We tested this hypothesis by evaluating membrane permeable analogs of acetylcholine and cannabinoids, both of which proved effective against chlorpyrifos- or reserpine-induced teratogenesis. Invertebrate test systems can provide both a screening procedure for mammalian neuroteratogenesis and may uncover novel mechanisms underlying developmental vulnerability as well as possible therapeutic approaches to prevent teratogenesis. PMID:17720543

  8. Accumbal noradrenaline that contributes to the alpha-adrenoceptor-mediated release of dopamine from reserpine-sensitive storage vesicles in the nucleus accumbens is derived from alpha-methyl-para-tyrosine-sensitive pools.

    PubMed

    Verheij, M M M; Cools, A R

    2009-04-01

    Alpha-adrenoceptors in the nucleus accumbens are known to inhibit accumbal dopamine release from reserpine-sensitive pools. The aim of this study was to test our previously reported hypothesis that accumbal noradrenaline that controls the dopamine release from these storage vesicles is derived from alpha-methyl-para-tyrosine-sensitive pools. The sensitivity of accumbal alpha-adrenoceptors to noradrenergic agents depends on the amount of noradrenaline that is available in the synapse. In case the synaptic noradrenaline levels decrease, the conformation of alpha-adrenoceptors changes into a state that makes these receptors more sensitive to its agonists. The effects of alpha-methyl-para-tyrosine, respectively reserpine, on the alpha-adrenoceptor-agonist-induced changes of accumbal dopamine release were investigated. Alpha-methyl-para-tyrosine, but not reserpine, made accumbal postsynaptic alpha-adrenoceptors more sensitive to phenylephrine. These results indicate that noradrenaline that inhibits the release of dopamine from reserpine-sensitive storage vesicles, via stimulation of accumbal postsynaptic alpha-adrenoceptors, is derived from alpha-methyl-para-tyrosine-sensitive pools. The clinical impact of these data is discussed.

  9. Locomotor response to L-DOPA in reserpine-treated rats following central inhibition of aromatic L-amino acid decarboxylase: further evidence for non-dopaminergic actions of L-DOPA and its metabolites.

    PubMed

    Alachkar, Amal; Brotchie, Jonathan M; Jones, Owen T

    2010-09-01

    L-DOPA is the most widely used treatment for Parkinson's disease. The anti-parkinsonian and pro-dyskinetic actions of L-DOPA are widely attributed to its conversion, by the enzyme aromatic L-amino acid decarboxylase (AADC), to dopamine. We investigated the hypothesis that exogenous L-DOPA can induce behavioural effects without being converted to dopamine in the reserpine-treated rat-model of Parkinson's disease. A parkinsonian state was induced with reserpine (3 mg/kg s.c.). Eighteen hours later, the rats were administered L-DOPA plus the peripherally acting AADC inhibitor benserazide (25 mg/kg), with or without the centrally acting AADC inhibitor NSD1015 (100 mg/kg). L-DOPA/benserazide alone reversed reserpine-induced akinesia (4158+/-1125 activity counts/6 h, cf vehicle 1327+/-227). Addition of NSD1015 elicited hyperactive behaviour that was approximately 7-fold higher than L-DOPA/benserazide (35755+/-5226, P<0.001). The hyperactivity induced by L-DOPA and NSD1015 was reduced by the alpha(2C) antagonist rauwolscine (1 mg/kg) and the 5-HT(2C) agonist MK212 (5 mg/kg), but not by the D2 dopamine receptor antagonist remoxipride (3 mg/kg) or the D1 dopamine receptor antagonist SCH23390 (1 mg/kg). These data suggest that L-DOPA, or metabolites produced via routes not involving AADC, might be responsible for the generation of at least some L-DOPA actions in reserpine-treated rats. PMID:20542064

  10. Different pathophysiology underlying animal models of fibromyalgia and neuropathic pain: comparison of reserpine-induced myalgia and chronic constriction injury rats.

    PubMed

    Nagakura, Yukinori; Takahashi, Masayasu; Noto, Takahisa; Sekizawa, Toshihiro; Oe, Tomoya; Yoshimi, Eiji; Tamaki, Keisuke; Shimizu, Yasuaki

    2012-01-01

    The reserpine-induced myalgia (RIM) rat manifests fibromyalgia-like chronic pain symptoms. The present study explored the pathophysiology underlying the pain symptoms in the RIM rat and the chronic constriction injury (CCI) rat, an animal model of neuropathic pain as a reference. Nerve tissue samples were collected from the nociception-tested animals for pathological examinations. Additionally, the therapeutic efficacy of a sodium channel blocker mexiletine was assessed in both rats. A slight vacuolization in the substantia nigra (SN) occurred in some of the RIM rats without any other histopathological changes in the brain or peripheral neurons. All the RIM rats, with or without vacuolization, showed hypersensitivity to tactile, muscle pressure, and cold stimuli. In the CCI rat, neurodegenerative changes were apparent in the sciatic nerve and the spinal cord only. CCI rats displayed muscle hyperalgesia in addition to tactile and cold allodynia. Pharmacotherapy with mexiletine did not attenuate the pain in the RIM rat, although it was effective in the CCI rat. Taken together, it is not likely that pain symptoms in RIM rats are caused by degenerative changes at the level of primary afferents and spinal cord, as is the case for CCI rats. The significance of the vacuolization in the SN is less clear at present because of the minor extent of the change and the lack of correlation with nociceptive sensitivity. The pain symptoms in RIM rats could be associated with dysfunction of biogenic amines-mediated CNS pain control even without apparent pathologies in the nervous system. PMID:21945299

  11. Kinetic properties of C-11 phenylephrine in isolated rat heart: Effects of di-deuterium substitution, age, MAO inhibition, and reserpine

    SciTech Connect

    Raffel, D.M.; Rosario, R.B. del; Tluczek, L.

    1995-05-01

    Elimination of the {alpha}-carbon CH{sub 3} group from C-11 hydroxyephedrine (HED) yields a new radiotracer for cardiac sympathetic neurons: C-11 phenylephrine (PHEN). This small structural change has profound effects on the tracer kinetics - HED is not metabolized by neuronal monoamine oxidase (MAO), while PHEN is an excellent MAO substrate. To assess the influence of MAO metabolism and vesicular storage on PHEN kinetics a series of constant infusion studies were performed. Isolated working rat hearts were perfused under control conditions for 25 min, then switched to a second perfusate circuit containing PHEN at tracer concentrations. PHEN was infused for 10 min then the heart switched back to normal perfusate to effect washout of PHEN. The amount of PHEN in the heart was externally measured using coinsidence detection. The data between 1 and 4 min were used to estimate an uptake constant, K{sub up} (ml/min/g wet). Washout data were fit to multiple exponentials. Several studies were done: (1) To slow MAO metabolism, the dideuterium substituted analog C-11 D{sub 2-}PHEN was made and studied as described above. (2) For both tracers, the effect of age on washout kinetics was studied as rat heart MAO levels steadily increase throughout the animal`s life. (3) The effect of MAO inhibition was studied using 100 {mu}M pargyline throughout the experiment. (4) Reserpine pretreated rats were used to assess the influence of vesicular storage on tracer kinetics.

  12. Transcallosal evoked potentials in relation to behavior in the rat: effects of atropine, p-chlorophenylalanine, reserpine, scopolamine and trifluoperazine.

    PubMed

    Vanderwolf, C H; Harvey, G C; Leung, L W

    1987-07-01

    Single pulse electrical stimulation of the sensorimotor cortex in waking rats produced an evoked response in the contralateral sensorimotor cortex. The slow wave response consisted of: (1) an early component that was negative at the pial surface and in layer V, and was associated with multiunit discharge; and (2) a late component that was mainly negative at the surface, positive in layer V, and was associated with multiunit suppression. Previous research suggests that the early component represents summed excitatory postsynaptic potentials; the late component summed inhibitory postsynaptic potentials. Both components could be elicited by direct stimulation of the corpus callosum and both were abolished by midline callosal section. The amplitude and duration of the late component varied with concurrent motor activity in a striking manner. It was large during waking immobility and also during face-washing, licking the paws, chewing food and drinking water, but was much reduced or absent during head movements, walking and changes in posture. Only minor changes were associated with the transition from waking immobility to slow wave sleep. A series of pharmacological experiments indicated that the behavior-related variation in the late component of the transcallosal evoked response was dependent on both cholinergic and serotonergic transmission.

  13. [Inhibitory effects of methyl o-(4-hydroxy-3-methoxycinnamoyl) reserpate (CD-3400) on the central nervous system (author's transl)].

    PubMed

    Shika, K; Nakata, C; Ogura, M; Tamada, T; Fujimoto, Y

    1977-10-01

    Effects of methyl o-(4-hydroxy-3-methoxycinnamoyl) reserpate (CD-3400) on the central nervous system in mice, rats and cats were investigated, and a comparison was made with such effects of reserpine and rescinamine. Inhibitory effects of CD-3400 on spontaneous motor activity and conditioned avoidance response were weaker and shorter than those of reserpine and rescinnamine. In the experiments of the inhibitory effects of the central actions such as ptosis, hypothermia, decrease in motor ability, potentiation of hexobarbital and taming, reserpine was found to be the most potent followed by rescinnamine and CD-3400, respectively. High doses of CD-3400 exhibited inhibitory effects on methamphetamine-induced hyperactivity in mice and this action was weaker than those of reserpine and rescinnamine. CD-3400, 80-160 mg/kg p.o., showed no significant effects on morphine-induced analgesia, while a slight inhibition was observed on the Straub-tail reaction using morphine. Reserpine, 0.5 mg/kg i.v., resulted in a drowsy pattern in the spontaneous EEG activity and the EEG arousal response was depressed, while with CD-3400, 5 mg/kg i.v., there was no drowsy pattern. CD-3400 as well as rescinnamine and reserpine remarkably depleted 5-HT levels in brain, heart and plasma and the potency of CD-3400, particularly in the brain, was weaker than the potency of reserpine and rescinnamine. These results indicate that CD-3400 is an antihypertensive agent with a low toxicity and a weak central action.

  14. Effect of deprivation of serotonin by p-chlorophenylalanine on induction and maintenance of pseudopregnancy in female rats.

    PubMed

    Maekawa, F; Yamanouchi, K

    1996-01-01

    The effect of serotonin synthesis inhibitor, p-chlorophenylalanine (PCPA), on induction and maintenance of pseudopregnancy as indicated by deciduoma formation was examined in female rats. Animals were injected with 1 mg/kg b.wt. of reserpine on the day of metestrus, and silk thread was passed through and placed in the left uterine horn 3 days after reserpine to induce deciduoma. PCPA (100 mg/kg b.wt.) was injected daily for 4 days before or after reserpine in 15 and 13 rats, respectively. A single injection of PCPA was administered before reserpine in nine females. In another group of rats (N = 16), instead of PCPA, saline was injected four times before reserpine. Nineteen female rats were treated with reserpine only as a control group. Results showed 89% of the control and 81.3% of the saline-treated females had massive deciduoma in traumatized uterine horn. In contrast, only 33.3% or 46.2% females with daily treatments of PCPA for 4 days before or after reserpine showed positive decidual reaction. In addition, 88.9% of females with single injection of PCPA possessed uterine horns with deciduoma. These results suggest that 4 days of treatment with PCPA eliminate induction and/or maintenance of pseudopregnancy. Thus, some levels of serotonin are required to induce and maintain pseudopregnancy.

  15. 75 FR 54889 - Draft Guidance for Industry on Suicidality: Prospective Assessment of Occurrence in Clinical...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-09

    ... tretinoins, beta blockers (especially those entering the brain), reserpine, drugs for smoking cessation, and... HUMAN SERVICES Food and Drug Administration Draft Guidance for Industry on Suicidality: Prospective Assessment of Occurrence in Clinical Trials; Availability AGENCY: Food and Drug Administration, HHS....

  16. The laser desorption/laser ionization mass spectra of some indole derivatives and alkaloids

    NASA Astrophysics Data System (ADS)

    Rogers, Kevin; Milnes, John; Gormally, John

    1992-06-01

    The laser desorption and laser ionization mass spectra of some indole derivatives and alkaloids are described with particular reference to their modes of fragmentation. Mass spectra of yohimbine, reserpine, quinine and quinidine are presented. Full experimental details are given.

  17. Gastric mucosal lesions induced by complete dopamine system failure in rats. The effects of dopamine agents, ranitidine, atropine, omeprazole and pentadecapeptide BPC 157.

    PubMed

    Sikiric, P; Separovic, J; Buljat, G; Anic, T; Stancic-Rokotov, D; Mikus, D; Duplancic, B; Marovic, A; Zoricic, I; Prkacin, I; Lovric-Bencic, M; Aralica, G; Ziger, T; Perovic, D; Jelovac, N; Dodig, G; Rotkvic, I; Mise, S; Seiwerth, S; Turkovic, B; Grabarevic, Z; Petek, M; Rucman, R

    2000-01-01

    Up to now, for gastric lesions potentiation or induction, as well as determination of endogenous dopamine significance, dopamine antagonist or dopamine vesicle depletor were given separately. Therefore, without combination studies, the evidence for dopamine significance remains split on either blockade of dopamine post-synaptic receptor or inhibition of dopamine storage, essentially contrasting with endogenous circumstances, where both functions could be simultaneously disturbed. For this purpose, a co-administration of reserpine and haloperidol, a dopamine granule depletor combined with a dopamine antagonist with pronounced ulcerogenic effect, was tested, and the rats were sacrificed 24 h after injurious agent(s) administration. Haloperidol (5 mg x kg(-1) b.w. i.p.), given alone, produced the lesions in all rats. Reserpine (5 mg x kg(-1) b.w. i.p.), given separately, also produced lesions. When these agents were given together, the lesions were apparently larger than in the groups injured with separate administration of either haloperidol or reserpine alone. Along with our previous results, when beneficial agents were co-administered, all dopaminomimetics (bromocriptine 10 mg, apomophine 1 mg, amphetamine 20 mg x kg(-1) i.p.) apparently attenuated the otherwise consistent haloperidol-gastric lesions. Likewise, an apparent inhibition of the reserpine-lesions was noted as well. However, if they were given in rats injured with combination of haloperidol and reserpine, their otherwise prominent beneficial effects were absent. Ranitidine (10 mg), omeprazole (10 mg), atropine (10 mg), pentadecapeptide BPC 157 (Gly-Glu-Pro-Pro-Pro-Gly-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val) (10 microg or 10 ng x kg(-1) i.p.) evidently prevented both haloperidol-gastric lesions and reserpine-gastric lesions. Confronted with potentiated lesions following a combination of haloperidol and reserpine, these agents maintained their beneficial effects, noted in the rats treated with either

  18. Magnesium Supplementation Prevents and Reverses Experimentally Induced Movement Disturbances in Rats: Biochemical and Behavioral Parameters.

    PubMed

    Kronbauer, Maikel; Segat, Hecson J; De David Antoniazzi, Caren Tatiane; Roversi, Karine; Roversi, Katiane; Pase, Camila S; Barcelos, Raquel C S; Burger, Marilise E

    2015-08-01

    Reserpine administration results in a predictable animal model of orofacial dyskinesia (OD) that has been largely used to access movement disturbances related to extrapyramidal oxidative damage. Here, OD was acutely induced by reserpine (two doses of 0.7 mg/kg subcutaneous (s.c.)), every other day for 3 days), which was administered after (experiment 1) and before (experiment 2) magnesium (Mg) supplementation (40 mg/kg/mL, peroral (p.o.)). In experiment 1, Mg was administered for 28 days before reserpine treatment, while in experiment 2, it was initiated 24 h after the last reserpine administration and was maintained for 10 consecutive days. Experiment 1 (prevention) showed that Mg supplementation was able to prevent reserpine-induced OD and catalepsy development. Mg was also able to prevent reactive species (RS) generation, thus preventing increase of protein carbonyl (PC) levels in both cortex and substantia nigra, but not in striatum. Experiment 2 (reversion) showed that Mg was able to decrease OD and catalepsy at all times assessed. In addition, Mg was able to decrease RS generation, with lower levels of PC in both cortex and striatum, but not in substantia nigra. These outcomes indicate that Mg is an important metal that should be present in the diet, since its intake is able to prevent and minimize the development of movement disorders closely related to oxidative damage in the extrapyramidal brain areas, such as OD.

  19. X-ray microanalysis of exocrine glands in animal models for cystic fibrosis

    SciTech Connect

    Mueller, R.M.R.; Roomans, G.M.

    1985-01-01

    Elemental distribution and ultrastructure of the submandibular gland, the parotid gland and the pancreas were investigated in three suggested animal models of the disease cystic fibrosis: the chronically reserpinized rat, the chronically isoproterenol-treated rat, and the chronically pilocarpine-treated rat. To elucidate the cellular mechanism underlying the effects of these treatments, chronic effects of specific alpha - and beta -adrenergic agonists, as well as acute effects of reserpine and various agonists were also investigated. Reserpine, isoproterenol, and pilocarpine cause an increase in the calcium concentration in submandibular gland acinar cells, due to an increased calcium content of the intracellular mucus. In the parotid gland, reserpine and isoproterenol cause a decrease of the calcium concentration in acinar cells, due to a lower calcium content of the zymogen granules. In the submandibular gland, a decreased cellular Na concentration was noted after chronic treatment with isoproterenol or pilocarpine, and after a single dose of reserpine or isoproterenol. Ultrastructural changes in the exocrine glands investigated included excessive accumulation of intracellular secretory material and formation of abnormal uncondensed secretion granules. A common pattern in the animal models appears to be (1) inhibition of secretion resulting in intracellular accumulation of secretory material, (2) synthesis of secretory macromolecules with altered cation-binding properties.

  20. Effects of chronic lesions in mesencephalic raphe nuclei on induction of pseudopregnancy.

    PubMed

    Maekawa, F; Yamanouchi, K

    1996-08-01

    The role of mesencephalic raphe nuclei in the induction of pseudopregnancy was investigated in female rats. The dorsal or median raphe nucleus lesions (DRL or MRL, respectively) were made by means of a radiofrequency lesion generator. Two or 3 weeks after the operation, in order to induce pseudopregnancy, the vagina was stimulated electrically on the day of proestrus or 1 mg/kg b.w. reserpine was injected on the day of diestrus I. Traumatization by passing thread to one uterine horn was performed to induce deciduoma 5 days after vaginal stimulation or 3 days after reserpine injection. As the results, decidual response was seen in most control and sham females in both vaginal stimulation and reserpine-treated groups. In contrast, incidences of deciduoma in DRL females with vaginal stimulation or reserpine-injection were significantly lower than those in control and sham groups. In the MRL females with either vaginal stimulation or reserpine-treatment, incidences of deciduoma were comparable to those of the control and sham operated groups. These results suggest that the dorsal raphe nucleus plays an important role in pseudopregnancy-inducing mechanisms in female rats.

  1. Comparative study between two animal models of extrapyramidal movement disorders: prevention and reversion by pecan nut shell aqueous extract.

    PubMed

    Trevizol, Fabiola; Benvegnú, Dalila M; Barcelos, Raquel C S; Pase, Camila S; Segat, Hecson J; Dias, Verônica Tironi; Dolci, Geisa S; Boufleur, Nardeli; Reckziegel, Patrícia; Bürger, Marilise E

    2011-08-01

    Acute reserpine and subchronic haloperidol are animal models of extrapyramidal disorders often used to study parkinsonism, akinesia and tardive dyskinesia. In humans, these usually irreversible and disabling extrapyramidal disorders are developed by typical antipsychotic treatment, whose pathophysiology has been related to oxidative damages development. So far, there is no treatment to prevent these problems of the psychiatric clinic, and therefore further studies are needed. Here we used the animal models of extrapyramidal disorders cited above, which were performed in two distinct experiments: orofacial dyskinesia (OD)/catalepsy induced by acute reserpine and subchronic haloperidol after (experiment 1) and before (experiment 2) oral treatment with pecan shell aqueous extract (AE), a natural and promissory antioxidant. When administered previously (exp.1), the AE prevented OD and catalepsy induced by both reserpine and haloperidol. When reserpine and haloperidol were administered before the extract (exp.2), the animals developed OD and catalepsy all the same. However, the orofacial parameter (but not catalepsy) in both animal models was reversed after 7 and 14 days of AE treatment. These results indicate that, acute reserpine and subchronic haloperidol administrations induced similar motor disorders, although through different mechanisms, and therefore are important animal models to study the physiopathology of extrapyramidal disorders. Comparatively, the pecan shell AE was able to both prevent and reverse OD but only to prevent catalepsy. These results reinforce the role of oxidative stress and validate the two animal models used here. Our findings also favor the idea of prevention of extrapyramidal disorders, rather than their reversal. PMID:21356248

  2. The role of brain biogenic amines in the control of pituitary-adrenocortical activity

    NASA Technical Reports Server (NTRS)

    Maickel, R. P.

    1975-01-01

    It was found that pretreatment of animals with desmethyl imipramine antagonized the reserpine-induced sedation without preventing the decline in brain amines or the hypersecretion of adrenocorticotropic hormone (ACTH). The antagonism of reserpine-induced ACTH hypersecretion by the monoamine oxidose (MAO) inhibitor pargyline (MO 911, N-methyl-N-benzyl-2-propynylamine) was studied. Evidence is presented that this antagonism is related to the level of brain biogenic amines maintained during the course of action of the drug. Pretreatment with MAO inhibitors does not affect the ACTH hypersecretion evoked by exposure to cold or chlorpromazine, lending further support to the hypothesis that reserpine-induced ACTH hypersecretion is related to brain amine changes.

  3. [The characteristics of the restructuring of the circadian dynamics in rat motor activity in response to a phase shift in the photoperiod in the experimental modelling of depression].

    PubMed

    Baturin, V A; Arushanian, E B

    1994-01-01

    Gradual reorganization of the locomotor activity of rats after a shift in the photoperiod was disrupted under the influence of depressogenic agents (reserpine or chronic pain stress). After the chronic use of the antidepressant amitriptyline the disruption of the reorganization of the daily motor activity typical for reserpine was not observed confirming a specificity of these changes. The results suggest that in the experimental model of depression there arise conditions for functional disturbance of the circadian pacemaker and an increase of sensitivity to the photic Zeitgeber. PMID:7941725

  4. Effect of spinal monoaminergic neuronal system dysfunction on pain threshold in rats, and the analgesic effect of serotonin and norepinephrine reuptake inhibitors.

    PubMed

    Tamano, Ryuta; Ishida, Mitsuhiro; Asaki, Toshiyuki; Hasegawa, Minoru; Shinohara, Shunji

    2016-02-26

    Dysfunction in the central serotonin (5-HT) and norepinephrine (NE) systems cause depression and pain. Descending spinal pain modulatory pathways are important in the analgesic mechanisms of antidepressants, particularly serotonin and norepinephrine reuptake inhibitors (SNRIs). While many non-clinical studies have demonstrated the roles of central monoaminergic systems in pain, there is little evidence to illuminate the direct contribution of spinal descending pain modulatory systems independently of depressive-like behavior. To examine the effects of dysfunction of spinal monoaminergic systems on pain sensitivity, we established a rat chronic pain model by administering lumbar-intrathecal reserpine to minimize its influence on brain. Lumbar-intrathecal reserpine evoked persistent mechanical hypersensitivity and corresponding reductions in spinal 5-HT and NE concentrations (from 767.2 to 241.6ng/g and from 455.9 to 41.7ng/g, respectively after reserpine 30nmol). Lumbar-intrathecal reserpine did not deplete brain monoamines or bring about depressive-like behavior in the forced swim test. Spinal monoamines depletion-induced pain sensitivity was ameliorated by lumbar-intrathecal administration of the SNRIs (duloxetine and milnacipran) in dose-dependent manners. These suggest that increased pain sensitivity could be induced by dysfunction solely of the descending pain modulatory system, regardless of depressive-like behavior, and lumbar-intrathecal administration of SNRIs could ameliorate the pain sensitivity which might be mediated by affecting the descending pain modulatory system in the spinal cord, not via their antidepressant effects. PMID:26806036

  5. Effects of 071031B, a novel serotonin and norepinephrine reuptake inhibitor, on monoamine system in mice and rats.

    PubMed

    Xue, Rui; He, Xin-Hua; Yuan, Li; Chen, Hong-Xia; Zhang, Li-Ming; Yong, Zheng; Yu, Gang; Fan, Shi-Yong; Li, Yun-Feng; Zhong, Bo-Hua; Zhang, You-Zhi

    2016-01-01

    Our previous study indicated that 071031B, a novel potential serotonin and norepinephrine reuptake inhibitor, showed robust antidepressant activity in multiple depression models, and could simultaneously inhibit 5-HT and NE reuptake in vitro. The present study was to evaluate the effects of 071031B on monoamine system in vivo, by using pharmacological models, including 5-HTP induced head-twitch test, yohimbine toxicity potentiation test, and reserpine induced hypothermia test, and determining monoamine transmitter levels in reserpine induced monoamine depletion model or chronic unpredictable stress (CUS) model. Results in pharmacological models indicated that acute administration of 071031B at 5-20 mg/kg significantly enhanced 5-HTP induced head-twitch behavior, potentiated yohimbine induced lethal rate, and reversed reserpine induced hypothermia. Further monoamine assays demonstrated that acute or chronic administration of 071031B at 10 or 20 mg/kg increased 5-HT and/or NE levels in various brain regions in reserpine or CUS induced monoamine depletion models, respectively, without effect on DA and its metabolites. Our results revealed that 071031B produces potent inhibition of 5-HT and NE reuptake in vivo.

  6. Neuroprotective effect of EGb761® and low-dose whole-body γ-irradiation in a rat model of Parkinson's disease.

    PubMed

    El-Ghazaly, Mona A; Sadik, Nermin A H; Rashed, Engy R; Abd-El-Fattah, Amal A

    2015-12-01

    Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. The present study was undertaken to investigate the pretreatment effects of standardized Ginkgo biloba extract (EGb761(®)) and low-dose whole-body γ-irradiation on the neurological dysfunction in the reserpine model of PD. Male Wistar rats were pretreated orally with EGb761 or fractionated low-dose whole-body γ-irradiation or their combination, then subjected to intraperitoneal injection of reserpine (5 mg/kg body weight) 24 h after the final dose of EGb761 or radiation. Reserpine injection resulted in the depletion of striatal dopamine (DA) level, increased catalepsy score, increased oxidative stress indicated via depletion of glutathione (GSH), increased malondialdehyde (MDA) and iron levels, decreased DA metabolites metabolizing enzymes; indicated by inhibition by glutathione-S-transferase, and nicotinamide adenine dinucleotide phosphate (NADPH)-quinone oxidoreductase (NQO) activities, mitochondrial dysfunction; indicated by declined complex I activity, and adenosine triphosphate (ATP) level and increased apoptosis; indicated by decreased mitochondrial B cell lymphoma-2 (Bcl-2) protein level and by transmission electron microscope. EGb761 and low-dose γ-radiation ameliorated the reserpine-induced state of oxidative stress, mitochondrial dysfunction, and apoptosis in brain. It can be concluded that EGb761, a widely used herbal medicine and low dose of γ-irradiation have protective effects for combating Parkinsonism possibly via replenishment of GSH levels.

  7. Quantification and characterization of alkaloids from roots of Rauwolfia serpentina using ultra high performance liquid chromatography-photo diode array-mass spectrometry (UHPLC-PDA-MS)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The roots of Rauwolfia serpentina (L.) Benth. ex Kurz has been used in native Indian medicine for treatment of various illnesses and has been mainly used to treat hypertension. Reserpine is potent substance which shared both central nervous system depressant and hypotensive actions. An UHPLC-UV meth...

  8. Sotalol

    MedlinePlus

    ... pain; other medications for high blood pressure or heart disease; reserpine; and vitamins.if you are taking aluminum- or magnesium-containing antacids (Maalox, Mylanta), take them at least 2 hours before or after ... had heart or liver disease; asthma or other lung disease; disease of the ...

  9. Injection of Resperpine into Zebrafish, Prevents Fish to Fish Communication of Radiation-Induced Bystander Signals: Confirmation in Vivo of a Role for Serotonin in the Mechanism

    PubMed Central

    Saroya, Rohin; Smith, Richard; Seymour, Colin; Mothersill, Carmel

    2009-01-01

    Serotonin (5-HT) has been implicated as a potential modulator of the bystander effect in cell cultures. To assess the relevance of serotonin in vivo experiments were done with the zebrafish (Danio rerio). This species, when irradiated, transmits bystander signals to non-irradiated fish. The animals were injected with reserpine, an inhibitor of serotonin at a dose of 80mg/kg of body mass. The results show that reserpine treated fish had only 27% of the serotonin in non-treated fish. Skin tissue samples were collected from the fish and assayed for bystander signal production using a reporter bioassay. Reserpine prevented the production and communication of signals between fish. Intracellular calcium flux, identified as a bystander response in the reporter cells confirmed this. Medium harvested from tissues of X-rayed fish and their bystanders, showed an oscillating pattern of calcium flux. Samples from X-rayed fish pretreated with reserpine produced a chaotic pattern of random fluctuations in the reporter cells, while their bystander fish led to increased calcium, but no oscillations. These results suggest that 5-HT is involved in bystander signalling in zebrafish, and by decreasing the amount of available 5-HT the bystander effect can be blocked. PMID:20877486

  10. Cellular potentials, electrogenic sodium pumping and sensitivity in guinea-pig atria.

    PubMed

    Schulz, J C; Fleming, W W; Westfall, D P; Millecchia, R

    1984-10-01

    Intracellular recording techniques in guinea-pig atrial pacemaker and nonpacemaker cells were used to investigate 1) the role of membrane potential changes in postjunctional supersensitivity, 2) the electrogenicity of the Na+,K+ pump and 3) the role of electrogenic pumping in sensitivity of the atria to agonists. In nonpacemaker cells, ouabain (10(-6) M) had no effect on resting membrane potential (left atria) or maximum diastolic potential (right atria). However, ouabain effectively suppressed the transient hyperpolarization that followed cessation of electrical stimulation. In pacemaker cells, ouabain and chronic treatment with reserpine (0.1 mg/kg/day) produced quite different patterns of changes in intracellular potentials. Chronic treatment with reserpine induced chronotropic supersensitivity to isoproterenol but not to histamine. Ouabain did not alter the chronotropic sensitivity to either agonist. The effects of isoproterenol and histamine on intracellular potentials in pacemaker cells were investigated in the presence and absence of ouabain and in control atria vs. atria from guinea pigs chronically pretreated with reserpine. Analysis of the data indicated that 1) electrophysiological measurements do not provide a discernible explanation for chronotropic supersensitivity, 2) the Na+ pump has the capacity for electrogenic pumping under conditions of Na+ loading, but demonstrates little indication of electrogenicity under basal conditions and 3) chronic treatment with reserpine does suppress the Na+,K+ pump in some areas of the right atrium, but this activity probably does not contribute to chronotropic supersensitivity. Other possible mechanisms of postjunctional supersensitivity in atria are discussed. PMID:6491974

  11. Hypertension after clonidine withdrawal.

    PubMed

    Husserl, F E; deCarvalho, J G; Batson, H M; Frohlich, E D

    1978-05-01

    Rebound hypertension occurred in two patients upon clonidine withdrawal. Treatment of the hypertensive crisis consists of both alpha- and beta-adrenergic receptor blockade, reserpine, or the reintroduction of clonidine. With effective control of pressure during the crisis, long-term antihypertensive therapy must be resumed.

  12. A Novel Way of Amelioration of Amyloid Beta Induced Toxicity in Caenorhabditis elegans

    PubMed Central

    Saharia, Kopal; Kumar, Ranjeet; Gupta, Kuldeep; Mishra, Shrilekha; Subramaniam, Jamuna R.

    2016-01-01

    Background With an incidence of 1 in 85 persons above the age of 60 years succumbing to the disease, Alzheimer's disease (AD), has been predicted to create havoc globally. In spite of enormous efforts and exhaustive research, no cure is in sight. Hence, it is critical to unravel the mechanism of AD development/protection and identification of a cure soon. Purpose This study is aimed at investigating the mechanism of reserpine action, which alleviates the toxicity of amyloid beta (Aβ) (AD-causing peptide) in Caenorhabditis elegans [1, 2]. Methods Determination of alleviation of Aβ toxicity with reserpine manifested as reduction in progressive paralysis, in the background of GFP reporter driven by the promoter of the FMRFamide neuropeptide, FLP-11 (AD; Pflp-11::GFP) and acetylcholine contribution through aldicarb (which inhibits acetylcholine esterase) treatment. Results The most significant protection against Aβ toxicity was obtained in the background of Pflp-11::GFP. This protection had 2 components. The promoter of FLP-11 with the reporter GFP, Pflp-11::GFP, per se gave significant protection. Further reserpine treatment provided additional alleviation. Together they could almost eliminate Aβ toxicity. These 2 components of Aβ toxicity alleviation are dependent on acetylcholine levels, as an increase in acetylcholine by aldicarb treatment reduces the protective effect. Conclusion A unique way to alleviate Aβ toxicity is reserpine treatment in combination with Pflp-11::GFP. Reserpine should be evaluated as a potential drug in a pilot study in AD patients. Furthermore, identification of the mechanism of Pflp-11::GFP-mediated reduction in Aβ toxicity is a potential pathway to develop therapeutics for AD. PMID:27721583

  13. Pharmacology of amezinium, a novel antihypotensive drug. VI. Effect on central nervous functions.

    PubMed

    Teschendorf, H J; Kretzschmar, R; Kreiskott, H; Weifenbach, H

    1981-01-01

    4-Amino-6-methoxy-1-phenyl-pyridazinium methyl sulfate (ameziniummetilsulfate, LU 1631, Regulton), in this study briefly called amezinium, was tested for possible central effects taking particular account of the mechanisms of action found for this substance in other studies. 1. The most conspicuous action of amezinium was in modifying reserpine-induced ptosis and reserpine-induced hypothermia. When amezinium is given before reserpine, the ED50 values are 0.15 and 3.9 mg/kg p.o. for both mouse and rat. These effects can be explained by a peripheral site of action since peripheral sympathomimetic effects can also be demonstrated in this dose range. Higher doses (10 mg/kg and upwards p.o.) were required to abolish reserpine-induced hypothermia 17 h after reserpine administration, an effect which probably requires a central site of action. But for imipramine, desipramine and pargyline the effective doses are the same in both experimental models (administration before and after reserpine, respectively). 2. Amezinium potentiated the effect of a threshold dose of L-dopa. Based on the central symptoms, higher doses (10 mg/kg p.o.) were also required for this effect. 3. With blood pressure increasing doses, the sleeping-waking pattern was modified in that duration and number of REM-episodes were reduced; in cats there was no parallel increase of wakefulness whilst in rats there was a slight relative increase of wakefulness. 4. Amezinium, particularly at high doses (46.4 mg/kg and upwards), exhibited a central depressant effect on the spontaneous behaviour of mice and rats and on orientational hyperactivity of mice. Based on the modification of aggregation toxicity, the effect of methamphetamine was reduced. In no dose range was there any evidence of methamphetamine-like effects (increase of motor activity, inhibition of food intake and increase of aggregation toxicity). 5. Amezinium did not affect the duration of hexobarbital anaesthesia or the coordination of mice on a

  14. Comparison of the pharmacological actions of desmethylclomipramine and clomipramine.

    PubMed

    Maj, J; Stala, L; Górka, Z; Adamus, A

    1982-01-01

    This research compares the effects, in mice and rats, of desmethylclomipramine (DCLOM) and clomipramine (CLOM). DCLOM antagonized the hypothermia induced in mice by reserpine or apomorphine to a much greater extent than CLOM. Reserpine ptosis in mice was depressed by DCLOM only. Similarly, only DCLOM was effective in the behavioral despair test in rats. DCLOM increased the 5-hydroxytryptamine (5-HT) pressor effect in pithed rats, but to a lesser extent than CLOM by several factors. Only DCLOM increased the noradrenaline (NA) pressor effect. The depletion of NA induced by 6-hydroxydopamine was depressed by DCLOM only. The 5-HT depletion induced by p-chloromethamphetamine was antagonized only by CLOM. The results obtained show that the noradrenergic mechanism is of prime importance in the action of DCLOM and of much more importance than in the action of CLOM.

  15. Combinatorial approaches with selected phytochemicals to increase antibiotic efficacy against Staphylococcus aureus biofilms.

    PubMed

    Abreu, Ana Cristina; Saavedra, Maria José; Simões, Lúcia C; Simões, Manuel

    2016-10-01

    Combinations of selected phytochemicals (reserpine, pyrrolidine, quinine, morin and quercetin) with antibiotics (ciprofloxacin, tetracycline and erythromycin) were tested on the prevention and control of Staphylococcus aureus biofilms. The phytochemicals were also studied for their ability to avoid antibiotic adaptation and to inhibit antibiotic efflux pumps. Morin, pyrrolidine and quercetin at subinhibitory concentrations had significant effects in biofilm prevention and/or control when applied alone and combined with antibiotics. Synergism between antibiotics and phytochemicals was found especially against biofilms of NorA overexpressing strain S. aureus SA1199B. This strain when growing with subinhibitory concentrations of ciprofloxacin developed increased tolerance to this antibiotic. However, this was successfully reversed by quinine and morin. In addition, reserpine and quercetin showed significant efflux pump inhibition. The overall results demonstrate the role of phytochemicals in co-therapies to promote more efficient treatments and decrease antimicrobial resistance to antibiotics, with substantial effects against S. aureus in both planktonic and biofilm states.

  16. [The new versus the old antidepressant drugs: a comparative study of their psychopharmacological profiles (author's transl)].

    PubMed

    Bourin, M; Puech, A J; Chermat, R; Doare, L; Poncelet, M; Simon, P

    1981-01-01

    We studied 13 known or potential antidepressants, choosen in different pharmacological classes: desipramine, imipramine, nialamide, dexamphetamine, AHR 1118, amineptine, iprindole, mianserine, nomifensine, salbutamol, TRH viloxazine, zimelidine. Each of these compounds was studied on 8 psychopharmacological tests: motor activity, reserpine induced hypothermia, reserpine induced ptosis, oxotremorine induced hypothermia, oxotremorine induced tremors, high doses apomorphine induced hypothermia, potentiation of toxic effects of yohimbine, behavioural despair. Clinical active compounds are efficient on yohimbine test and at least on one model of hypothermia; with a few exceptions, easy to explain, substances with a clearly demonstrated antidepressant activity in human have some common effects; these common effects can be used to predict, from animal experiments, an antidepressant effect in man.

  17. Antidepressant-like effects of L-theanine in the forced swim and tail suspension tests in mice.

    PubMed

    Yin, Cui; Gou, Lingshan; Liu, Yi; Yin, Xiaoxing; Zhang, Ling; Jia, Genguang; Zhuang, Xuemei

    2011-11-01

    L-theanine (γ-glutamylethylamide), an amino acid component of green tea, has been shown to reduce mental and physical stress, and to improve memory function. In this study, the antidepressant effect of L-theanine was investigated in mice using the forced swim test, tail suspension test, open-field test and reserpine test. L-theanine produced an antidepressant-like effect, since the administration of L-theanine at doses of 1, 4 and 20 mg/kg for 10 successive days significantly reduced the immobility time in both the forced swim test and tail suspension test, compared with the control group, without accompanying changes in ambulation in the open-field test. Moreover, L-theanine significantly antagonized reserpine-induced ptosis and hypothermia. Taken together, these results indicate that L-theanine possessed an antidepressant-like effect in mice, which may be mediated by the central monoaminergic neurotransmitter system.

  18. Combinatorial approaches with selected phytochemicals to increase antibiotic efficacy against Staphylococcus aureus biofilms.

    PubMed

    Abreu, Ana Cristina; Saavedra, Maria José; Simões, Lúcia C; Simões, Manuel

    2016-10-01

    Combinations of selected phytochemicals (reserpine, pyrrolidine, quinine, morin and quercetin) with antibiotics (ciprofloxacin, tetracycline and erythromycin) were tested on the prevention and control of Staphylococcus aureus biofilms. The phytochemicals were also studied for their ability to avoid antibiotic adaptation and to inhibit antibiotic efflux pumps. Morin, pyrrolidine and quercetin at subinhibitory concentrations had significant effects in biofilm prevention and/or control when applied alone and combined with antibiotics. Synergism between antibiotics and phytochemicals was found especially against biofilms of NorA overexpressing strain S. aureus SA1199B. This strain when growing with subinhibitory concentrations of ciprofloxacin developed increased tolerance to this antibiotic. However, this was successfully reversed by quinine and morin. In addition, reserpine and quercetin showed significant efflux pump inhibition. The overall results demonstrate the role of phytochemicals in co-therapies to promote more efficient treatments and decrease antimicrobial resistance to antibiotics, with substantial effects against S. aureus in both planktonic and biofilm states. PMID:27643487

  19. Biogenic amine depletion causes chronic muscular pain and tactile allodynia accompanied by depression: A putative animal model of fibromyalgia.

    PubMed

    Nagakura, Yukinori; Oe, Tomoya; Aoki, Toshiaki; Matsuoka, Nobuya

    2009-11-01

    Fibromyalgia is a prevalent and burdensome disorder characterized by chronic widespread pain and complex comorbid symptoms. To develop better treatments for pain-centered fibromyalgia symptoms, there is still a need for animal models which mimic the features of fibromyalgia patients. In the present study, we have established a fibromyalgia animal model by utilizing a never-before-published pharmacological effect of reserpine. Repeated administration of reserpine (1mg/kg s.c., once daily, for three consecutive days) causes a significant decrease in the muscle pressure threshold and tactile allodynia, which are sustained for 1week or more in both male and female rats. This treatment regimen decreases the amount of biogenic amines (dopamine, norepinephrine, and 5-hydroxytryptamine) in the spinal cord, thalamus, and prefrontal cortex, which are deeply involved in pain signal processing. It also significantly increases immobility time in the forced swim test, which is indicative of depression, a common comorbid symptom of fibromyalgia. Pregabalin, duloxetine, and pramipexole significantly attenuated the reserpine-induced decrease in muscle pressure threshold, but diclofenac did not. The validity of the use of this reserpinized animal as a fibromyalgia model is demonstrated from three different aspects, i.e., face validity (manifestation of chronic pain and comorbid symptoms), construct validity (dysfunction of biogenic amine-mediated central nervous system pain control is involved), and predictive validity (similar responses to treatments used in fibromyalgia patients). This animal model is expected to contribute to the better understanding of fibromyalgia pathophysiology and the evaluation of drugs, especially those which would activate biogenic amine system.

  20. Are NPY and enkephalins costored in the same noradrenergic neurons and vesicles?

    PubMed

    Kong, J Y; Thureson-Klein, A K; Klein, R L

    1990-01-01

    Separate studies show that NPY and enkephalins are widely distributed in peripheral noradrenergic neurons. In the present study, the subcellular costorage and release in response to intense sympathetic stimulation and reserpine at near therapeutic doses (0.05 mg/kg every other day) were examined. In young pig arteries and vas deferens, enkephalin and D beta H immunofluorescence show consistent but not total overlap. Also NPY is colocalized with D beta H in many fibers but with VIP (nonnoradrenergic) in others. Ultrastructural immunogold labeling indicates that individual terminals contain large dense cored vesicles (LDVs) which store either NPY or enkephalins, even though costorage of both peptides occurs. Some LDVs costore NPY and VIP, especially in the middle cerebral artery and in the lamina propria of vas deferens. Acute CNS ischemia depletes enkephalins and norepinephrine in all tissues analyzed without parallel loss of NPY. Reserpine depletes norepinephrine 70-85% but does not deplete NPY or enkephalins. The latter is in contrast to commonly used high doses known to produce nonspecific, detergent-like effects. In fact, low doses of reserpine induce a time-dependent new synthesis and processing of NPY precursor peptides in vas deferns. Contrasting effects of reserpine on NPY and enkephalin contents, new synthesis and apparent processing, and a differential response to acute CNS ischemia were found in every tissue studied. Activation of precursor neuropeptide processing occurred immediately upon intense sympathetic stimulation in most tissues. Dual localization of NPY in noradrenergic and nonnoradrenergic fibers and differences in subcellular LDV storage help explain why enkephalin correlates better than NPY with norepinephrine loss in response to acute CNS ischemia. Furthermore, the costorage of NPY and enkephalins in distinct subpopulations of noradrenergic fibers, which varies according to tissue, is likely to be under separate CNS control.

  1. Viloxazine as a betamimetic antidepressant drug.

    PubMed

    Bourin, M; Ortega, A; Larousse, C

    1987-01-01

    A comparison was made between the effects of maprotiline, the sole action of which is to inhibit the reuptake of noradrenaline, of salbutamol and of viloxazine on hypothermia induced by reserpine, oxotremorine or apomorphine. The dose/effect curves in the three tests showed a similarity in profile between viloxazine and salbutamol, whereas no resemblance was evident between these two drugs and maprotiline. These facts suggest that viloxazine which has a weak effect on noradrenaline reuptake acts probably as antidepressant by betamimetic activity.

  2. Is serotonin in enteric nerves required for distension-evoked peristalsis and propulsion of content in guinea-pig distal colon?

    PubMed

    Sia, T C; Flack, N; Robinson, L; Kyloh, M; Nicholas, S J; Brookes, S J; Wattchow, D A; Dinning, P; Oliver, J; Spencer, N J

    2013-06-14

    Recent studies have shown genetic deletion of the gene that synthesizes 5-HT in enteric neurons (tryptophan hydroxylase-2, Tph-2) leads to a reduction in intestinal transit. However, deletion of the Tph-2 gene also leads to major developmental changes in enteric ganglia, which could also explain changes in intestinal transit. We sought to investigate this further by acutely depleting serotonin from enteric neurons over a 24-h period, without the confounding influences induced by genetic manipulation. Guinea-pigs were injected with reserpine 24h prior to euthanasia. Video-imaging and spatio-temporal mapping was used to record peristalsis evoked by natural fecal pellets, or slow infusion of intraluminal fluid. Immunohistochemical staining for 5-HT was used to detect the presence of serotonin in the myenteric plexus. It was found that endogenous 5-HT was always detected in myenteric ganglia of control animals, but never in guinea-pigs treated with reserpine. Interestingly, peristalsis was still reliably evoked by either intraluminal fluid, or fecal pellets in reserpine-treated animals that also had their entire mucosa and submucosal plexus removed. In these 5-HT depleted animals, there was no change in the frequency of peristalsis or force generated during peristalsis. In control animals, or reserpine treated animals, high concentrations (up to 10 μM) of ondansetron and SDZ-205-557, or granisetron and SDZ-205-557 had no effect on peristalsis. In summary, acute depletion of serotonin from enteric nerves does not prevent distension-evoked peristalsis, nor propulsion of luminal content. Also, we found no evidence that 5-HT3 and 5-HT4 receptor activation is required for peristalsis, or propulsion of contents to occur. Taken together, we suggest that the intrinsic mechanisms that generate peristalsis and entrain propagation along the isolated guinea-pig distal colon are independent of 5-HT in enteric neurons or the mucosa, and do not require the activation of 5-HT3 or 5

  3. Is serotonin in enteric nerves required for distension-evoked peristalsis and propulsion of content in guinea-pig distal colon?

    PubMed

    Sia, T C; Flack, N; Robinson, L; Kyloh, M; Nicholas, S J; Brookes, S J; Wattchow, D A; Dinning, P; Oliver, J; Spencer, N J

    2013-06-14

    Recent studies have shown genetic deletion of the gene that synthesizes 5-HT in enteric neurons (tryptophan hydroxylase-2, Tph-2) leads to a reduction in intestinal transit. However, deletion of the Tph-2 gene also leads to major developmental changes in enteric ganglia, which could also explain changes in intestinal transit. We sought to investigate this further by acutely depleting serotonin from enteric neurons over a 24-h period, without the confounding influences induced by genetic manipulation. Guinea-pigs were injected with reserpine 24h prior to euthanasia. Video-imaging and spatio-temporal mapping was used to record peristalsis evoked by natural fecal pellets, or slow infusion of intraluminal fluid. Immunohistochemical staining for 5-HT was used to detect the presence of serotonin in the myenteric plexus. It was found that endogenous 5-HT was always detected in myenteric ganglia of control animals, but never in guinea-pigs treated with reserpine. Interestingly, peristalsis was still reliably evoked by either intraluminal fluid, or fecal pellets in reserpine-treated animals that also had their entire mucosa and submucosal plexus removed. In these 5-HT depleted animals, there was no change in the frequency of peristalsis or force generated during peristalsis. In control animals, or reserpine treated animals, high concentrations (up to 10 μM) of ondansetron and SDZ-205-557, or granisetron and SDZ-205-557 had no effect on peristalsis. In summary, acute depletion of serotonin from enteric nerves does not prevent distension-evoked peristalsis, nor propulsion of luminal content. Also, we found no evidence that 5-HT3 and 5-HT4 receptor activation is required for peristalsis, or propulsion of contents to occur. Taken together, we suggest that the intrinsic mechanisms that generate peristalsis and entrain propagation along the isolated guinea-pig distal colon are independent of 5-HT in enteric neurons or the mucosa, and do not require the activation of 5-HT3 or 5

  4. Contribution of vesicular and cytosolic dopamine to the increased striatal dopamine efflux elicited by intrastriatal injection of SKF38393.

    PubMed

    Saigusa, Tadashi; Aono, Yuri; Sekino, Reiko; Uchida, Takuya; Takada, Koji; Oi, Yoshiyuki; Koshikawa, Noriaki; Cools, Alexander R

    2009-12-10

    Like dexamphetamine, SKF38393 induces an increase in striatal dopamine efflux which is insensitive for tetrodotoxin, Ca(2+) independent and prevented by a dopamine transporter inhibitor. The dexamphetamine-induced striatal dopamine efflux originates from both the reserpine-sensitive vesicular dopamine pool and the alpha-methyl-para-tyrosine-sensitive cytosolic dopamine pool. Given the similarities between dexamphetamine and SKF38393, we hypothesized that both types of pool also contribute to the striatally applied SKF38393-induced dopamine efflux. Using in vivo microdialysis technique, we analysed the contribution of these pools to the SKF38393-induced striatal dopamine efflux in freely moving rats. The increase of dopamine efflux induced by 1.5 microg SKF38393 was largely prevented by either reserpine (5mg/kg i.p., given 24h earlier) or alpha-methyl-para-tyrosine (250 mg/kg i.p., given 2h earlier), showing that both the vesicular dopamine pool and the cytosolic dopamine pool contribute to the SKF38393-induced increase in striatal dopamine efflux. The sum of the amounts of dopamine that was sensitive to either reserpine or alpha-methyl-para-tyrosine, was greater than 100%, namely 137.6% of the basal dopamine level and 143.9% of the SKF38393-induced dopamine level, suggesting that striatally applied SKF38393 promotes the redistribution of dopamine from vesicles to the cytosol, and vice versa. The finding that the combined treatment of reserpine and alpha-methyl-para-tyrosine only inhibited the SKF38393-induced striatal dopamine efflux till 86.0% of the control, is ascribed to the notion that SKF38393 can also inhibit the re-uptake of dopamine. The latter conclusion has far-reaching consequences for studies in which the effects of SKF38393 are simply ascribed to its dopamine D1 receptor stimulation capacity.

  5. Subchronic Arsenic Exposure Induces Anxiety-Like Behaviors in Normal Mice and Enhances Depression-Like Behaviors in the Chemically Induced Mouse Model of Depression.

    PubMed

    Chang, Chia-Yu; Guo, How-Ran; Tsai, Wan-Chen; Yang, Kai-Lin; Lin, Li-Chuan; Cheng, Tain-Junn; Chuu, Jiunn-Jye

    2015-01-01

    Accumulating evidence implicates that subchronic arsenic exposure causes cerebral neurodegeneration leading to behavioral disturbances relevant to psychiatric disorders. However, there is still little information regarding the influence of subchronic exposure to arsenic-contaminated drinking water on mood disorders and its underlying mechanisms in the cerebral prefrontal cortex. The aim of this study is to assess the effects of subchronic arsenic exposure (10 mg/LAs2O3 in drinking water) on the anxiety- and depression-like behaviors in normal mice and in the chemically induced mouse model of depression by reserpine pretreatment. Our findings demonstrated that 4 weeks of arsenic exposure enhance anxiety-like behaviors on elevated plus maze (EPM) and open field test (OFT) in normal mice, and 8 weeks of arsenic exposure augment depression-like behaviors on tail suspension test (TST) and forced swimming test (FST) in the reserpine pretreated mice. In summary, in this present study, we demonstrated that subchronic arsenic exposure induces only the anxiety-like behaviors in normal mice and enhances the depression-like behaviors in the reserpine induced mouse model of depression, in which the cerebral prefrontal cortex BDNF-TrkB signaling pathway is involved. We also found that eight weeks of subchronic arsenic exposure are needed to enhance the depression-like behaviors in the mouse model of depression. These findings imply that arsenic could be an enhancer of depressive symptoms for those patients who already had the attribute of depression.

  6. Subchronic Arsenic Exposure Induces Anxiety-Like Behaviors in Normal Mice and Enhances Depression-Like Behaviors in the Chemically Induced Mouse Model of Depression

    PubMed Central

    Chang, Chia-Yu; Guo, How-Ran; Tsai, Wan-Chen; Yang, Kai-Lin; Lin, Li-Chuan

    2015-01-01

    Accumulating evidence implicates that subchronic arsenic exposure causes cerebral neurodegeneration leading to behavioral disturbances relevant to psychiatric disorders. However, there is still little information regarding the influence of subchronic exposure to arsenic-contaminated drinking water on mood disorders and its underlying mechanisms in the cerebral prefrontal cortex. The aim of this study is to assess the effects of subchronic arsenic exposure (10 mg/LAs2O3 in drinking water) on the anxiety- and depression-like behaviors in normal mice and in the chemically induced mouse model of depression by reserpine pretreatment. Our findings demonstrated that 4 weeks of arsenic exposure enhance anxiety-like behaviors on elevated plus maze (EPM) and open field test (OFT) in normal mice, and 8 weeks of arsenic exposure augment depression-like behaviors on tail suspension test (TST) and forced swimming test (FST) in the reserpine pretreated mice. In summary, in this present study, we demonstrated that subchronic arsenic exposure induces only the anxiety-like behaviors in normal mice and enhances the depression-like behaviors in the reserpine induced mouse model of depression, in which the cerebral prefrontal cortex BDNF-TrkB signaling pathway is involved. We also found that eight weeks of subchronic arsenic exposure are needed to enhance the depression-like behaviors in the mouse model of depression. These findings imply that arsenic could be an enhancer of depressive symptoms for those patients who already had the attribute of depression. PMID:26114099

  7. Control of Analyte Electrolysis in Electrospray Ionization Mass Spectrometry Using Repetitively Pulsed High Voltage

    SciTech Connect

    Kertesz, Vilmos; Van Berkel, Gary J

    2011-01-01

    Analyte electrolysis using a repetitively pulsed high voltage ion source was investigated and compared to that using a regular, continuously operating direct current high voltage ion source in electrospray ionization mass spectrometry. The extent of analyte electrolysis was explored as a function of the length and frequency of the high voltage pulse using the model compound reserpine in positive ion mode. Using +5 kV as the maximum high voltage amplitude, reserpine was oxidized to its 2, 4, 6 and 8-electron oxidation products when direct current high voltage was employed. In contrast, when using a pulsed high voltage, oxidation of reserpine was eliminated by employing the appropriate high voltage pulse length and frequency. This effect was caused by inefficient mass transport of the analyte to the electrode surface during the duration of the high voltage pulse and the subsequent relaxation of the emitter electrode/ electrolyte interface during the time period when the high voltage was turned off. This mode of ESI source operation allows for analyte electrolysis to be quickly and simply switched on or off electronically via a change in voltage pulse variables.

  8. A behavioural study of the effect of pentadecapeptide BPC 157 in Parkinson's disease models in mice and gastric lesions induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydrophyridine.

    PubMed

    Sikiric, P; Marovic, A; Matoz, W; Anic, T; Buljat, G; Mikus, D; Stancic-Rokotov, D; Separovic, J; Seiwerth, S; Grabarevic, Z; Rucman, R; Petek, M; Ziger, T; Sebecic, B; Zoricic, I; Turkovic, B; Aralica, G; Perovic, D; Duplancic, B; Lovric-Bencic, M; Rotkvic, I; Mise, S; Jagic, V; Hahn, V

    1999-12-01

    The effect of a stomach pentadecapeptide, BPC 157, on Parkinson's disease in mice was investigated, along with its salutary activity on stomach lesions induced by parkinsongenic agents. Parkinsongenic agents, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (30.0 mg x kg(-1)b.w. i.p. once daily for 6d, and after 4d once 50.0 mg x kg(-1)b.w. i.p.) or reserpine (5.0 mg x kg(-1)b.w. i.p.) were applied i.p. BPC 157 (1.50 microg or 15.0 ng x kg(-1)b.w. i.p.) was applied 15 min before or alternatively 15 min after each MPTP administration. In reserpine studies, BPC 157 (10.0 microg or 10.0 ng x kg(-1)b.w. i.p.) was given either 15 min before reserpine or in the already established complete catalepsy 24 h thereafter. BPC 157 strongly improved the MPTP-impaired somatosensory orientation and reduced the MPTP-induced hyperactivity, and most importantly, MPTP-motor abnormalities (tremor, akinesia, catalepsy -otherwise very prominent in saline control), leading to almost complete abolition of otherwise regularly lethal course of MPTP treatment in controls. Likewise, in reserpine experiments, BPC 157 strongly prevented the development of otherwise very prominent catalepsy and when applied 24 h thereafter reversed the established catalepsy. In addition, a reduction of reserpine-hypothermy (BPC 157 pre-treatment) and reversal of further prominent temperature fall (BPC 157 post-treatment) have been consistently observed. Taking together these data, as the two most suitable animal models were consistently used and since the high effectiveness was demonstrated in pre- and post-treatment, microg and ng regimens, BPC 157 as an organoprotector should be further therapeutically investigated. Additionally, given in either regimen, pentadecapeptide BPC 157 strongly attenuated the stomach lesions in mice that otherwise consistently appeared in mice treated with the parkinsogenic neurotoxin MPTP. PMID:10672997

  9. GZ-793A, a lobelane analog, interacts with the vesicular monoamine transporter-2 to inhibit the effect of methamphetamine.

    PubMed

    Horton, David B; Nickell, Justin R; Zheng, Guangrong; Crooks, Peter A; Dwoskin, Linda P

    2013-10-01

    (R)-3-[2,6-cis-Di(4-methoxyphenethyl)piperidin-1-yl]propane-1,2-diol (GZ-793A) inhibits methamphetamine-evoked dopamine release from striatal slices and methamphetamine self-administration in rats. GZ-793A potently and selectively inhibits dopamine uptake at the vesicular monoamine transporter-2 (VMAT2). This study determined GZ-793A's ability to evoke [³H]dopamine release and inhibit methamphetamine-evoked [³H]dopamine release from isolated striatal synaptic vesicles. Results show GZ-793A concentration-dependent [³H]dopamine release; nonlinear regression revealed a two-site model of interaction with VMAT2 (High- and Low-EC₅₀ = 15.5 nM and 29.3 μM, respectively). Tetrabenazine and reserpine completely inhibited GZ-793A-evoked [³H]dopamine release, however, only at the High-affinity site. Low concentrations of GZ-793A that interact with the extravesicular dopamine uptake site and the High-affinity intravesicular DA release site also inhibited methamphetamine-evoked [³H]dopamine release from synaptic vesicles. A rightward shift in the methamphetamine concentration-response was evident with increasing concentrations of GZ-793A, and the Schild regression slope was 0.49 ± 0.08, consistent with surmountable allosteric inhibition. These results support a hypothetical model of GZ-793A interaction at more than one site on the VMAT2 protein, which explains its potent inhibition of dopamine uptake, dopamine release via a High-affinity tetrabenazine- and reserpine-sensitive site, dopamine release via a Low-affinity tetrabenazine- and reserpine-insensitive site, and a low-affinity interaction with the dihydrotetrabenazine binding site on VMAT2. GZ-793A inhibition of the effects of methamphetamine supports its potential as a therapeutic agent for the treatment of methamphetamine abuse.

  10. GZ-793A, a lobelane analog, interacts with the vesicular monoamine transporter-2 to inhibit the effect of methamphetamine

    PubMed Central

    Horton, David B.; Nickell, Justin R.; Zheng, Guangrong; Crooks, Peter A.; Dwoskin, Linda P.

    2013-01-01

    GZ-793A inhibits methamphetamine-evoked dopamine release from striatal slices and methamphetamine self-administration in rats. GZ-793A potently and selectively inhibits dopamine uptake at the vesicular monoamine transporter-2 (VMAT2). The present study determined GZ-793A’s ability to evoke [3H]dopamine release and inhibit methamphetamine-evoked [3H]dopamine release from isolated striatal synaptic vesicles. Results show GZ-793A concentration-dependent [3H]dopamine release; nonlinear regression revealed a two-site model of interaction with VMAT2 (High- and Low-EC50 = 15.5 nM and 29.3 µM, respectively). Tetrabenazine and reserpine completely inhibited the GZ-793A-evoked [3H]dopamine release, however, only at the High-affinity site. Low concentrations of GZ-793A that interact with the extravesicular dopamine uptake site and the High-affinity intravesicular DA release site also inhibited methamphetamine-evoked [3H]dopamine release from synaptic vesicles. A rightward shift in the methamphetamine concentration-response was evident with increasing concentrations of GZ-793A, and the Schild regression slope was 0.49±0.08, consistent with surmountable allosteric inhibition. These results support a hypothetical model of GZ-793A interaction at more than one site on VMAT2 protein, which explains its potent inhibition of dopamine uptake, dopamine release via a High-affinity tetrabenazine- and reserpine-sensitive site, dopamine release via a Low-affinity tetrabenazine- and reserpine-insensitive site, and low-affinity interaction with the dihydrotetrabenazine binding site on VMAT2. GZ-793A-inhibition of the effects of methamphetamine supports its potential as a therapeutic agent for the treatment of methamphetamine abuse. PMID:23875622

  11. Photosensitizer-induced fluorescence of the rat adrenal gland and rat pheochromocytoma cells (PC 12) by meso-tetra(hydroxyphenyl)chlorin (mTHPC)

    NASA Astrophysics Data System (ADS)

    Colombo-Benkmann, Mario; Muhm, Markus; Gahlen, Johannes; Heym, Christine; Senninger, Norbert

    1997-12-01

    Rat adrenal glands exhibit an intense mTHPC-induced fluorescence. The objective of our study was the identification of adrenal cells exhibiting mTHPC-induced fluorescence under normal conditions and under stimulation of adrenal proliferation by reserpine. Furthermore mTHPC-uptake of rat pheochromocytoma (PC 12) cells was investigated. Four male Wistar rats received 0.5 mg mTHPC/kg iv 48 hours before perfusion. Furthermore four rats received reserpine (2 mg/kg im od), bromo-deoxy-uridine (BrdU; 50 mg/kg ip od) each for one week and mTHPC (0.5 mg/kg) 48 hours before perfusion. BrdU was detected immunohistochemically. PC 12-cells were incubated with 0.5 mg mTHPC/l culture medium for 24 or 48 hours. Cells and tissues were examined by fluorescence microscopy. The adrenal cortex exhibited an intense mTHPC-induced fluorescence. The adrenal medulla fluoresced faintly. Reserpine increased fluorescence of intramedullary cells, not coinciding with adrenal proliferation. Cortical fluorescence remained unchanged. PC 12-cells lying singly or in small groups and differentiating cells showed a more intense mTHPC- induced fluorescence than confluent cells. Differences of cortical and medullary uptake of mTHPC are independent of proliferation and may be explained by lipophilia of mTHPC, since adrenocytes have an uptake mechanism for cholesterol. The difference of mTHPC-uptake between PC 12-cells and chromaffin cells implicate the possibility of photodynamic applications for medullary neoplasia.

  12. Effects of cocaine or denervation on responses of isolated strips of cat spleen to (—)-noradrenaline and (—)-isoprenaline

    PubMed Central

    Granata, A. R.; Langer, S. Z.

    1973-01-01

    1. A study has been made of the effects of cocaine and sympathetic denervation on responses of the cat spleen to (—)-noradrenaline and (—)-isoprenaline. 2. Responses of isolated strips of spleen capsule to (—)-noradrenaline or to (—)-isoprenaline were not affected by reserpine-pretreatment. 3. In adult cats, cocaine (1 and 10 μg/ml) or denervation produced a shift to the left of dose-response curves to (—)-noradrenaline, whereas they failed to modify dose-response curves to (—)-isoprenaline. 4. There was an increase in the maximum development of tension to (—)-noradrenaline after denervation or in the presence of cocaine (10 μg/ml). These procedures did not increase the maximal responses to (—)-isoprenaline. 5. Cocaine (10 μg/ml) did not affect dose-response curves to (—)-noradrenaline or (—)-isoprenaline in the denervated spleen. 6. In the kitten spleen, cocaine (1 and 10 μg/ml) produced a shift to the left of dose-response curves to (—)-noradrenaline both in untreated and in reserpine-pretreated tissues. 7. There was a small shift to the left in dose-response curves to (—)-isoprenaline in the presence of cocaine in the untreated but not in the reserpine-pretreated kitten spleen. 8. It is concluded that the potentiation of responses to (—)-noradrenaline in the cat's spleen is due to a prejunctional effect of cocaine. PMID:4788210

  13. Phytotherapy of experimental depression: Kalanchoe integra Var. Crenata (Andr.) Cuf Leaf Extract

    PubMed Central

    Kukuia, Kennedy K. E.; Asiedu-Gyekye, Isaac J.; Woode, Eric; Biney, Robert P.; Addae, Emmanuel

    2015-01-01

    Context: Kalanchoe sp. have been used since 1921 for central nervous system (CNS) disorders such as psychosis and depression. It is known to possess CNS depressant effects. Aims: To investigate the antidepressant properties of the aqueous leaf extract of Kalanchoe integra. Settings and Design: The study was carried out at the Kwame Nkrumah University of Science and Technology between 6 a.m. and 3 p.m. Materials and Methods: ICR mice were subjected to the forced swimming test (FST) and tail suspension test (TST) after they had received extract (30-300 mg/kg), fluoxetine (3-30 mg/kg), desipramine (3-30 mg/kg) orally, or water (as vehicle). In a separate experiment, mice were pre-treated with reserpine (1 mg/kg), α-methyl paratyrosine (AMPT; 400 mg/kg), both reserpine (1 mg/kg) and AMPT (200 mg/kg) concomitantly, or p-chlorophenylalanine (pCPA; 200 mg/kg) to ascertain the role of the noradrenergic and serotoninergic systems in the mode of action of the extract. Statistical analysis used: Means were analyzed by analysis of variance (ANOVA) followed by Newman-Keuls’ post hoc test. P < 0.05 was considered significant. Results: In both FST and TST, the extract induced a decline in immobility, indicative of antidepressant-like effect. This diminution in immobility was reversed by pCPA, but not by reserpine and/or AMPT. The extract increased the swimming and climbing scores in the FST, suggestive of possible interaction with serotoninergic and noradrenergic systems. In the TST, the extract produced increases in both curling and swinging scores, suggestive of opioidergic monoaminergic activity, respectively. Conclusions: The present study has demonstrated the antidepressant potential of the aqueous leaf extract of K. integra is mediated possibly by a complex interplay between serotoninergic, opioidergic, and noradrenergic systems. PMID:25709333

  14. Paradoxical sleep deprivation modulates tyrosine hydroxylase expression in the nigrostriatal pathway and attenuates motor deficits induced by dopaminergic depletion.

    PubMed

    Lima, Marcelo M S; Andersen, Monica L; Reksidler, Angela B; Ferraz, Anete C; Vital, Maria A B F; Tufik, Sergio

    2012-06-01

    The nigrostriatal pathway is very likely involved in sleep regulation, considering the occurrence and high prevalence of sleep-related disorders in patients with Parkinson's disease. Indeed, dopaminergic neurons in the ventral tegmental area were recently shown to fire in bursts during paradoxical sleep (PS), but little is known about the activity of the nigrostriatal dopamine (DA) cells in relation to PS. In view of that we hypothesized that paradoxical sleep deprivation (PSD) may play a relevant role in nigrostriatal tyrosine hydroxylase (TH) expression and, subsequently, in sleep rebound. The present study was designed to determine the effects of PSD in the nigrostriatal pathway in mice by means of neurochemical and behavioral approaches. Intraperitoneal reserpine (1 mg/kg) associated to α-methyl-p-tyrosine (αMT) (250 mg/kg) to produce catecholamine depletion, or rotenone (10 mg/kg) to increase striatal DA turnover were injected 30 min before the 24 h of PSD. Catalepsy and open-field tests indicated that motor deficits induced by reserpine-αMT were counteracted by PSD, which, in contrast, potentiated the motor impairment induced by rotenone. Besides, PSD produced down-regulation on TH expression within the substantia nigra pars compacta and striatum, without affecting the number or the optical density of dopaminergic neurons present in the respective areas. Interestingly, PSD potentiated the downregulation of TH expression in the substantia nigra pars compacta and striatum induced by the co-administration of reserpine-αMT. These results reinforce the notion of a strong participation of DA in PS, as a consequence of the modulation of TH protein expression in the nigrostriatal pathway.

  15. [The reciprocal relationships between the epiphysis and the suprachiasmatic nuclei of the hypothalamus during the restructuring of the circadian mobility in rats under an altered light regimen].

    PubMed

    Arushanian, E B; Baturin, V A; Popov, A V

    1993-01-01

    Pinealectomy and reserpine advanced the reorganization of the circadian rhythm of motor activity of rats following a ten-hour shift in the photoperiod. Bilateral electrolytic lesion of the hypothalamic suprachiasmatic nuclei and administration of the antidepressant drug, imipramine, on the contrary, delayed the rhythm change. The results suggest a possible antagonistic reciprocal relationship between the pineal gland and the main pacemaker, whose balance causes a gradual adaptation of animals to the changing environment. Fast reorganization of motor activity at pineal dysfunction or under the influence of depressogenic drugs could cause desynchronization and psychiatric disorders in a form of depression.

  16. Generalization of norcocaine to the discriminative stimulus properties of cocaine.

    PubMed

    Mckenna, M L; Ho, B T; Englert, L F

    1979-02-01

    In rats trained to discriminate 10 mg/kg cocaine from 1 mg/kg saline, norcocaine, the N-demethylated metabolite, at doses of 2.5 mg/kg, 5 mg/kg and 10 mg/kg, produced a dose response curve similar to that of cocaine and generalized to cocaine at the two higher doses. As with cocaine, the discriminative stimulus produced by the norcocaine was partially attenuated by the dopaminergic antagonist pimozide and the amine depletor reserpine. Benzoylecgonine, benzoylnorecgonine and ecgonine methyl ester in doses of 10 mg/kg and 20 mg/kg did not generalize to cocaine.

  17. Synthesis and psychotropic activity of functionally substituted diaziridines and bisdiaziridines

    SciTech Connect

    Kostyanovskii, R.G.; Shustov, G.V.; Nabiev, O.G.; Denisenko, S.N.; Sukhanova, S.A.; Lavretskaya, E.F.

    1987-04-01

    The authors examine the psychotropic activity of diaziridines which differ considerable in their structures and the C- and N-substituents. Diaziridines are monoamine oxidase inhibitors in the brain and, thus, are potential antidepressants. The acute toxicities and some pharmacological effects of diaziridines are shown. Mice were used in the experiments. The bisdiaziridines obtained differ in their /sup 1/H and /sup 13/C NMR spectra. The effect is presented of functionally substituted diaziridines on the effects of reserpine, 5-hydroxytryptophan, tryptamine, corazole, and apomorphine hypothermia.

  18. Is iprindole an indirect betamimetic drug?

    PubMed

    Ganry, H; Bourin, M

    1988-01-01

    Iprindole, an active antidepressant in clinical use, has no effect on norepinephrine reuptake and does not bind to receptors of the noradrenergic system. Iprindole weakly antagonizes reserpine hypothermia and potentiates yohimbine toxicity. This effect is antagonized by propranolol but not by atenolol or metoprolol. In an acute dose, iprindole potentiates the effect of maprotiline on yohimbine toxicity. Beta 2-adrenergic agonists and antagonists specifically modify the effect of iprindole on spontaneous motility. These results indicate that iprindole has an indirect beta 2-mimetic effect.

  19. Treatment of upper extremity reflex sympathetic dystrophy with joint stiffness using sympatholytic Bier blocks and manipulation.

    PubMed

    Duncan, K H; Lewis, R C; Racz, G; Nordyke, M D

    1988-06-01

    Twenty patients with reflex sympathetic dystrophy involving the upper extremity with associated joint stiffness were treated by manipulation under Bier blocks composed of lidocaine, methylprednisolone, and reserpine or guanethidine. Depending on the patients' response, repeat blocks were performed at 48- to 72-hour intervals. Range of motion in the affected joints (primarily the hand and wrist) improved from a pre-block mean of 46% to 81% of normal following the blocks. Patients also reported an 80% mean improvement in their pain. The treatment of advanced reflex sympathetic dystrophy using joint manipulation under sympatholytic Bier blocks appears to be a safe and effective method of treatment.

  20. Regulation of dihydropyridine calcium antagonist binding sites in the rat hippocampus following neurochemical lesions.

    PubMed

    Bolger, G T; Basile, A S; Janowsky, A J; Paul, S M; Skolnick, P

    1987-01-01

    The effects of catecholaminergic, cholinergic, serotonergic, and glutaminergic terminal destruction and neurotransmitter depletion on [3H]nitrendipine binding to rat brain membranes were determined using the neurotoxins 6-hydroxydopamine, 5,7-dihydroxytryptamine, and kainic acid and the neurotransmitter-depleting agent reserpine. Following intracisternal injection of 6-hydroxydopamine there were time-dependent increases (14-23%) in the density but not change in the affinity of hippocampal [3H]nitrendipine binding sites. 6-Hydroxydopamine significantly increased [3H]nitrendipine binding in the hippocampus 4 and 10 days following injection. However, no significant change in binding was observed at 16 and 26 days. [3H]Nitrendipine binding in the cerebral cortex, striatum, cerebellum, and brain stem was unaffected by 6-hydroxydopamine. Neither 5,7-dihydroxytryptamine nor kainic acid affected [3H]nitrendipine binding in the hippocampus and cerebral cortex. Acute and chronic reserpinization also did not affect [3H]nitrendipine binding in the hippocampus and cerebral cortex. These results indicate that dihydropyridine calcium antagonist bindings sites in rat brain are subject to brain region-specific regulation following neurochemical lesions and may be present in their largest densities on postsynaptic membranes.

  1. Overexpression and functional characterization of an ABC (ATP-binding cassette) transporter encoded by the genes drrA and drrB of Mycobacterium tuberculosis.

    PubMed Central

    Choudhuri, Baisakhee Saha; Bhakta, Sanjib; Barik, Rajib; Basu, Joyoti; Kundu, Manikuntala; Chakrabarti, Parul

    2002-01-01

    The genes encoding ATP-binding cassette (ABC) transporters occupy 2.5% of the genome of Mycobacterium tuberculosis. However, none of these putative ABC transporters has been characterized so far. We describe the development of expression systems for simultaneous expression of the ATP-binding protein DrrA and the membrane integral protein DrrB which together behave as a functional doxorubicin efflux pump. Doxorubicin uptake in Escherichia coli or Mycobacterium smegmatis expressing DrrAB was inhibited by reserpine, an inhibitor of ABC transporters. The localization of DrrA to the membrane depended on the simultaneous expression of DrrB. ATP binding was positively regulated by doxorubicin and daunorubicin. At the same time, DrrB appeared to be sensitive to proteolysis when expressed alone in the absence of DrrA. Simultaneous expression of the two polypeptides was essential to obtain a functional doxorubicin efflux pump. Expression of DrrAB in E. coli conferred 8-fold increased resistance to ethidium bromide, a cationic compound. 2',7'-bis-(2-Carboxyethyl)-5(6)-carboxyfluorescein (BCECF), a neutral compound, also behaved as a substrate of the reconstituted efflux pump. When expressed in M. smegmatis, DrrAB conferred resistance to a number of clinically relevant, structurally unrelated antibiotics. The resistant phenotype could be reversed by verapamil and reserpine, two potent inhibitors of ABC transporters. PMID:12057006

  2. 3H-metaraminol releasing action of mescaline from rat hypothalamus in vitro.

    PubMed

    Gulati, O D; Shah, N S

    1977-11-15

    The amine releasing action of mescaline was investigated in rat isolated hypothalamus labeled with 3H-metaraminol. Mescaline had no effect on the uptake of 3H-metaraminol but produced its release in a concentration-related manner. 4 x 10(-4) M mescaline, which produced submaximal effects was used for subsequent experiments. 3 x 10(-5) M cocaine had no effect on the 3H-metaraminol releasing action of mescaline. Mescaline was fully effective in Ca2+-free medium while 6 x 10(-2) M KCl was ineffective. 3 x 10(-7) M tetrodotoxin or 6 x 10(-5) M lidocaine partially blocked mescaline-induced release but substantially or completely blocked 3 x 10(-2) M KCl-induced release. Prior exposure of hypothalamus to 3 x 10(-4) M tyramine reduced the releasing action of mescaline. Thus, mescaline appears to release 3H-metaraminol both by Ca2+-independent (tyramine-like) and Ca2+-dependent (lidocaine-sensitive) mechanisms. 3 x 10(-4) M tyramine and 6 x 10(-2) M KCl released 14C from control hypothalamus labelled with 14C-mescaline, but not from reserpinized hypothalamus. The amounts of 14C recovered in 14C-mescaline labeled control and reserpinized hypothalamus at the end of 50 min of efflux were similar suggesting a poor retention of 14C-mescaline by storage particles.

  3. Norepinephrine storage, distribution, and release in diabetic cardiomyopathy

    SciTech Connect

    Ganguly, P.K.; Beamish, R.E.; Dhalla, K.S.; Innes, J.R.; Dhalla, N.S.

    1987-06-01

    The ability of hearts to store, distribute, and release norepinephrine (NE) was investigated in rats 8 wk after the induction of diabetes by an injection of streptozotocin. Chronic diabetes was associated with increased content and concentration of NE in heart and in other tissues such as kidney, brain, and spleen. Reserpine or tyramine treatment resulted in depletion of endogenous cardiac NE in control and diabetic rats. The depletion of NE stores at different times after a dose of reserpine was greater in diabetic hearts. On the other hand, NE stores in diabetic hearts were less sensitive than control hearts to low doses of tyramine but were more sensitive to high doses. The uptake of (/sup 3/H)NE was greater in diabetic hearts in isolated perfused preparations. In comparison with the control values, diabetic hearts showed a decrease in (/sup 3/H)NE in the granular fraction and an increase in the supernatant fraction. Diabetic hearts also showed an accelerated spontaneous release of (/sup 3/H)NE. The increased cardiac NE and the uptake and release of NE in diabetic animals were reversible upon treatment with insulin. These results are consistent with the view that sympathetic activity is increased in diabetic cardiomyopathy and indicate that cardiac NE in diabetic rats is maintained at a higher level partly due to an increased uptake of released NE by adrenergic nerve terminals.

  4. Central action of phenylethylamine in rats.

    PubMed

    Jagiełło-Wójtowicz, E

    1981-01-01

    Phenylethylamine (PEA), 10, 50 and 100 microgram/rat ivc depressed the spontaneous and explorative motor activities, did not affect the body temperature and potentiated the action of hypnotics. The PEA-induced depression of motor activity was antagonized by spiperone, phenoxybenzamine, propranolol and, slightly, by alpha-MT. In rats with total chemical destruction of catecholamine neurons and in rats with selective lesion of dopamine neurons, PEA increased motor activity. Similar effect was observed after administration of reserpine, reserpine together with 6-hydroxydopamine and yohimbine. PEA potentiated the amphetamine and apomorphine stereotypy but inhibited amphetamine hypermotility: in the latter experiment slight periodical stereotyped head movements were observed. PEA did not affect haloperidol and fluphenazine induced catalepsy. It did not change the immobility period in the behavioral despair test. In doses of 0 . 1, 1 and 10 mg/kg iv it potentiated flexor reflex of the hind paw of the spinal rat. Phentolamine (10 mg/kg iv) and propranolol (5 mg/kg iv) slightly potentiated the stimulatory effect of PEA. In doses of 50 and 100 microgram ivc PEA did not affect the level and utilization of noradrenaline, and did not change the level of dopamine but depressed its utilization in the cerebral cortex, striatum and hippocampus. PMID:7196039

  5. Coadministration of Resveratrol and Rice Oil Mitigates Nociception and Oxidative State in a Mouse Fibromyalgia-Like Model

    PubMed Central

    Peres Klein, Caroline; Rodrigues Cintra, Marcos; Binda, Nancy; Montijo Diniz, Danuza; Gomez, Marcus Vinicius; Souto, Andre Arigony; de Souza, Alessandra Hubner

    2016-01-01

    The mechanism underlying pain symptoms in fibromyalgia (FM) is not fully understood. Oxidative stress has emerged as pathophysiological event occurring during the development of the disease. The present study aimed at investigating the efficacy of resveratrol associated with rice bran oil on fibromyalgia-like mice model. Subcutaneous injection of reserpine (0.25 mg/Kg) during 3 days produced fibromyalgia-like symptoms. Resveratrol and/or rice oil or pregabalin were administered through oral route in therapeutic (single dose) and preventive (four doses) schemes. In both schemes, treatment with resveratrol associated with rice bran oil and pregabalin significantly reduced mechanical allodynia and thermal hyperalgesia in animals. The preventive scheme displayed antidepressant effect which was demonstrated by the forced swimming test as well as reduced reactive species in the cerebrospinal fluid of reserpinized animals. Taken together, our data provide evidences that the intake of resveratrol associated with rice bran oil plays antinociceptive and antidepressant actions probably through reducing reactive species and suggests the involvement of oxidative stress in this model of FM as possible underlying mechanism of pathogenesis of the disease. PMID:27069683

  6. Coadministration of Resveratrol and Rice Oil Mitigates Nociception and Oxidative State in a Mouse Fibromyalgia-Like Model.

    PubMed

    Peres Klein, Caroline; Rodrigues Cintra, Marcos; Binda, Nancy; Montijo Diniz, Danuza; Gomez, Marcus Vinicius; Souto, Andre Arigony; de Souza, Alessandra Hubner

    2016-01-01

    The mechanism underlying pain symptoms in fibromyalgia (FM) is not fully understood. Oxidative stress has emerged as pathophysiological event occurring during the development of the disease. The present study aimed at investigating the efficacy of resveratrol associated with rice bran oil on fibromyalgia-like mice model. Subcutaneous injection of reserpine (0.25 mg/Kg) during 3 days produced fibromyalgia-like symptoms. Resveratrol and/or rice oil or pregabalin were administered through oral route in therapeutic (single dose) and preventive (four doses) schemes. In both schemes, treatment with resveratrol associated with rice bran oil and pregabalin significantly reduced mechanical allodynia and thermal hyperalgesia in animals. The preventive scheme displayed antidepressant effect which was demonstrated by the forced swimming test as well as reduced reactive species in the cerebrospinal fluid of reserpinized animals. Taken together, our data provide evidences that the intake of resveratrol associated with rice bran oil plays antinociceptive and antidepressant actions probably through reducing reactive species and suggests the involvement of oxidative stress in this model of FM as possible underlying mechanism of pathogenesis of the disease. PMID:27069683

  7. The fight and flight responses of crickets depleted of biogenic amines.

    PubMed

    Stevenson, P A; Hofmann, H A; Schoch, K; Schildberger, K

    2000-05-01

    Aggressive and escape behaviors were analysed in crickets (Orthoptera) treated with either reserpine, a nonspecific depleter of biogenic amines, or the synthesis inhibitors alpha-methyltryptophan (AMTP) and alpha-methyl-p-tyrosine (AMT) to specifically deplete serotonin, respectively dopamine and octopamine. Standard immunocytochemical techniques were used to verify depletion from central nervous tissue, and determine the effective dosages. Reserpinized crickets became exceedingly lethargic and had severely depressed escape responses. However, they were still able to express all the major elements of the escalating sequences of stereotype motor performances that typifies normal aggressive behavior in the cricket. AMT and AMTP treatment had opposing influences on escape behavior, being enhanced by serotonin depletion, but depressed by dopamine/octopamine depletion. AMTP-induced serotonin depletion had no influence on aggressive or submissive behaviors. AMT-treated crickets could normally only be brought to fight by coaxing. Though capable of expressing aggressive behavior per se, agonistic encounters between AMT-treated crickets were shorter, and rarely involved actual physical interactions. Hence, although amines seem to have similar actions on escape behavior in insects and crustaceans, the aminergic control of aggression seems to be fundamentally different in these arthropods groups. We conclude that amines are not in principle required for the initiation and operation of the motor circuits underlying aggression in the cricket. However, octopamine and/or dopamine seem necessary for establishing a level of excitability sufficient for aggressive behavior to become overt in response to appropriate natural releasing stimuli.

  8. Endogenous dopamine (DA) modulates (3H)spiperone binding in vivo in rat brain

    SciTech Connect

    Bischoff, S.; Krauss, J.; Grunenwald, C.; Gunst, F.; Heinrich, M.; Schaub, M.; Stoecklin, K.V.; Vassout, A.; Waldmeier, P.; Maitre, L. )

    1991-01-01

    (3H)spiperone (SPI) binding in vivo, biochemical parameters and behavior were measured after modulating DA levels by various drug treatments. DA releasers and uptake inhibitors increased SPI binding in rat striatum. In other brain areas, the effects were variable, but only the pituitary remained unaffected. Surprisingly, nomifensine decreased SPI binding in frontal cortex. The effects of these drugs were monitored by measuring DA, serotonin (5-HT) and their metabolites in the same rats. The increased SPI binding in striatum was parallel to the locomotor stimulation with the following rank order: amfonelic acid greater than nomifensine greater than D-amphetamine greater than or equal to methylphenidate greater than amineptine greater than bupropion. Decreasing DA levels with reserpine or alpha-methyl-para-tyrosine reduced SPI binding by 45% in striatum only when both drugs were combined. In contrast, reserpine enhanced SPI binding in pituitary. Thus, the amount of releasable DA seems to modulate SPI binding characteristics. It is suggested that in vivo, DA receptors are submitted to dynamic regulation in response to changes in intrasynaptic concentrations of DA.

  9. Mechanism of cardiovascular actions of heptanolamines

    PubMed Central

    Garrett, J.; Osswald, W.; Moreira, M. Gonçalves

    1962-01-01

    It has been suggested that heptaminol and methylheptaminol should be used as myocardial stimulants because they have cardiotonic actions similar to those of cardiac glycosides. However, as these aliphatic amines show definite sympathomimetic effects, the mechanism of their actions on the heart was investigated, in order to determine whether digitalis-like properties are involved in these effects. The pattern of pharmacological actions of heptaminol and methylheptaminol was compared with that of catechol amines, tyramine and k-strophanthin. The influence of atropine, hexamethonium, cocaine and reserpine was also investigated. The results show that both heptanolamines have a long-lasting cardiostimulant action which is abolished by cocaine and absent in reserpine pretreated animals. The pharmacological activity of these drugs may be entirely attributed to an indirect sympathomimetic action of the tyramine type, probably due to release of endogenous catechol amines. None of the experimental findings is consistent with the alleged digitalis-like action of these compounds. ImagesFig. 5Fig. 6 PMID:13897064

  10. Fluoroquinolone Efflux in Streptococcus suis Is Mediated by SatAB and Not by SmrA ▿

    PubMed Central

    Escudero, Jose Antonio; San Millan, Alvaro; Gutierrez, Belen; Hidalgo, Laura; La Ragione, Roberto M.; AbuOun, Manal; Galimand, Marc; Ferrándiz, María José; Domínguez, Lucas; de la Campa, Adela G.; Gonzalez-Zorn, Bruno

    2011-01-01

    Streptococcus suis is an emerging zoonotic pathogen. With the lack of an effective vaccine, antibiotics remain the main tool to fight infections caused by this pathogen. We have previously observed a reserpine-sensitive fluoroquinolone (FQ) efflux phenotype in this species. Here, SatAB and SmrA, two pumps belonging to the ATP binding cassette (ABC) and the major facilitator superfamily (MFS), respectively, have been analyzed in the fluoroquinolone-resistant clinical isolate BB1013. Genes encoding these pumps were overexpressed either constitutively or in the presence of ciprofloxacin in this strain. These genes could not be cloned in plasmids in Escherichia coli despite strong expression repression. Finally, site-directed insertion of smrA and satAB in the amy locus of the Bacillus subtilis chromosome using ligated PCR amplicons allowed for the functional expression and study of both pumps. Results showed that SatAB is a narrow-spectrum fluoroquinolone exporter (norfloxacin and ciprofloxacin), susceptible to reserpine, whereas SmrA was not involved in fluoroquinolone resistance. Chromosomal integration in Bacillus is a novel method for studying efflux pumps from Gram-positive bacteria, which enabled us to demonstrate the possible role of SatAB, and not SmrA, in fluoroquinolone efflux in S. suis. PMID:21930876

  11. Changes in Fluoroquinolone-Resistant Streptococcus pneumonia after 7-Valent Conjugate Vaccination, Spain

    PubMed Central

    Ardanuy, Carmen; Balsalobre, Luz; Pérez-Trallero, Emilio; Marimón, Jose M.; Fenoll, Asunción; Liñares, Josefina

    2009-01-01

    Among 4,215 Streptococcus pneumoniae isolates obtained in Spain during 2006, 98 (2.3%) were ciprofloxacin resistant (3.6% from adults and 0.14% from children). In comparison with findings from a 2002 study, global resistance remained stable. Low-level resistance (30 isolates with MIC 4–8 μg/mL) was caused by a reserpine-sensitive efflux phenotype (n = 4) or single topoisomerase IV (parC [n = 24] or parE [n = 1]) changes. One isolate did not show reserpine-sensitive efflux or mutations. High-level resistance (68 isolates with MIC ≥16 μg/mL) was caused by changes in gyrase (gyrA) and parC or parE. New changes in parC (S80P) and gyrA (S81V, E85G) were shown to be involved in resistance by genetic transformation. Although 49 genotypes were observed, clones Spain9V-ST156 and Sweden15A-ST63 accounted for 34.7% of drug-resistant isolates. In comparison with findings from the 2002 study, clones Spain14-ST17, Spain23F-ST81, and ST8819F decreased and 4 new genotypes (ST9710A, ST57016, ST43322, and ST71733) appeared in 2006. PMID:19523289

  12. Ofloxacin resistance in Mycobacterium tuberculosis is associated with efflux pump activity independent of resistance pattern and genotype.

    PubMed

    Sun, Zhaogang; Xu, Yuhui; Sun, Yong; Liu, Yi; Zhang, Xuxia; Huang, Hairong; Li, Chuanyou

    2014-12-01

    Drug-resistance to ofloxacin (OFX) in Mycobacterium tuberculosis is due to missense mutations in gyrA and other factors, such as alterations in the activity of drug efflux pumps. In this study, we identified 8 extensively drug resistant tuberculosis (XDR-TB), 40 multidrug resistant TB (MDR-TB), 38 polydrug resistant TB (PDR-TB), and 16 single OFX-resistant TB from 102 clinical isolates. We tested the effect of three efflux inhibitors, reserpine, verapamil, and carbonyl cyanide m-chlorophenyl hydrazone (CCCP), on changes in the OFX minimum inhibitory concentration (MIC) using Resazurin microtitre assay. These three inhibitors changed the MICs from 2- to 32-fold, with CCCP having the strongest effect. A total of 55%, 74%, and 83% of the tested isolates had changes in MIC of more than two-fold by reserpine, verapamil, and CCCP, respectively. The inhibitors led to similar fold-changes of OFX MICs in the XDR, MDR, PDR, and single OFX-resistant isolates. For each inhibitor, a higher resistance to OFX was associated with the greater efflux pump activity. There were no significant differences in the effect of efflux pump inhibitors upon Beijing and non-Beijing M. tuberculosis genotypes. Taken together, these results indicate that the efflux pump activity was greater in the isolates higher resistant to OFX and had similar effects on isolates with different drug resistant pattern, and had similar effects on Beijing and non-Beijing genotypes.

  13. Drug-induced regulation of 1,4-dihydropyridine Ca sup 2+ channel antagonist binding sites in the brain and heart

    SciTech Connect

    Ramkumar, V.

    1987-01-01

    The ability of drugs to regulate the voltage-sensitive Ca{sup 2+} channels were assessed by determining the bind of ({sup 3}H)dihydropyridine Ca{sup 2+} channel antagonists in the heart and brain following administration of these drugs to rats and mice. Mice and rats implanted with morphine pellets for 3 days showed an increase in dihydropyridine binding sites in the brain, compared to non-treated or placebo treated controls. No increase in dihydropyridine binding sites was observed in the heart. The significance of the increase in binding to physical dependence on morphine is implied from the findings that pretreatment with Ca{sup 2+} channel antagonist drugs led to an attenuation of naloxone-precipitated withdrawal signs in both dependent rats and mice. Administration of other drugs, known to depress the CNS, was undertaken to determine whether the changes observed with morphine was a nonspecific response of the brain to depressant drugs. Prolonged administration of reserpine to rats resulted in no changes in dihydropyridine binding sites in the brain, even though the {beta}-adrenergic receptors in this tissue are upregulated. However, reserpine decreased the density of ({sup 3}H)nimodipine binding sites in the heart of this is accompanied by concomitant increases in {beta}-adrenergic receptors.

  14. Anti depressant activity of Mamsyadi Kwatha: An Ayurvedic compound formulation.

    PubMed

    Shreevathsa, M; Ravishankar, B; Dwivedi, Rambabu

    2013-01-01

    Depression is a psychiatric condition in which there is loss of interest in all pleasurable outlets, viz. food, sex, work, friends, hobbies and entertainment. The prevalence rate of the disease is 6-8% in women and 3-5% in men. Ayurveda, the science of life, provides systematic management principles for depression. Mamsyadi Kwatha is one such formulation stated by Yadavji Trikamji Acharya in Siddha Yoga Sangraha and Bheshaja Samhita, which is said to be effective in psychiatric conditions. The ingredients are Jatamansi (Nardostachys jatamansi), Ashwagandh (Withania somnifera) and Parasika Yavani (Hyocymus niger) in an 8:4:1 ratio, respectively. The test drug was subjected for antidepressant activity in experimental models. The models selected for anti depressant activity were behavioral despair test, anti-reserpine test and Chronic Fatigue Syndrome (CFS) test in albino mice. The test formulation showed significant inhibition of behavioural despair (P < 0.05), weak to moderate anti-reserpine activity - ptosis (P < 0.001), catatonia (P < 0.01), sedation (P < 0.01) and moderate effect in CFS test (P < 0.050). These effects clearly show that Mamsyadi Kwatha has an anti-depressant activity. PMID:24049416

  15. The importance of active efflux systems in the quinolone resistance of clinical isolates of Salmonella spp.

    PubMed

    Escribano, Isabel; Rodríguez, Juan Carlos; Cebrian, Laura; Royo, Gloria

    2004-11-01

    The aim of this study was to determine the importance of the active elimination of antibiotics by active efflux systems, in the decrease in fluoroquinolone sensitivity of clinical isolates of Salmonella spp. as well as the intrinsic antibiotic activity of certain active efflux system inhibitors. The effect of the active efflux system on the decrease in sensitivity to nalidixic acid, ciprofloxacin, ofloxacin and sparfloxacin was studied by investigating the variation in the in vitro activity of these compounds when assayed in association with reserpine and MC 207.110. The active efflux systems inhibited by reserpine displayed low activity in the elimination of these compounds, whereas those inhibited by MC 207.110 showed high activity in the elimination of nalidixic acid and sparfloxacin, but were less effective in the elimination of ofloxacin and ciprofloxacin. These two compounds did not exhibit intrinsic inhibitory activity against Salmonella spp. at the concentrations assayed. These mechanisms of resistance to antibiotics are complex and vary depending on the chemical composition of the antibiotics used, and perhaps the inhibitors of these systems, although they do not exhibit any intrinsic antibiotic activity, may be used as adjuvants to increase the activity of certain antibiotics. These mechanisms complement the mutations in the gyrA gene and this supports the thesis that it is necessary to lower the breakpoint established by the NCCLS for ciprofloxacin, since the strains studied have resistance mechanisms that reduce the activity of this drug and may favour the emergence of resistant mutants during treatment.

  16. A study of the role of noradrenaline in behavioral changes produced in the rat by psychotomimetic drugs.

    PubMed

    Sugrue, M F

    1969-02-01

    1. LSD-25, psilocybin and JB-329 reduced the noradrenaline content of the rat hypothalamus.2. All three drugs affected the acquisition of a conditioned avoidance response, LSD-25 and psilocybin retarding and JB-329 enhancing the acquisition. With the exception of JB-329, doses affecting the acquisition of a conditioned avoidance response were lower than those required to decide hypothalamic noradrenaline concentrations. The time of peak drug effect on the acquisition of a conditioned avoidance response occurred approximately 1.5 hr after injection as opposed to 3 hr in the case of noradrenaline content.3. The amount of LSD-25, psilocybin and JB-329 necessary to elicit gross behavioural excitation was similar to the dose producing noradrenaline depletion. Here also the peak behavioural effect was detected earlier.4. Pretreatment with reserpine and alpha-MT had no effect on the intensity of gross behavioural excitation induced by LSD-25 and psilocybin but shortened the duration of the response. The excitation induced by JB-329 was abolished by reserpine pretreatment and was markedly reduced both in intensity and duration by the prior injection of alpha-MT.

  17. CO2 asphyxia increases plasma norepinephrine in rats via sympathetic nerves.

    PubMed

    Borovsky, V; Herman, M; Dunphy, G; Caplea, A; Ely, D

    1998-01-01

    The objective of this study was to determine whether the plasma norepinephrine (NE) increase in rats exposed to CO2 asphyxia was due to adrenal gland release or sympathetic nerve ending (SNS) release. Plasma NE was measured by high-performance liquid chromatography in hypertensive and normotensive rats using the following protocol: control session, CO2 exposure, N2 exposure, reserpine + CO2, and adrenalectomy + CO2. Four strains of male and female rats were used: spontaneously hypertensive rats, Wistar-Kyoto rats, and two congenic strains with different Y chromosomes. The same rats were used throughout the experiment (n = 80). Blood pressure measured by aortic telemetry increased approximately 50-60 mmHg in response to CO2 in all strains. CO2 increased NE 6-10x in all strains and both genders. N2 produced a significant increase in NE (73% of CO2 response). Reserpine significantly decreased (67%) plasma NE after CO2. Adrenalectomy did not significantly reduce the NE response to CO2. In conclusion, the increase in plasma NE after CO2 was associated with SNS release and not adrenal medullary release, was mainly due to hypoxia, and was not a specific response to CO2.

  18. VMAT2 identified as a regulator of late-stage β-cell differentiation.

    PubMed

    Sakano, Daisuke; Shiraki, Nobuaki; Kikawa, Kazuhide; Yamazoe, Taiji; Kataoka, Masateru; Umeda, Kahoko; Araki, Kimi; Mao, Di; Matsumoto, Shirou; Nakagata, Naomi; Andersson, Olov; Stainier, Didier; Endo, Fumio; Kume, Kazuhiko; Uesugi, Motonari; Kume, Shoen

    2014-02-01

    Cell replacement therapy for diabetes mellitus requires cost-effective generation of high-quality, insulin-producing, pancreatic β cells from pluripotent stem cells. Development of this technique has been hampered by a lack of knowledge of the molecular mechanisms underlying β-cell differentiation. The present study identified reserpine and tetrabenazine (TBZ), both vesicular monoamine transporter 2 (VMAT2) inhibitors, as promoters of late-stage differentiation of Pdx1-positive pancreatic progenitor cells into Neurog3 (referred to henceforth as Ngn3)-positive endocrine precursors. VMAT2-controlled monoamines, such as dopamine, histamine and serotonin, negatively regulated β-cell differentiation. Reserpine or TBZ acted additively with dibutyryl adenosine 3',5'-cyclic AMP, a cell-permeable cAMP analog, to potentiate differentiation of embryonic stem (ES) cells into β cells that exhibited glucose-stimulated insulin secretion. When ES cell-derived β cells were transplanted into AKITA diabetic mice, the cells reversed hyperglycemia. Our protocol provides a basis for the understanding of β-cell differentiation and its application to a cost-effective production of functional β cells for cell therapy.

  19. Efflux pump-mediated benzalkonium chloride resistance in Listeria monocytogenes isolated from retail food.

    PubMed

    Jiang, Xiaobing; Yu, Tao; Liang, Yu; Ji, Shengdong; Guo, Xiaowei; Ma, Jianmin; Zhou, Lijun

    2016-01-18

    In this study, efflux pump-mediated benzalkonium chloride (BC) resistance, including plasmid-encoded (Qac protein family and BcrABC) and chromosome-borne efflux pumps, was investigated in Listeria monocytogenes from retail food in China. Among the 59 L. monocytogenes strains, 13 (22.0%) strains were resistant to BC. The PCR results showed that bcrABC was harbored by 2 of 13 BC resistant strains. However, none of the qac genes were detected among the 59 strains. The bcrABC was absent in both of the plasmid cured strains, indicating that this BC resistance determinant was plasmid-encoded in the two bcrABC-positive strains. In the presence of reserpine, most of the bcrABC-negative strains had decreases in the MICs of BC, suggesting the existence of other efflux pumps and their role in BC resistance. After exposed to reserpine, the reduction in BC MICs was observed in the two cured strains, indicating that efflux pumps located on chromosome was also involved in BC resistance. Our findings suggest that food products may act as reservoirs for BC resistant isolates of L. monocytogenes and plasmid- and chromosome-encoded efflux pumps could mediate the BC resistance of L. monocytogenes, which is especially relevant to the adaption of this organism in food-related environments with frequent BC use. PMID:26513255

  20. The involvement of noradrenergic mechanisms in the suppressive effects of diazepam on the hypothalamic-pituitary-adrenal axis activity in female rats

    PubMed Central

    Švob Štrac, Dubravka; Muck-Šeler, Dorotea; Pivac, Nela

    2012-01-01

    Aim To elucidate the involvement of noradrenergic system in the mechanism by which diazepam suppresses basal hypothalamic-pituitary-adrenal (HPA) axis activity. Methods Plasma corticosterone and adrenocorticotropic hormone (ACTH) levels were determined in female rats treated with diazepam alone, as well as with diazepam in combination with clonidine (α2-adrenoreceptor agonist), yohimbine (α2-adrenoreceptor antagonist), alpha-methyl-p-tyrosine (α-MPT, an inhibitor of catecholamine synthesis), or reserpine (a catecholamine depleting drug) and yohimbine. Results Diazepam administered in a dose of 2.0 mg/kg suppressed basal HPA axis activity, ie, decreased plasma corticosterone and ACTH levels. Pretreatment with clonidine or yohimbine failed to affect basal plasma corticosterone and ACTH concentrations, but abolished diazepam-induced inhibition of the HPA axis activity. Pretreatment with α-MPT, or with a combination of reserpine and yohimbine, increased plasma corticosterone and ACTH levels and prevented diazepam-induced inhibition of the HPA axis activity. Conclusion The results suggest that α2-adrenoreceptors activity, as well as intact presynaptic noradrenergic function, are required for the suppressive effect of diazepam on the HPA axis activity. PMID:22661134

  1. The medical treatment of Parkinson disease from James Parkinson to George Cotzias.

    PubMed

    Fahn, Stanley

    2015-01-01

    It took exactly 150 years since James Parkinson's description in 1817 of the illness bearing his name until the development of effective therapy for this disorder, namely, the introduction of high-dosage levodopa by George Cotzias in 1967. During the first 50 years, no effective therapy was available, but neurologists reported using different agents, including metals. Then, around 1867, Charcot found solanaceous alkaloids to be somewhat helpful, and these became the accepted and popular therapy for the next 75 years. When basic scientists discovered that these alkaloids had central antimuscarinic activity, pharmaceutical chemists developed synthetic chemical agents that were equally effective, with possibly less adverse effects, and around 1950 these synthetic drugs became the standard medical therapy for Parkinson's disease (PD). The link between dopamine and PD did not take place until 1957, 140 years after Parkinson's Essay. The clue came from research on reserpine, a drug derived from the Rauwolfia plant that caused a sedative effect, now recognized as a drug-induced parkinsonian state. Initial investigations revealed that reserpine caused the release and depletion of serotonin stores in the brain. With that knowledge, Arvid Carlsson, a young pharmacologist in Sweden, decided to explore the possibility that reserpine might also affect brain catecholamines. In his now famous, elegant, and simple experiment, he showed that injecting l-dopa, the precursor of catecholamines, alleviated the reserpine-induced parkinsonian state in animals, whereas the precursor of serotonin failed to do so. Carlsson then developed a highly sensitive assay to measure dopamine, and his lab found that dopamine is selectively present in high concentrations in the striatum and that administered l-dopa could restore the dopamine depleted by reserpine. Carlsson postulated that all these findings implicate dopamine in motor disorders. Oleh Hornykiewicz, a young pharmacologist in Vienna, on

  2. Room-temperature super-extraction system (RTSES) optimizes the anxiolytic- and antidepressant-like behavioural effects of traditional Xiao-Yao-San in mice

    PubMed Central

    2012-01-01

    Background Xiao-Yao-San (XYS) is a Chinese medicinal formula for treating anxiety and depression. This study aims to evaluate the use of a room-temperature super-extraction system (RTSES) to extract the major active components of XYS and enhance their psycho-pharmacological effects. Methods The neuroprotective roles of XYS/RTSES against reserpine-derived neurotoxicity were evaluated using a glial cell injury system (in vitro) and a depression-like C57BL/6 J mouse model (in vivo). The anxiolytic-behavioural effects were measured by the elevated plus-maze (EPM) test and the antidepressant effects were evaluated by the forced swimming test (FST) and tail suspension test (TST). Glucose tolerance and insulin resistance were assayed by ELISA. The expression of 5-HT1A receptors in the prefrontal cortex was examined by western blotting. Results XYS/RTSES (300 μg/mL) diminished reserpine-induced glial cell death more effectively than either XYS (300 μg/mL) or fluoxetine (30 μM) at 24 h (P = 0.0481 and P = 0.054, respectively). Oral administration of XYS/RTSES (500 mg/kg/day) for 4 consecutive weeks significantly elevated the ratios of entries (open arms/closed arms; P = 0.0177) and shuttle activity (P = 0.00149) on the EPM test, and reduced the immobility time by 90% on the TST (P = 0.00000538) and FST (P = 0.0000053839). XYS/RTSES also improved the regulation of blood glucose (P = 0.0305) and increased the insulin sensitivity (P = 0.0093). The Western blot results indicated that the activation of cerebral 5-HT1A receptors may be involved in the mechanisms of XYS/RTSES actions. Conclusion The RTSES could provide a novel method for extracting effective anxiolytic- and antidepressant-like substances. XYS/RTSES improved the regulation of blood glucose and increased the insulin sensitivity in reserpine-induced anxiety and depression. Neuroprotection of glial cells and activation of cerebral 5-HT1A receptors were also involved. PMID:23134744

  3. Reproducible preparation of nanospray tips for capillary electrophoresis coupled to mass spectrometry using 3D printed grinding device.

    PubMed

    Tycova, Anna; Prikryl, Jan; Foret, Frantisek

    2016-04-01

    The use of high quality fused silica capillary nanospray tips is critical for obtaining reliable and reproducible electrospray/MS data; however, reproducible laboratory preparation of such tips is a challenging task. In this work, we report on the design and construction of low-cost grinding device assembled from 3D printed and commercially easily available components. Detailed description and characterization of the grinding device is complemented by freely accessible files in stl and skp format allowing easy laboratory replication of the device. The process of sharpening is aimed at achieving maximal symmetricity, surface smoothness and repeatability of the conus shape. Moreover, the presented grinding device brings possibility to fabricate the nanospray tips of desired dimensions regardless of the commercial availability. On several samples of biological nature (reserpine, rabbit plasma, and the mixture of three aminoacids), performance of fabricated tips is shown on CE coupled to MS analysis. The special interest is paid to the effect of tip sharpness. PMID:26626777

  4. Antidepressant-like activity of adhyperforin, a novel constituent of Hypericum perforatum L.

    PubMed Central

    Tian, Jingwei; Zhang, Fangxi; Cheng, Jucan; Guo, Shuren; Liu, Pinglan; Wang, Hongbo

    2014-01-01

    Adhyperforin is a novel constituent of Hypericum perforatum L., but its antidepressant-like activity remains unclear. To explore that, several well-validated animal models of depression as well as neurotransmitter reuptake and transporter binding assays were conducted. The results showed adhyperforin could reduce the immobility time of mice in the forced swimming test and tail suspension assay, antagonize the behaviors induced by reserpine, and have no effect on locomotor activity. Furthermore, following establishment of a chronic unpredictable mild stress model, adhyperforin increased the number of crossings and rearings in rats in the open field test and increased the sucrose consumption. Finally, adhyperforin inhibited uptake of serotonin, norepinephrine, and dopamine, and displayed robust binding affinities for the serotonin and norepinephrine transporters. Overall, the current study provides the first evidence that adhyperforin is a novel, active ingredient of Hypericum perforatum L. with robust antidepressant-like activity. PMID:25005489

  5. Catecholamines and 5-hydroxytryptamine in nervous tissue of cephalopods

    PubMed Central

    Juorio, A. V.

    1971-01-01

    1. Catecholamines and 5-hydroxytryptamine were measured fluorimetrically in nervous tissue of cephalopod molluscs. 2. The only catecholamines found present in nervous tissue of Eledone, Octopus and Sepia were dopamine and noradrenaline. The highest concentrations were found in the optic lobes and in the superior buccal lobe. The concentrations of dopamine and noradrenaline were smaller in other regions of the nervous tissue taken. 3. 5-Hydroxytryptamine was also found in most of the regions investigated. The highest concentration was found in the inferior buccal ganglia and in the optic lobes. 4. The administration of reserpine produced a marked decrease in the concentration of catecholamines and 5-hydroxytryptamine in octopod nervous tissue. 5. These findings suggest that dopamine, noradrenaline and 5-hydroxytryptamine may function as neurotransmitters in cephalopod molluscs. PMID:5558355

  6. Management of hypertension by reduction in sympathetic activity.

    PubMed

    Mathias, C J

    1991-04-01

    The sympathetic nervous system may initiate or maintain hypertension, and a range of approaches that reduce sympathetic activity is often of value in management. These may include nonpharmacological methods, such as the various forms of behavioral therapy (e.g., meditation, relaxation, and biofeedback techniques); weight reduction and avoidance of particular foods and agents that stimulate sympathetic activity (including caffeine and alcohol), and regular physical exercise. Pharmacological therapy includes centrally acting drugs such as alpha-methyldopa, clonidine, and reserpine; ganglionic blockers such as hexamethonium; agents acting on sympathetic nerve terminals such as guanethidine and debrisoquine; and drugs that may act at multiple sites, such as the beta-adrenergic blockers. The role of reducing sympathetic activity in the current management of hypertension and its complications is considered in this overview.

  7. Effective doping of low energy ions into superfluid helium droplets

    PubMed Central

    Zhang, Jie; Chen, Lei; Freund, William M.; Kong, Wei

    2015-01-01

    We report a facile method of doping cations from an electrospray ionization (ESI) source into superfluid helium droplets. By decelerating and stopping the ion pulse of reserpine and substance P from an ESI source in the path of the droplet beam, about 104 ion-doped droplets (one ion per droplet) can be recorded, corresponding to a pickup efficiency of nearly 1 out of 1000 ions. We attribute the success of this simple approach to the long residence time of the cations in the droplet beam. The resulting size of the doped droplets, on the order of 105/droplet, is measured using deflection and retardation methods. Our method does not require an ion trap in the doping region, which significantly simplifies the experimental setup and procedure for future spectroscopic and diffraction studies. PMID:26298127

  8. Development and characterisation of molecularly imprinted polymers based on methacrylic acid for selective recognition of drugs.

    PubMed

    Shi, Xizhi; Wu, Aibo; Qu, Guorun; Li, Rongxiu; Zhang, Dabing

    2007-09-01

    Specific molecularly imprinted polymers (MIPs) for the drug reserpine (RES) using methacrylic acid (MAA) as the functional monomer were developed and characterised for the first time in this study. Evaluation of the various polymers by binding assays indicated that the optimum ratio of functional monomer to template was 4:1. Furthermore, the imprinting effect of the MIPs was assessed by the chromatographic method, which demonstrated that the MIPs had better chromatographic behavior and selectivity than those of the corresponding NIPs. A combination of BET, NMR, UV spectroscopy, and MISPE analyses for investigation of the imprinting and recognition properties revealed that strong specific interactions between the functional monomer and RES in the prepolymerization solutions and the aqueous solutions were probably responsible for RES recognition. The preparation of RES MIPs and elucidation of imprinting and recognition mechanisms may serve as useful references for other drug MIPs.

  9. Natural substances in psychiatry (Ginkgo biloba in dementia).

    PubMed

    Itil, T; Martorano, D

    1995-01-01

    Natural substances and/or their synthetically developed active ingredients are frequently used in medicine. In psychiatry, two of the most well known natural compounds are reserpine and Ginkgo biloba extract (EGb). EGb is among the most popular over-the-counter medicines in Europe and is also available in the United States, primarily in health food stores. Already the European medical community has recognized EGb as an effective compound in the treatment of cerebral insufficiency. In a pilot bioequivalency study, the effects of three different commercially available EGb products were examined. Findings indicated significant quantitative central nervous system (CNS) effects in, at least, one of the three. Furthermore, the CNS effects of Ginkgold were similar to other psychoactive compounds classified as cognitive activators. Recent studies in which EGb 761 demonstrated therapeutic effects in the treatment of dementia have earned EGb the approval of the German BGA (Bundesgesundheit Amt) for use in the treatment of dementia. PMID:7675979

  10. Natural substances in psychiatry (Ginkgo biloba in dementia).

    PubMed

    Itil, T; Martorano, D

    1995-01-01

    Natural substances and/or their synthetically developed active ingredients are frequently used in medicine. In psychiatry, two of the most well known natural compounds are reserpine and Ginkgo biloba extract (EGb). EGb is among the most popular over-the-counter medicines in Europe and is also available in the United States, primarily in health food stores. Already the European medical community has recognized EGb as an effective compound in the treatment of cerebral insufficiency. In a pilot bioequivalency study, the effects of three different commercially available EGb products were examined. Findings indicated significant quantitative central nervous system (CNS) effects in, at least, one of the three. Furthermore, the CNS effects of Ginkgold were similar to other psychoactive compounds classified as cognitive activators. Recent studies in which EGb 761 demonstrated therapeutic effects in the treatment of dementia have earned EGb the approval of the German BGA (Bundesgesundheit Amt) for use in the treatment of dementia.

  11. Mechanistic Study on the Antidepressant-Like Effect of Danggui-Shaoyao-San, a Chinese Herbal Formula

    PubMed Central

    Huang, Zhen; Mao, Qing-Qiu; Zhong, Xiao-Ming; Li, Zhao-Yi; Qiu, Feng-Mei; Ip, Siu-Po

    2012-01-01

    Danggui-Shaoyao-San (DSS), a famous Chinese herbal formula, has been widely used in the treatment of various diseases. Previous studies have shown that DSS produces antidepressant-like effect in rodents. This study aims to investigate the mechanism(s) underlying the antidepressant-like action of DDS. The results showed that DSS treatment significantly antagonized reserpine-induced ptosis in mice. In addition, DSS treatment significantly increased sucrose consumption in chronic unpredictable stress- (CUS-) treated mice. DSS treatment also markedly attenuated CUS-induced decreases in noradrenaline and dopamine concentrations in mouse brain. Furthermore, DSS treatment significantly reversed CUS-induced increase in serum malondialdehyde (MDA) content and decrease in serum superoxide dismutase (SOD) activity in mice. The results suggest that the antidepressant-like activity of DSS is probably mediated by the modulation of central monoamine neurotransmitter systems and the reduction of oxidative stress. PMID:22924052

  12. Effects of hysterectomy, administration of uterine extract, posterior pituitary extract and aspirin on the length of pseudopregnancy in rats.

    PubMed

    Uddin Kabiraj, M; Fariduddin, K M

    1975-10-01

    Effects of hysterectomy, administration of uterine extract, posterior pituitary extract and aspirin on the length of pseudopregnancy were investigated in 174 virgin, female rats. Pseudopregnancy was induced by injecting a single dose of reserpine (1 mg/kg body weight) subcutaneously on the 1st day of diestrus. The mean length of pseudopregnancy in the control group was 13.8 days. There was an increase (p less than .001) in the duration of pseudopregnancy to 17.1 days following hysterectomy. The administration of uterine extract reduced the duration to 15.9 days. Administration of posterior pituitary extract reduced the duration of pseudopregnancy in the pseudopregnant hysterectomized rats to 12.4 days (p less than .001). Aspirin treatment did not effect the length of pseudopregnancy. It is concluded that there is a definite pituitary-utero-ovarian relationship. The neurohypophyseal hormones may be involved in the mechanism of regression of corpora lutea of pseudopregnancy in rats.

  13. A 2-amino-2-oxazoline derivative as an antidepressant in mice.

    PubMed

    Bourin, M; Creuzet, M H; Jarry, C; Colombel, M C

    1988-05-01

    2-Amino-2-oxazolines are heterocyclic compounds with interesting pharmacological properties. Several derivatives of this chemical series were studied in psychopharmacological tests. One derivative 4,5-dihydro-5-[methyl(4-phenyl-1-piperazinyl)]-2-oxazolamine (COR 32-24), had an antidepressant profile. Its structure can be compared to trazodone in its phenylpiperazine group and to toloxatone in its oxazoline group. This molecule antagonized reserpine-induced hypothermia and ptosis, oxotremorine-induced hypothermia and high-dose apomorphine-induced hypothermia. It also potentiated yohimbine-induced sublethality and decreased the immobility of forced swimming. It had no monoamine oxidase inhibitory activity. These results suggest a profile close to that of viloxazine and to that of a classic antidepressant.

  14. The antidepressant-like effects of paeoniflorin in mouse models

    PubMed Central

    QIU, FENGMEI; ZHONG, XIAOMING; MAO, QINGQIU; HUANG, ZHEN

    2013-01-01

    Peony is often used in Chinese herbal medicine for the treatment of depression-like disorders. Our previous studies have demonstrated that the total glycosides of peony exert antidepressant-like effects in animal models. Paeoniflorin is the main active glycoside of peony. The aim of this study was to evaluate the antidepressant-like effects of paeoniflorin in mice, as well as its active mechanisms. The results revealed that intraperitoneally injected paeoniflorin significantly reduced the duration of immobility in forced swimming and tail suspension tests. The doses that affected the immobility response did not affect locomotor activity. Furthermore, paeoniflorin antagonized reserpine-induced ptosis, akinesia and hypothermia. Paeoniflorin also significantly increased the levels of serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the hippocampus. These results suggest that the upregulation of serotonergic systems may be an important mechanism for the antidepressant-like effects of paeoniflorin in mice. PMID:23599734

  15. Identification of a mammalian vesicular polyamine transporter.

    PubMed

    Hiasa, Miki; Miyaji, Takaaki; Haruna, Yuka; Takeuchi, Tomoya; Harada, Yuika; Moriyama, Sawako; Yamamoto, Akitsugu; Omote, Hiroshi; Moriyama, Yoshinori

    2014-01-01

    Spermine and spermidine act as neuromodulators upon binding to the extracellular site(s) of various ionotropic receptors, such as N-methyl-d-aspartate receptors. To gain access to the receptors, polyamines synthesized in neurons and astrocytes are stored in secretory vesicles and released upon depolarization. Although vesicular storage is mediated in an ATP-dependent, reserpine-sensitive fashion, the transporter responsible for this process remains unknown. SLC18B1 is the fourth member of the SLC18 transporter family, which includes vesicular monoamine transporters and vesicular acetylcholine transporter. Proteoliposomes containing purified human SLC18B1 protein actively transport spermine and spermidine by exchange of H(+). SLC18B1 protein is predominantly expressed in the hippocampus and is associated with vesicles in astrocytes. SLC18B1 gene knockdown decreased both SLC18B1 protein and spermine/spermidine contents in astrocytes. These results indicated that SLC18B1 encodes a vesicular polyamine transporter (VPAT).

  16. The plant alkaloid piperine as a potential inhibitor of ethidium bromide efflux in Mycobacterium smegmatis.

    PubMed

    Jin, Jing; Zhang, Jiyu; Guo, Na; Feng, Haihua; Li, Lei; Liang, Junchao; Sun, Kai; Wu, Xiuping; Wang, Xuelin; Liu, Mingyuan; Deng, Xuming; Yu, Lu

    2011-02-01

    Piperine, a major plant alkaloid found in black pepper (Piper nigrum) and long pepper (Piper longum), has shown potential for inhibiting the efflux pump (EP) of Staphylococcus aureus. In this study, a modulation assay showed that piperine could decrease the MIC of ethidium bromide (EtBr) twofold at 32 μg ml(-1) and fourfold at 64 μg ml(-1) against Mycobacterium smegmatis mc(2) 155 ATCC 700084. A real-time, 96-well plate fluorometric method was employed to evaluate the EP inhibition ability of piperine in M. smegmatis. Reserpine, chlorpromazine, verapamil and carbonyl cyanide m-chlorophenylhydrazone were used as positive controls. Piperine significantly enhanced accumulation and decreased the efflux of EtBr in M. smegmatis, which suggests that it has the ability to inhibit mycobacterial EPs.

  17. Effective doping of low energy ions into superfluid helium droplets

    SciTech Connect

    Zhang, Jie; Chen, Lei; Freund, William M.; Kong, Wei

    2015-08-21

    We report a facile method of doping cations from an electrospray ionization (ESI) source into superfluid helium droplets. By decelerating and stopping the ion pulse of reserpine and substance P from an ESI source in the path of the droplet beam, about 10{sup 4} ion-doped droplets (one ion per droplet) can be recorded, corresponding to a pickup efficiency of nearly 1 out of 1000 ions. We attribute the success of this simple approach to the long residence time of the cations in the droplet beam. The resulting size of the doped droplets, on the order of 10{sup 5}/droplet, is measured using deflection and retardation methods. Our method does not require an ion trap in the doping region, which significantly simplifies the experimental setup and procedure for future spectroscopic and diffraction studies.

  18. Nanoelectrospray ion generation for high-throughput mass spectrometry using a micromachined ultrasonic ejector array

    SciTech Connect

    Aderogba, S.; Meacham, J.M.; Degertekin, F.L.; Fedorov, A.G.; Fernandez, F.M.

    2005-05-16

    Ultrasonic electrospray ionization (ESI) for high-throughput mass spectrometry is demonstrated using a silicon micromachined microarray. The device uses a micromachined ultrasonic atomizer operating in the 900 kHz-2.5 MHz range for droplet generation and a metal electrode in the fluid cavity for ionization. Since the atomization and ionization processes are separated, the ultrasonic ESI source shows the potential for operation at low voltages with a wide range of solvents in contrast with conventional capillary ESI technology. This is demonstrated using the ultrasonic ESI microarray to obtain the mass spectrum of a 10 {mu}M reserpine sample on a time of flight mass spectrometer with 197:1 signal-to-noise ratio at an ionization potential of 200 V.

  19. The real catecholamine content of secretory vesicles in the CNS revealed by electrochemical cytometry

    PubMed Central

    Omiatek, Donna M.; Bressler, Amanda J.; Cans, Ann-Sofie; Andrews, Anne M.; Heien, Michael L.; Ewing, Andrew G.

    2013-01-01

    Resolution of synaptic vesicle neurotransmitter content has mostly been limited to the study of stimulated release in cultured cell systems, and it has been controversial as to whether synaptic vesicle transmitter levels are saturated in vivo. We use electrochemical cytometry to count dopamine molecules in individual synaptic vesicles in populations directly sampled from brain tissue. Vesicles from the striatum yield an average of 33,000 dopamine molecules per vesicle, an amount considerably greater than typically measured during quantal release at cultured neurons. Vesicular content was markedly increased by L-DOPA or decreased by reserpine in a time-dependent manner in response to in vivo administration of drugs known to alter dopamine release. We investigated the effects of the psychostimulant amphetamine on vesicle content, finding that vesicular transmitter is rapidly depleted by 50% following in vivo administration, supporting the “weak base hypothesis” that amphetamine reduces synaptic vesicle transmitter and quantal size. PMID:23486177

  20. Management of Frostbite Injuries

    PubMed Central

    Espinosa, Gustavo A.

    1981-01-01

    The role of interventional radiology in the management and diagnosis of frostbite injury in 18 patients at the West Side VA Medical Center is presented. Conservative treatment and the use of intra-arterial long acting vasodilators, such as reserpine, are emphasized, even in patients referred 48 to 72 hours after the initial injury. This modality of treatment should be attempted before surgical decision or amputation is necessary. Satisfactory responses were obtained in most of the treated subjects and in some cases, results were dramatic with significant recovery and a minimum of sequelae. Generally clinical principles and physiopathology in frostbite injuries are reviewed. ImagesFigure 1Figure 2Figure 3Figure 4Figure 5 PMID:7328687

  1. Effective doping of low energy ions into superfluid helium droplets.

    PubMed

    Zhang, Jie; Chen, Lei; Freund, William M; Kong, Wei

    2015-08-21

    We report a facile method of doping cations from an electrospray ionization (ESI) source into superfluid helium droplets. By decelerating and stopping the ion pulse of reserpine and substance P from an ESI source in the path of the droplet beam, about 10(4) ion-doped droplets (one ion per droplet) can be recorded, corresponding to a pickup efficiency of nearly 1 out of 1000 ions. We attribute the success of this simple approach to the long residence time of the cations in the droplet beam. The resulting size of the doped droplets, on the order of 10(5)/droplet, is measured using deflection and retardation methods. Our method does not require an ion trap in the doping region, which significantly simplifies the experimental setup and procedure for future spectroscopic and diffraction studies.

  2. Fragment-Based Strategy for Investigating and Suppressing the Efflux of Bioactive Small Molecules.

    PubMed

    Compton, Corey L; Carney, Daniel W; Groomes, Patrice V; Sello, Jason K

    2015-01-01

    Membrane protein-mediated drug efflux is a phenomenon that compromises our ability to treat both infectious diseases and cancer. Accordingly, there is much interest in the development of strategies for suppression of the mechanisms by which therapeutic agents are effluxed. Here, using resistance to the cyclic acyldepsipeptide (ADEP) antibacterial agents as a model, we demonstrate a new counter-efflux strategy wherein a fragment of an actively exported bioactive compound competitively interferes with its efflux and potentiates its activity. A fragment comprising the N-heptenoyldifluorophenylalanine side chain of the pharmacologically optimized ADEPs potentiates the antibacterial activity of the ADEPs against actinobacteria to a greater extent than reserpine, a well-known efflux inhibitor. Beyond their validation of a new approach to studying molecular recognition by drug efflux pumps, our findings have important implications for killing Mycobacterium tuberculosis with ADEPs and reclaiming the efficacies of therapeutic agents whose activity has been compromised by efflux pumps. PMID:27620145

  3. Investigation of thin ZnO layers in view of laser desorption-ionization

    NASA Astrophysics Data System (ADS)

    Grechnikov, A. A.; Georgieva, V. B.; Alimpiev, S. S.; Borodkov, A. S.; Nikiforov, S. M.; Simanovsky, Ya O.; Dimova-Malinovska, D.; Angelov, O. I.

    2010-04-01

    Thin zinc oxide films (ZnO) were developed as a matrix-free platform for surface assisted laser desorption-ionization (SALDI) time-of-flight mass spectrometry. The ZnO films were deposited by RF magnetron sputtering of ZnO ceramic targets in Ar atmospheres on monocrystalline silicon. The generation under UV (355 nm) laser irradiation of positive ions of atenolol, reserpine and gramicidin S from the ZnO layers deposited was studied. All analytes tested were detected as protonated molecules with no or very structure-specific fragmentation. The mass spectra obtained showed low levels of chemical background noise. All ZnO films studied exhibited high stability and good reproducibility. The detection limits for test analytes are in the 10 femtomol range.

  4. Antagonism of haloperidol-induced swim impairment in L-dopa and caffeine treated mice: a pre-clinical model to study Parkinson's disease.

    PubMed

    Luthra, Pratibha Mehta; Barodia, Sandeep Kumar; Raghubir, Ram

    2009-04-15

    Parkinson's disease (PD) exhibits symptoms of motor dysfunction such as tremor, akinesia and rigidity. Agents that selectively disrupt or destroy catecholaminergic systems, such as reserpine, methamphetamine, 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine, have been used to develop PD models and to study the animal behavior like catalepsy, akinesia, swim-test, etc. The major apprehension while working with these chemicals is their irreversible neuro-toxic effect. Haloperidol is a classical antipsychotic drug, which produces extra-pyrimidal Parkinson's symptoms (EPS). Measuring catalepsy and akinesia in the treated mice monitored the haloperidol-induced EPS. Alternatively, swimming disability was tested as a new parameter to monitor haloperidol-induced EPS. The results showed that the restoration of swimming disability in haloperidol-induced L-dopa and caffeine pre-treated mice could be used as pre-clinical model to study PD.

  5. Effect of central neurotropic substances on the hypophysisadrenal cortex system during immobilization of animals

    NASA Technical Reports Server (NTRS)

    Ryzhenkov, V. Y.

    1980-01-01

    The immobilization of guinea pigs for 5, 12, 24 and 48 hours, by securing to a slab, results in a persistent rise of the blood plasma 17-oxycorticosteroid concentration. Repeated administration of phenobarbital (50 mg/kg) and of the sodium salt of gamma-oxybutyric acid (500 mg/kg), as well as the combined administration of central m- and n-cholinolytics with small doses of phenobarbital tends to inhibit activation of the adrenal cortex during 48 hour immobilization of the animals. Repeated administration of aminazine (20 mg/kg) tends to decrease activation of the adrenal cortex. The administration of reserpine (0.1-5 mg/kg) 12-18 hours before immobilization of guinea pigs increases the response of the hypophysis-adrenal cortex system.

  6. Pharmacological properties of beta-amyrin palmitate, a novel centrally acting compound, isolated from Lobelia inflata leaves.

    PubMed

    Subarnas, A; Tadano, T; Oshima, Y; Kisara, K; Ohizumi, Y

    1993-06-01

    Effects of beta-amyrin palmitate isolated from the leaves of Lobelia inflata were studied on the central nervous system of mice and were compared with those of antidepressant drugs, mianserin and imipramine. In the forced swimming test, beta-amyrin palmitate, like mianserin and imipramine, reduced the duration of immobility of mice significantly in a dose-dependent manner (5, 10 and 20 mg kg-1). beta-Amyrin palmitate (5, 10 and 20 mg kg-1) or mianserin (5, 10 and 20 mg kg-1) elicited a dose-related reduction in locomotor activity of mice and antagonized locomotor stimulation induced by methamphetamine. In contrast, imipramine (5, 10 and 20 mg kg-1) increased locomotor activity and potentiated methamphetamine-induced hyperactivity. beta-Amyrin palmitate showed no effect on reserpine-induced hypothermia, whilst mianserin (10 mg kg-1) and imipramine (10 and 20 mg kg-1) antagonized the reserpine-induced effect. Unlike imipramine, beta-amyrin palmitate and mianserin did not affect haloperidol-induced catalepsy, tetrabenazine-induced ptosis and apomorphine-induced stereotypy. beta-Amyrin palmitate and imipramine had no effects on the head-twitch response induced by 5-hydroxytryptophan, whereas mianserin (5, 10 and 20 mg kg-1) decreased it in a dose-dependent manner. A potentiating effect of beta-amyrin palmitate (5, 10 and 20 mg kg-1) on narcosis induced by sodium pentobarbitone was stronger than that of imipramine (10, 20 and 40 mg kg-1) but weaker than that of mianserin (2.5, 5 and 10 mg kg-1). These results suggest that beta-amyrin palmitate has similar properties in some respects to mianserin and might possess a sedative action.(ABSTRACT TRUNCATED AT 250 WORDS)

  7. Distribution and expression of the Ade multidrug efflux systems in Acinetobacter baumannii clinical isolates.

    PubMed

    Pagdepanichkit, Sirawit; Tribuddharat, Chanwit; Chuanchuen, Rungtip

    2016-09-01

    One hundred Acinetobacter baumannii clinical isolates were examined for inhibitory effect of reserpine and carbonyl cyanide m-chlorophenylhydrazone (CCCP) on the antimicrobial susceptibility and expression of 4 resistant-nodulation-cell division (RND)-type multidrug efflux systems, including AdeABC, AdeDE, AdeIJK, and AdeFGH, using RT-PCR. Ten A. baumannii isolates expressing AdeABC, AdeIJK, or AdeFGH were randomly selected for determination of transcription level and regulatory mutations. While all the isolates were resistant to multiple drugs, the reserpine and CCCP experiment showed that the multidrug resistance phenotype in most A. baumannii isolates was associated with efflux pumps. Most isolates expressed at least one of the RND-type efflux pumps tested (97%). AdeIJK expression was most common (97%), but none of the isolates produced AdeDE. Fifty-two percent of the A. baumannii isolates simultaneously produced up to 3 RND-type efflux systems (i.e., AdeABC, AdeFGH, and AdeIJK). No good correlation between the expression of RND-type efflux pumps and the type of antimicrobial resistance was observed. Overexpression of AdeABC, AdeIJK, and AdeFGH was not always related to the presence of mutations in their corresponding regulatory genes. This study highlights (i) the universal presence of the RND-type efflux pumps with variable levels of expression level among the A. baumannii in this collection and (ii) the complexity of their regulation of expression. PMID:27332787

  8. Myocardial kinetics of carbon-11-epinephrine in the isolated working rat heart

    SciTech Connect

    Nguyen, N.T.B.; DeGrado, T.R.; Chakraborty, P.

    1997-05-01

    The kinetics of EPI were studied in the isolated rat heart model to evaluate {sup 11}C-epinephrine (EPI) as a radiotracer for the assessment of sympathetic neuronal function in the heart. Isolated rat hearts were perfused in a working mode. Carbon-11-EPI was added to the perfusate during wash-in period of 20 min, followed by a washout period of 40 min. Radioactivity in the heart was externally monitored and time-activity curves were recorded as a function of time. Effluent samples were collected throughout each study to determine the fraction of {sup 11}C radioactivity as intact tracer. Time-activity curves of control hearts showed that {sup 11}C-EPI is taken up and retained by the myocardium. Desipramine inhibition (DMI) of uptake-1 resulted in a significant decrease in myocardial uptake and retention of {sup 11}C-EPI by 91% compared to controls. Addition of DMI to the perfusion medium during washout did not affect kinetics of {sup 11}C-EPI compared to control hearts. Reserpine pretreated rat hearts also showed significant decrease in tracer retention of 95% compared to controls. The metabolic data showed that, in control conditions, about 61% of {sup 11}C-EPI taken up by the rat heart is rapidly metabolized and released. Carbon-11-EPI traces sympathetic nerve terminals in the isolated rat heart. Uptake blockade by DMI and reserpine suggest that uptake and storage of {sup 11}C-EPI appear to be similar to that of norepinephrine. However, the prominent metabolic pathway warrants further consideration. These results suggest that {sup 11}C-EPI may be a suitable radiolabeled tracer for the evaluation of sympathetic vesicular function of the heart by PET. 23 refs., 3 figs., 3 tabs.

  9. Pharmacology of bevantolol hydrochloride.

    PubMed

    Kaplan, H R

    1986-11-26

    Bevantolol is a cardioselective, beta-adrenoreceptor antagonist, devoid of intrinsic beta sympathomimetic activity and with weak membrane-stabilizing and local anesthetic properties. The 3,4-dimethoxyphenylethylamino moiety, substituted on the side chain amine function, confers cardioselectivity, which has been confirmed by a number of experiments. In vitro, bevantolol demonstrated greater antagonism of atrial than tracheal responses to isoproterenol. In vivo, bevantolol preferentially inhibited isoproterenol-induced tachycardias in conscious and anesthetized dogs, compared with the nonselective agent propranolol. Conversely, its effect on blood pressure after isoproterenol was minimal compared with propranolol, reflecting its muted effect on beta 2 peripheral receptors. A functional difference between bevantolol and propranolol was demonstrated in histamine-challenged guinea pigs. Bevantolol had little effect on the antiasthmatic effect of isoproterenol, whereas propranolol blocked it totally. Bevantolol's lack of intrinsic sympathomimetic activity was demonstrated in normal and reserpinized dogs, where it was devoid of intrinsic sympathomimetic activity at doses up to 10 mg/kg. Similarly, intravenous doses of 10 mg/kg had to be administered before direct myocardial depression occurred in the reserpinized animals. Metabolite 3, which is excreted in trace amounts in human urine, demonstrates intrinsic sympathomimetic activity when administered in pharmacologic doses to dogs; however, any clinical relevance remains to be established. Several laboratories have demonstrated that bevantolol interacts at alpha-adrenergic sites. These data require further investigation. The dose-related antihypertensive effect of bevantolol has been demonstrated in spontaneously hypertensive and 2 kidney, 1 clip renal hypertensive rats. Animal experiments also suggest that bevantolol may be useful in angina: It caused a favorable redistribution of blood flow in dogs in which the left

  10. Molecular Analysis of Rising Fluoroquinolone Resistance in Belgian Non-Invasive Streptococcus pneumoniae Isolates (1995-2014).

    PubMed

    Ceyssens, Pieter-Jan; Van Bambeke, Françoise; Mattheus, Wesley; Bertrand, Sophie; Fux, Frédéric; Van Bossuyt, Eddie; Damée, Sabrina; Nyssen, Henry-Jean; De Craeye, Stéphane; Verhaegen, Jan; Tulkens, Paul M; Vanhoof, Raymond

    2016-01-01

    We present the results of a longitudinal surveillance study (1995-2014) on fluoroquinolone resistance (FQ-R) among Belgian non-invasive Streptococcus pneumoniae isolates (n = 5,602). For many years, the switch to respiratory fluoroquinolones for the treatment of (a)typical pneumonia had no impact on FQ-R levels. However, since 2011 we observed a significant decrease in susceptibility towards ciprofloxacin, ofloxacin and levofloxacin with peaks of 9.0%, 6.6% and 3.1% resistant isolates, respectively. Resistance to moxifloxacin arised sporadically, and remained <1% throughout the entire study period. We observed classical topoisomerase mutations in gyrA (n = 25), parC (n = 46) and parE (n = 3) in varying combinations, arguing against clonal expansion of FQ-R. The impact of recombination with co-habiting commensal streptococci on FQ-R remains marginal (10.4%). Notably, we observed that a rare combination of DNA Gyrase mutations (GyrA_S81L/GyrB_P454S) suffices for high-level moxifloxacin resistance, contrasting current model. Interestingly, 85/422 pneumococcal strains display MICCIP values which were lowered by at least four dilutions by reserpine, pointing at involvement of efflux pumps in FQ-R. In contrast to susceptible strains, isolates resistant to ciprofloxacin significantly overexpressed the ABC pump PatAB in comparison to reference strain S. pneumoniae ATCC 49619, but this could only be linked to disruptive terminator mutations in a fraction of these. Conversely, no difference in expression of the Major Facilitator PmrA, unaffected by reserpine, was noted between susceptible and resistant S. pneumoniae strains. Finally, we observed that four isolates displayed intermediate to high-level ciprofloxacin resistance without any known molecular resistance mechanism. Focusing future molecular studies on these isolates, which are also commonly found in other studies, might greatly assist in the battle against rising pneumococcal drug resistance. PMID:27227336

  11. Overexpression of the Novel MATE Fluoroquinolone Efflux Pump FepA in Listeria monocytogenes Is Driven by Inactivation of Its Local Repressor FepR

    PubMed Central

    Guérin, François; Galimand, Marc; Tuambilangana, Fabrice; Courvalin, Patrice; Cattoir, Vincent

    2014-01-01

    Whereas fluoroquinolone resistance mainly results from target modifications in gram-positive bacteria, it is primarily due to active efflux in Listeria monocytogenes. The aim of this study was to dissect a novel molecular mechanism of fluoroquinolone resistance in this important human pathogen. Isogenic L. monocytogenes clinical isolates BM4715 and BM4716, respectively susceptible and resistant to fluoroquinolones, were studied. MICs of norfloxacin and ciprofloxacin were determined in the presence or in the absence of reserpine (10 mg/L). Strain BM4715 was susceptible to norfloxacin (MIC, 4 mg/L) and ciprofloxacin (MIC, 0.5 mg/L) whereas BM4716 was highly resistant to both drugs (MICs 128 and 32 mg/L, respectively). Reserpine was responsible for a 16-fold decrease in both norfloxacin and ciprofloxacin MICs against BM4716 suggesting efflux associated resistance. Whole-genome sequencing of the strains followed by comparative genomic analysis revealed a single point mutation in the gene for a transcriptional regulator, designated fepR (for fluoroquinolone efflux protein regulator) belonging to the TetR family. The frame-shift mutation was responsible for the introduction of a premature stop codon resulting in an inactive truncated protein. Just downstream from fepR, the structural gene for an efflux pump of the MATE family (named FepA) was identified. Gene expression was quantified by qRT-PCR and demonstrated that fepA expression was more than 64-fold higher in BM4716 than in BM4715. The clean deletion of the fepR gene from BM4715 was responsible for an overexpression of fepA with resistance to norfloxacin and ciprofloxacin, confirming the role of FepR as a local repressor of fepA. In conclusion, we demonstrated that overexpression of the new MATE efflux pump FepA is responsible for fluoroquinolone resistance in L. monocytogenes and secondary to inactivation of the FepR repressor. PMID:25188450

  12. Voltage-Sensitive K+ Channels Inhibit Parasympathetic Ganglion Transmission and Vagal Control of Heart Rate in Hypertensive Rats

    PubMed Central

    Berg, Torill

    2015-01-01

    Parasympathetic withdrawal plays an important role in the autonomic dysfunctions in hypertension. Since hyperpolarizing, voltage-sensitive K+ channels (KV) hamper transmitter release, elevated KV-activity may explain the disturbed vagal control of heart rate (HR) in hypertension. Here, the KV inhibitor 3,4-diaminopyridine was used to demonstrate the impact of KV on autonomic HR control. Cardiac output and HR were recorded by a flow probe on the ascending aorta in anesthetized, normotensive (WKY), and spontaneously hypertensive rats (SHR), and blood pressure by a femoral artery catheter. 3,4-diaminopyridine induced an initial bradycardia, which was greater in SHR than in WKY, followed by sustained tachycardia in both strains. The initial bradycardia was eliminated by acetylcholine synthesis inhibitor (hemicholinium-3) and nicotinic receptor antagonist/ganglion blocker (hexamethonium), and reversed to tachycardia by muscarinic receptor (mAchR) antagonist (atropine). The latter was abolished by sympatho-inhibition (reserpine). Reserpine also eliminated the late, 3,4-diaminopyridine-induced tachycardia in WKY, but induced a sustained atropine-sensitive bradycardia in SHR. Inhibition of the parasympathetic component with hemicholinium-3, hexamethonium, or atropine enhanced the late tachycardia in SHR, whereas hexamethonium reduced the tachycardia in WKY. In conclusion, 3,4-diaminopyridine-induced acetylcholine release, and thus enhanced parasympathetic ganglion transmission, with subsequent mAchR activation and bradycardia. 3,4-diaminopyridine also activated tachycardia, initially by enhancing sympathetic ganglion transmission, subsequently by activation of norepinephrine release from sympathetic nerve terminals. The 3,4-diaminopyridine-induced parasympathetic activation was stronger and more sustained in SHR, demonstrating an enhanced inhibitory control of KV on parasympathetic ganglion transmission. This enhanced KV activity may explain the dysfunctional vagal HR

  13. Neuronal uptake and metabolism of 2- and 6-fluorodopamine: false neurotransmitters for positron emission tomographic imaging of sympathetically innervated tissues

    SciTech Connect

    Eisenhofer, G.; Hovevey-Sion, D.; Kopin, I.J.; Miletich, R.; Kirk, K.L.; Finn, R.; Goldstein, D.S.

    1989-01-01

    The neuronal uptake and metabolism of 2-fluorodopamine (2F-dopamine), 6-fluorodopamine (6F-dopamine) and tritium-labeled dopamine were compared in heart, submaxillary gland and spleen of rats to assess the utility of 18F-labeled 2F- or 6F-dopamine for positron emission tomographic imaging of sympathetically innervated tissues. Tritiated dopamine with and without 2F- or 6F-dopamine, or tritiated 2F-dopamine alone, were injected i.v. into rats that were or were not pretreated with desipramine to block catecholamine neuronal uptake or with reserpine to block vesicular translocation of catecholamines. Tissue and plasma samples were obtained at intervals up to 1 hr after injections. At 1 hr after injection of tritiated dopamine, tritium-labeled norepinephrine, dopamine, dihydroxyphenylacetic acid and dihydroxyphenylglucol accounted for less than 2% of the tritium in plasma but up to 92% of that in tissues; tritiated norepinephrine accounted for 70% or more of the tritium in tissues. In contrast, at 1 hr after injection of tritiated 2F-dopamine, tritiated 2F-norepinephrine accounted for 30 to 46% of the tritium in tissues. Desipramine and reserpine pretreatment blocked the tissue accumulation of tritiated and fluorinated dopamine as well as their dihydroxy-metabolites, indicating that accumulation of exogenous norepinephrine and dopamine analogs was within sympathetic storage vesicles. Relative to the doses of dopamine precursors, less 2F- and 6F-norepinephrine accumulated in tissues than tritiated norepinephrine, due largely to inefficient beta-hydroxylation of fluorinated dopamine.

  14. [A unique psychopharmacologic profile of adrafinil in mice].

    PubMed

    Rambert, F A; Pessonnier, J; de Sereville, J E; Pointeau, A M; Duteil, J

    1986-01-01

    The following psychopharmacological effects of adrafinil have been observed in mice: increase in locomotor activity (64-256 mg.kg-1), antagonism (16-128 mg.kg-1) of the hypnotic effects of barbitone but not of pentobarbitone, reduction of immobility duration in the forced swimming test (16-256 mg.kg-1); slight antagonism (256 mg.kg-1) of electroshock-induced convulsions; no modification of rectal temperature; no stereotyped or climbing behaviour; no increase in lethality in aggregated mice (LD50 isolated = 1022 mg.kg-1, LD50 aggregated = 859 mg.kg-1); lack of effects on the provisional tests for antidepressants: no interaction with reserpine-, oxotremorine-, or apomorphine-induced hypothermia but potentiation of yohimbine-induced toxicity; lack of peripheral sympathetic effects (no mydriasis, no salivation, no contraction of the pilomotor muscles, no antagonism of reserpine-induced ptosis); lack of peripheral anticholinergic effects (no mydriasis, no antagonism of oxotremorine-induced salivation or lacrimation). As compared to no analeptic, anticholinergic or antidepressant drugs, adrafinil shows a unique behavioural profile in mice defined on the one hand by a specific stimulant activity associated with antidepressant-like effects that do no seem related to a beta-adrenergic mechanism and on the other hand by a lack of dopaminergic effects. Most adrafinil-induced effects (increase in locomotor activity, reduction of immobility duration in the forced swimming test) may correspond to a central alpha 1-adrenergic stimulation, but the unexpected lack of peripheral sympathetic effects remains unexplained. PMID:3713198

  15. Is it possible to predict the activity of a new antidepressant in animals with simple psychopharmacological tests?

    PubMed

    Bourin, M

    1990-01-01

    Behavioural tests for predicting antidepressant activity in the animal provide a closer approximation than other tests of states of depression in man but are often long and costly to perform (except the behavioural despair test). The tests proposed here presuppose a pharmacological interaction (except the Porsolt test) but are simple enough to allow screening: included are antagonism of reserpine hypothermia, ptosis and akinesia; antagonism of effects induced by oxotremorine; antagonism of high-dose apomorphine; and potentiation of yohimbine toxicity. In combination with the study of motor activity in the mouse, these tests allow assessment of the specificity of antidepressant activity by establishing a ratio between the "antidepressant" dose and the "stimulant" or "sedative" dose. It can be predicted that a substance will be antidepressant and sedative or stimulant at the same dose if the ratio is close to 1; if the ratio is less than 1, at antidepressant doses the substance will be very sedative or stimulant according to the case. The specificity of the tests discussed can be debatable. Antagonism of reserpine-induced hypothermia indicates substances with direct or indirect beta-mimetic activity, ptosis antagonism, substances with alpha-adrenergic (not antidepressants) or serotoninergic (possibly antidepressants) activity; and akinesia antagonism, a direct or indirect dopaminergic activity (sometimes found in antidepressants) with psychostimulant activity. The oxotremorine test is related to the anticholinergic activity of substances, except in the case of hypothermia antagonism. The high-dose apomorphine test seems to be specific for substances inhibiting norepinephrine reuptake. The yohimbine test is simple to carry out, relatively inexpensive and does not fail to screen any molecule known to be effective to-date. The behavioural despair test is a good complement for screening except for drugs having a beta-agonist activity, it appears that this test is

  16. Antidepressant-like activity of sildenafil following acute and subchronic treatment in the forced swim test in mice: effects of restraint stress and monoamine depletion.

    PubMed

    Socała, Katarzyna; Nieoczym, Dorota; Pieróg, Mateusz; Szuster-Ciesielska, Agnieszka; Wyska, Elżbieta; Wlaź, Piotr

    2016-10-01

    Sildenafil is a highly effective oral agent for the treatment of erectile dysfunction of multiple etiologies. Although in clinical practice sildenafil is often used in depressed patients, its influence on the pathophysiology of depression remains unclear. The aim of the present study was to evaluate the antidepressant-like activity following acute and subchronic treatment with sildenafil in naïve mice as well as in mice with reserpine- and restraint stress-induced depressive-like behavior. Since corticosterone is released in response to acute stress, we also aimed to assess the influence of sildenafil on serum corticosterone level in non-stressed and stressed animals. The antidepressant activity of sildenafil was assessed in the forced swim test. Corticosterone serum level was determined by using ELISA method, while brain and serum sildenafil level via HPLC method. Sildenafil administered acutely exerted an antidepressant-like effect. Subchronic (14 days) administration of sildenafil resulted only in a weak antidepressant-like effect when evaluated 24 h after the last dose. Acute but not subchronic sildenafil administration reversed the reserpine- and stress-induced immobility in the forced swim test. The lack of effects of sildenafil after subchronic treatment could have been related to its complete elimination from the brain within 24 h from the last injection. Interestingly, acute administration of sildenafil produced a marked increase in serum corticosterone level in both non-stressed and stressed animals. Sildenafil exerts differential effects in the forced swim test after acute and subchronic administration. Further studies on the antidepressant activity of sildenafil are required. PMID:27283174

  17. Occupancy of dopamine D2/3 receptors in rat brain by endogenous dopamine measured with the agonist positron emission tomography radioligand [11C]MNPA.

    PubMed

    Seneca, Nicholas; Zoghbi, Sami S; Skinbjerg, Mette; Liow, Jeih-San; Hong, Jinsoo; Sibley, David R; Pike, Victor W; Halldin, Christer; Innis, Robert B

    2008-10-01

    Estimates of dopamine D(2/3) receptor occupancy by endogenous dopamine using positron emission tomography (PET) in animals have varied almost threefold. This variability may have been caused by incomplete depletion of dopamine or by the use of antagonist radioligands, which appear less sensitive than agonist radioligands to changes in endogenous dopamine. PET scans were performed in rats with the agonist PET radioligand [(11)C]MNPA ([O-methyl-(11)C]2-methoxy-N-propylnorapomorphine). [(11)C]MNPA was injected as a bolus plus constant infusion to achieve steady-state concentration in the body and equilibrium receptor binding in the brain. Radioligand binding was compared at baseline and after treatment with reserpine plus alpha-methyl-para-tyrosine, which cause approximately 95% depletion of endogenous dopamine. Depletion of dopamine increased radioligand binding in striatum but had little effect in cerebellum. Striatal [(11)C]MNPA binding potential was 0.93 +/- 0.12 at baseline and increased to 1.99 +/- 0.25 after dopamine depletion. Occupancy of D(2/3) receptors by endogenous dopamine at baseline was calculated to be approximately 53%. Striatal binding was displaceable with raclopride, but not with BP 897 (a selective D(3) compound), thus confirming the D(2) receptor specificity of [(11)C]MNPA binding. Radioactivity extracted from rat brain contained only 8-10% radiometabolites and was insignificantly altered by administration of reserpine plus alpha-methyl-para-tyrosine. Hence, dopamine depletion did not increase the PET measurements via an effect on radiotracer metabolism. Our in vivo estimate of dopamine's occupancy of D(2/3) receptors at baseline is higher than that previously reported using antagonist radioligands and PET, but is similar to that reported using agonist radioligands and ex vivo measurements.

  18. Molecular Analysis of Rising Fluoroquinolone Resistance in Belgian Non-Invasive Streptococcus pneumoniae Isolates (1995-2014)

    PubMed Central

    Ceyssens, Pieter-Jan; Van Bambeke, Françoise; Mattheus, Wesley; Bertrand, Sophie; Fux, Frédéric; Van Bossuyt, Eddie; Damée, Sabrina; Nyssen, Henry-Jean; De Craeye, Stéphane; Verhaegen, Jan; Tulkens, Paul M.; Vanhoof, Raymond

    2016-01-01

    We present the results of a longitudinal surveillance study (1995–2014) on fluoroquinolone resistance (FQ-R) among Belgian non-invasive Streptococcus pneumoniae isolates (n = 5,602). For many years, the switch to respiratory fluoroquinolones for the treatment of (a)typical pneumonia had no impact on FQ-R levels. However, since 2011 we observed a significant decrease in susceptibility towards ciprofloxacin, ofloxacin and levofloxacin with peaks of 9.0%, 6.6% and 3.1% resistant isolates, respectively. Resistance to moxifloxacin arised sporadically, and remained <1% throughout the entire study period. We observed classical topoisomerase mutations in gyrA (n = 25), parC (n = 46) and parE (n = 3) in varying combinations, arguing against clonal expansion of FQ-R. The impact of recombination with co-habiting commensal streptococci on FQ-R remains marginal (10.4%). Notably, we observed that a rare combination of DNA Gyrase mutations (GyrA_S81L/GyrB_P454S) suffices for high-level moxifloxacin resistance, contrasting current model. Interestingly, 85/422 pneumococcal strains display MICCIP values which were lowered by at least four dilutions by reserpine, pointing at involvement of efflux pumps in FQ-R. In contrast to susceptible strains, isolates resistant to ciprofloxacin significantly overexpressed the ABC pump PatAB in comparison to reference strain S. pneumoniae ATCC 49619, but this could only be linked to disruptive terminator mutations in a fraction of these. Conversely, no difference in expression of the Major Facilitator PmrA, unaffected by reserpine, was noted between susceptible and resistant S. pneumoniae strains. Finally, we observed that four isolates displayed intermediate to high-level ciprofloxacin resistance without any known molecular resistance mechanism. Focusing future molecular studies on these isolates, which are also commonly found in other studies, might greatly assist in the battle against rising pneumococcal drug resistance. PMID:27227336

  19. The hyperglycaemic effect of morphine

    PubMed Central

    Feldberg, W.; Shaligram, S. V.

    1972-01-01

    1. In the unanaesthetized cat, an injection of 0·75 mg of morphine into a lateral cerebral ventricle produced strong hyperglycaemia; on intravenous injection, 10 to 30 times larger doses were required. Other effects produced with both injections were shivering, pupillary dilatation, opening of the eyes, miaowing, periods of excitation, and analgesia. Between the periods of excitation the cat did not react to objects moving in front of its eyes and it had a vacant stare. 2. Noradrenaline, adrenaline, and 5-hydroxytryptamine (5-HT) injected intraventricularly (250 μg, twice) depressed the hyperglycaemia due to intraventricular morphine, and noradrenaline also depressed the hyperglycaemia due to intravenous morphine. Adrenaline produced the strongest and 5-HT the weakest depression. 5-HT did not depress the other effects of morphine, but the catecholamines depressed most of them; only analgesia and the vacant stare appeared to be unaffected. 3. Reserpine injected intraventricularly (0·5 mg, twice) greatly accentuated the hyperglycaemia as well as the other effects produced by intraventricular morphine, but pupillary dilatation and opening of the eyes no longer occurred; the protrusion of the nictitating membranes produced by the reserpine persisted. 4. Pentobarbitone sodium injected intraperitoneally in an anaesthetizing dose practically abolished the morphine hyperglycaemia, but injected intraventricularly in a dose of a few milligrammes, it had a two fold effect: depression followed by enhancement of the morphine hyperglycaemia. The enhancement may be due to sensitization of the effect of the adrenaline released by morphine, since adrenaline hyperglycaemia was enhanced as well. 5. Morphine did not seem to act on structures in the walls of either the lateral or third ventricle when producing its hyperglycaemic effect on intraventricular injection. The action may therefore be on more caudally situated parts of the neuro-axis, on the central grey, on structures in

  20. Gastric anti-ulcer and cytoprotective effect of selenium in rats

    SciTech Connect

    Parmar, N.S.; Tariq, M.; Ageel, A.M.

    1988-01-01

    Selenium, a trace element, in the form of sodium selenite has been studied for its ability to protect the gastric mucosa against the injuries caused by hypothermic restraint stress, aspirin, indomethacin, reserpine, dimaprit, and various other gastric mucosal-damaging (necrotizing) agents in rats. The results demonstrate that oral administration of sodium selenite produces a significant inhibition of the gastric mucosal damage induced by all the procedures used in this study. Selenium, in a nonantisecretory dose, produced a marked cytoprotective effect against all the necrotizing agents. The cytoprotective effect of selenium against the effects of 80% ethanol and 0.6 M HCl was significantly reversed by prior treatment with a dose of indomethacin that inhibits prostaglandin biosynthesis. These data indicate that sodium selenite inhibits the formation of these lesions by the mucosal generation of prostaglandins. The concentrations of nonprotein sulfhydryls (NP-SH) were significantly decreased in the gastric mucosa following the administration of necrotizing agents--80% ethanol and 0.6 M HCl. Treatment with sodium selenite, which significantly reduced the intensity of gastric lesions, did not replenish the reduced levels of gastric mucosal NP-SH, thus ruling out the mediation of its protective effect through sulfhydryls. The antisecretory effect of sodium selenite, which becomes evident only in the high dose of 20 mumol/kg, may be responsible for the inhibition of gastric lesions induced by aspirin, indomethacin, reserpine, and dimaprit. Our findings show that selenium possesses significant anti-ulcer and adaptive cytoprotective effects. However, further detailed studies are required to confirm these effects, to establish its mechanism(s) of action, and to determine its role in the prophylaxis and treatment of peptic ulcer disease.

  1. Characteristics of the internal anal sphincter and the rectum of the vervet monkey.

    PubMed Central

    Rayner, V

    1979-01-01

    1. The physiology of the internal anal sphincter of the vervet monkey was investigated. 2. Strips of sphincter in vitro contracted to noradrenaline and adrenaline; adrenoceptors were mainly alpha-excitatory. Strips of rectal circular muscle relaxed to noradrenaline and contained both inhibitory alpha- and beta-adrenoceptors. 3. All strips contracted to acetylcholine. After hyoscine or atropine, high doses of acetylcholine relaxed all strips by stimulating intramural inhibitory neurones as relaxations were blocked by tetrodotoxin and hexamethonium. Nicotine and DMPP gave relaxations with similar characteristics. 4. It was concluded that relaxations to acetylcholine, nicotine and DMPP were not adrenergic as relaxations still occurred in strips from sympathetically denervated or reserpinized animals. The block of these relaxations by propranolol and guanethidine was considered to be unrelated to their actions as adrenergic blocking drugs. 5. All strips relaxed to field electrical stimulation (1--5 Hz) through stimulation of intramural inhibitory neurones as tetrodotoxin blocked these relaxations. Adrenergic blocking drugs, prior reserpinization or prior section of the hypogastric nerves did not block these responses. The relaxations were not therefore adrenergic. 6. 5-Hydroxytryptamine relaxed all strips but was not the transmitter in relaxations to acetylcholine, DMPP or nicotine, nor to field electrical stimulation, as desensitization of strips of 5-HT did not alter these responses. 7. The circular smooth muscle of the internal anal sphincter had a dense terminal adrenergic innervation which rapidly decreased orad. 8. In vivo, hypogastric nerve stimulation relaxed the rectum but contracted the sphincter. Sacral nerve root stimulation caused an after-contraction in both rectum and sphincter. In vivo, a close arterial injection of adrenaline or noradrenaline inhibited the spontaneous contraction waves of the rectum, but contracted the sphincter. Both these responses

  2. A new dopamine-β-hydroxylase inhibitor

    PubMed Central

    Andén, N. -E.; Fuxe, K.

    1971-01-01

    1. The dopamine-β-hydroxylase inhibitor bis(4-methyl-1-homopiperazinyl-thiocarbonyl) disulphide (FLA-63; 25 mg/kg i.p.) caused within 4 h a 65% loss of noradrenaline throughout the intact rat spinal cord and also cranial to a transection of the cut spinal cord. Caudal to the lesion, there was only an insignificant depletion of 17% indicating the importance of nerve impulses for the disappearance of noradrenaline. 2. Dopamine accumulated in the spinal cord after treatment with FLA-63 although the amounts were not sufficient to replace the missing noradrenaline. Even after treatment with L-3,4-dihydroxyphenylalanine (L-DOPA), the catecholamine store was incompletely replenished by dopamine. 3. After a large depletion of the noradrenaline stores, induced by repeated doses of FLA-63 or by reserpine plus FLA-63, the L-DOPA-induced increase in flexor reflex activity of the hind limbs of spinal rats was inhibited much more than after pretreatment with α-methyl-tyrosine or reserpine. FLA-63 blocked the formation of noradrenaline but not of dopamine from L-DOPA. 4. The increase in flexor reflex activity induced by the noradrenaline receptor stimulating agent clonidine was not changed by FLA-63, indicating that the noradrenaline receptor sensitivity was not influenced. 5. After depletion of the noradrenaline stores, the small formation of noradrenaline from L-DOPA may be of greater functional significance for the noradrenaline receptor stimulation than the greater formation of dopamine, but the dopamine formed also has a slight action. With intact noradrenaline stores, displacement of endogenous noradrenaline by newly formed dopamine contributes, at least after monoamine oxidase inhibition, to the increase in the flexor reflex activity caused by L-DOPA. PMID:4339882

  3. Antidepressant-like activity of sildenafil following acute and subchronic treatment in the forced swim test in mice: effects of restraint stress and monoamine depletion.

    PubMed

    Socała, Katarzyna; Nieoczym, Dorota; Pieróg, Mateusz; Szuster-Ciesielska, Agnieszka; Wyska, Elżbieta; Wlaź, Piotr

    2016-10-01

    Sildenafil is a highly effective oral agent for the treatment of erectile dysfunction of multiple etiologies. Although in clinical practice sildenafil is often used in depressed patients, its influence on the pathophysiology of depression remains unclear. The aim of the present study was to evaluate the antidepressant-like activity following acute and subchronic treatment with sildenafil in naïve mice as well as in mice with reserpine- and restraint stress-induced depressive-like behavior. Since corticosterone is released in response to acute stress, we also aimed to assess the influence of sildenafil on serum corticosterone level in non-stressed and stressed animals. The antidepressant activity of sildenafil was assessed in the forced swim test. Corticosterone serum level was determined by using ELISA method, while brain and serum sildenafil level via HPLC method. Sildenafil administered acutely exerted an antidepressant-like effect. Subchronic (14 days) administration of sildenafil resulted only in a weak antidepressant-like effect when evaluated 24 h after the last dose. Acute but not subchronic sildenafil administration reversed the reserpine- and stress-induced immobility in the forced swim test. The lack of effects of sildenafil after subchronic treatment could have been related to its complete elimination from the brain within 24 h from the last injection. Interestingly, acute administration of sildenafil produced a marked increase in serum corticosterone level in both non-stressed and stressed animals. Sildenafil exerts differential effects in the forced swim test after acute and subchronic administration. Further studies on the antidepressant activity of sildenafil are required.

  4. Effect of venlafaxine on experimental colitis in normal and reserpinised depressed rats

    PubMed Central

    Minaiyan, Mohsen; Hajhashemi, Valiollah; Rabbani, Mohammad; Fattahian, Ehsan; Mahzouni, Parvin

    2015-01-01

    Psychological disorders such as depression have more prevalence in inflammatory bowel disease patients and can exacerbate the clinical course of the disease, so anti-depressant therapy may have a potential to positively impact the disease course. On the other hand several antidepressant drugs have shown anti-inflammatory and immunomodulatory properties. Thus, this study aimed to explore the beneficial effects of venlafaxine on experimental colitis in normal and reserpinised depressed rats. Acetic acid colitis was induced in both reserpinised and non-reserpinised rats. Reserpinised groups received reserpine at dose of 6 mg/kg i.p.1 h prior to colitis induction and then treated with venlafaxine at doses of 10, 20, 40 mg/kg given i.p. 2 h after induction of colitis and daily for 4 consecutive days. Non-reserpinised groups treated with 10, 20, 40 mg/kg venlafaxine i.p. 2 h after the induction of colitis and daily for 4 successive days. Dexamethasone (1 mg/kg, i.p.) was used as reference drug. Colonic inflammation was evaluated using macroscopic, histological and myeloperoxidase activity measurements. Results showed that reserpine at dose of 6 mg/kg exacerbated the colitis damage. Compared to acetic acid control, venlafaxine at dose of 40 mg/kg as well as dexamethasone significantly improved colitis parameters in both reserpinised and non-reserpinised animals. Venlafaxine reduced inflammatory injury in this animal model of induced ulcerative colitis. These effects are probably mediated first through depressive behavioral changes that could be mediated through the brain-gut axis and second for the anti-inflammatory effect of the drug. PMID:26600857

  5. Prevalence and Antimicrobial Resistance of Enterococcus Species: A Hospital-Based Study in China

    PubMed Central

    Jia, Wei; Li, Gang; Wang, Wen

    2014-01-01

    Objective: to investigate the prevalence and antimicrobial resistance of Enterococcus species isolated from a university hospital, and explore the mechanisms underlying the antimicrobial resistance, so as to provide clinical evidence for the inappropriate clinical use of antimicrobial agents and the control and prevention of enterococcal infections. Methods: a total of 1,157 enterococcal strains isolated from various clinical specimens from January 2010 to December 2012 in the General Hospital of Ningxia Medical University were identified to species level with a VITEK-2 COMPACT fully automated microbiological system, and the antimicrobial susceptibility of Enterococcus species was determined using the Kirby-Bauer disc diffusion method. The multiple-drug resistant enterococcal isolates were screened from the clinical isolates of Enterococcus species from the burns department. The minimal inhibitory concentration (MIC) of Enterococcus species to the three fluoroquinolones, including ciprofloxacin, gatifloxacin and levofloxacin was determined with the agar dilution method, and the changes in the MIC of Enterococcus species to the three fluoroquinolones following reserpine treatment were evaluated. The β-lactam, aminoglycoside, tetracycline, macrolide, glycopeptide resistance genes and the efflux pump emeA genes were detected in the enterococcal isolates using a polymerase chain reaction (PCR) assay. Results: the 1,157 clinical isolates of Enterococcus species included 679 E. faecium isolates (58.7%), 382 E. faecalis isolates (33%), 26 E. casseliflavus isolates (2.2%), 24 E. avium isolates (2.1%), and 46 isolates of other Enterococcus species (4%). The prevalence of antimicrobial resistance varied significantly between E. faecium and E. faecalis, and ≤1.1% of these two Enterococcus species were found to be resistant to vancomycin, teicoplanin or linezolid. In addition, the Enterococcus species isolated from different departments of the hospital exhibited various

  6. Norzotepine, a major metabolite of zotepine, exerts atypical antipsychotic-like and antidepressant-like actions through its potent inhibition of norepinephrine reuptake.

    PubMed

    Shobo, M; Kondo, Y; Yamada, H; Mihara, T; Yamamoto, N; Katsuoka, M; Harada, K; Ni, K; Matsuoka, N

    2010-06-01

    The antipsychotic drug zotepine [ZTP; 2-[(8-chlorodibenzo[b,f]thiepin-10-yl)oxy]-N,N-dimethylethan-1-amine] is known to have not only atypical antipsychotic effects but also antidepressive effects in schizophrenia patients. Norzotepine [norZTP; N-desmethylzotepine, 2-[(8-chlorodibenzo[b,f]thiepin-10-yl)oxy]-N-methylethan-1-amine] has been postulated to be a major metabolite of ZTP in humans. Here, we characterized norZTP through several in vitro studies and in animal models of psychosis, depression, and extrapyramidal symptoms (EPS) and compared the pharmacological profiles with those of ZTP. Although both compounds showed similar overall neurotransmitter receptor binding profiles, norZTP showed 7- to 16-fold more potent norepinephrine reuptake inhibition than ZTP. In a pharmacokinetic study, both ZTP and norZTP showed good brain permeability when administered individually in mice, although norZTP was not detected in either plasma or brain after intraperitoneal injection of ZTP. In the methamphetamine-induced hyperlocomotion test in mice, norZTP and ZTP showed similar antipsychotic-like effects at doses above 1 mg/kg i.p. In contrast, unlike ZTP, norZTP did not induce catalepsy up to 10 mg/kg i.p. norZTP significantly antagonized the hypothermia induced by reserpine [(3beta,16beta,17alpha,18beta,20alpha)-11,17-dimethoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]yohimban-16-carboxylic acid methyl ester], suggesting in vivo inhibition of the norepinephrine transporter. In the forced-swim test, norZTP exerted an antidepressant-like effect at the effective doses for its antipsychotic action, whereas ZTP neither antagonized reserpine-induced hypothermia nor showed antidepressant-like effect. These results collectively demonstrate that norZTP exerts more potent inhibitory action than ZTP on norepinephrine transporters both in vitro and in vivo, presumably accounting for its antidepressant-like effect and low EPS propensity. Given that norZTP is the major metabolite observed in

  7. Evaluation of the analgesic effects of ammoxetine, a novel potent serotonin and norepinephrine reuptake inhibitor

    PubMed Central

    Zhang, Ting-ting; Xue, Rui; Zhu, Lei; Li, Juan; Fan, Qiong-yin; Zhong, Bo-hua; Li, Yun-feng; Ye, Cai-ying; Zhang, You-zhi

    2016-01-01

    Aim: The selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitors (SNRIs) are commonly used for the treatment of neuropathic pain and fibromyalgia. Ammoxetine ((±)-3-(benzo[d] [1,3]dioxol-4-yloxy)-N-methyl-3-(thiophen-2-yl)propan-1-amine) has been identified as a novel potent SNRI. In this study, we evaluated the acute analgesic properties of ammoxetine in different animal models of pain, and examined the involvement of monoamines in its analgesic actions. Methods: The analgesic effects of ammoxetine were assayed using models of acetic acid- and formalin-induced pain in mice, neuropathic pain induced by sciatic nerve injury (SNI), chronic constriction injury (CCI) and reserpine-induced fibromyalgia pain in rats. The contents of 5-HT and NE in brain regions of fibromyalgia rats were measured using HPLC-ECD. In all the experiments, duloxetine was used as a positive control drug. Results: Oral administration of ammoxetine (0.625–10 mg/kg) or duloxetine (2.5–40 mg/kg) dose-dependently decreased the number of acetic acid-induced writhing and formalin-induced first phase and second phase paw licking time in mice. Oral administration of ammoxetine (2.5–10 mg/kg) or duloxetine (10 mg/kg) alleviated mechanical allodynia in SNI and CCI rats and thermal hyperalgesia in CCI rats. The antiallodynic effect of ammoxetine in CCI rats was abolished by pretreatment with para-chlorophenylalanine methyl ester hydrochloride (PCPA, a 5-HT synthesis inhibitor) or α-methyl-para-tyrosine methylester (AMPT, a catecholamine synthesis inhibitor). Oral administration of ammoxetine (30 mg/kg) or duloxetine (50 mg/kg) significantly attenuated tactile allodynia in rats with reserpine-induced fibromyalgia. In the fibromyalgia rats, administration of ammoxetine (10, 30 mg/kg) or duloxetine (30, 50 mg/kg) dose-dependently increased the levels of 5-HT and NE, and decreased the metabolite ratio of 5-HT (5-HIAA/5-HT) in the spinal cord, hypothalamus, thalamus and prefrontal cortex

  8. Cardiovascular effects of the novel histamine H2 receptor agonist amthamine: interaction with the adrenergic system.

    PubMed

    Coruzzi, G; Gambarelli, E; Bertaccini, G; Timmerman, H

    1996-03-01

    The cardiovascular effects of the new histamine H2 receptor agonist amthamine were studied in the anaesthetized rat, with particular reference to a possible interaction with the adrenergic system. Amthamine (0.03-3 mumol/kg i.v.) caused vasodepressor responses which were antagonized by famotidine (3 mumol/kg i.v.). At higher doses (30-100 mumol/kg i.v.), amthamine induced a modest increase in the mean arterial pressure, which was significantly enhanced by the blockade of H2 receptors and significantly reduced by the alpha 2 adrenoceptor antagonist yohimbine (1 mumol/kg i.v.). The vasopressor response to amthamine was not modified in rats pre-treated with reserpine or 6-hydroxydopamine, and was only minimally modified in adrenalectomized animals, thus suggesting a predominant interaction with postjunctional alpha 2 adrenoceptors in the vascular muscle. The H2 receptor agonist dimaprit (0.3-100 mumol/kg i.v.) caused a reduction in arterial pressure, which was antagonized by famotidine, no pressor response being unmasked. Dimaprit (0.1-30 mumol/kg i.v.) did not modify heart rate but caused a modest bradycardia at 100 mumol/kg i.v. Amthamine (1-100 mumol/kg i.v.) induced a dose-dependent tachycardia, which was only partially (approximately 20%) reduced by famotidine and was totally blocked by propranolol (0.3 mg/kg i.v.). This effect was significantly reduced in rats pre-treated with reserpine or 6-hydroxydopamine and was further reduced by cocaine, thus suggesting a tyramine-like action of amthamine. In conclusion, these data demonstrate that the H2 receptor agonist amthamine can also interact with the adrenergic system when used at doses higher than those necessary to activate H2 receptors. Whereas the increase in blood pressure induced by amthamine seems to be mainly mediated by a direct activation of postjunctional alpha 2 adrenoceptors, the increase in heart rate is predominantly due to neuronal release of catecholamines. These effects should be considered when

  9. A review of the gastroprotective effects of ginger (Zingiber officinale Roscoe).

    PubMed

    Haniadka, Raghavendra; Saldanha, Elroy; Sunita, Venkatesh; Palatty, Princy L; Fayad, Raja; Baliga, Manjeshwar Shrinath

    2013-06-01

    The rhizomes of Zingiber officinale Roscoe (Zingiberaceae), commonly known as ginger is an important kitchen spice and also possess a myriad health benefits. The rhizomes have been used since antiquity in the various traditional systems of medicine to treat arthritis, rheumatism, sprains, muscular aches, pains, sore throats, cramps, hypertension, dementia, fever, infectious diseases, catarrh, nervous diseases, gingivitis, toothache, asthma, stroke and diabetes. Ginger is also used as home remedy and is of immense value in treating various gastric ailments like constipation, dyspepsia, belching, bloating, gastritis, epigastric discomfort, gastric ulcerations, indigestion, nausea and vomiting and scientific studies have validated the ethnomedicinal uses. Ginger is also shown to be effective in preventing gastric ulcers induced by nonsteroidal anti-inflammatory drugs [NSAIDs like indomethacin, aspirin], reserpine, ethanol, stress (hypothermic and swimming), acetic acid and Helicobacter pylori-induced gastric ulcerations in laboratory animals. Various preclinical and clinical studies have also shown ginger to possess anti-emetic effects against different emetogenic stimuli. However, conflicting reports especially in the prevention of chemotherapy-induced nausea and vomiting and motion sickness prevent us from drawing any firm conclusion on its effectiveness as a broad spectrum anti-emetic. Ginger has been shown to possess free radical scavenging, antioxidant; inhibition of lipid peroxidation and that these properties might have contributed to the observed gastroprotective effects. This review summarizes the various gastroprotective effects of ginger and also emphasizes on aspects that warranty future research to establish its activity and utility as a gastroprotective agent in humans.

  10. Inhibitive effects of Fructus Psoraleae extract on dopamine transporter and noradrenaline transporter.

    PubMed

    Zhao, Gang; Li, Sheng; Qin, Guo-Wei; Fei, Jian; Guo, Li-He

    2007-07-25

    A petroleum ether extract (FP) from Fructus Psoraleae, seeds of Psoralea corylifolia L. (Leguminosae), was found to strongly inhibit dopamine (DA) uptake by dopamine transporter (DAT) heterogeneously expressed cells (D8 cells) and noradrenaline (NE) uptake by noradrenaline transporter (NET) heterogeneously expressed cells, which, however, had no effect on gamma-aminobutyric acid transporter heterogeneously expressed cells and serotonin transporter heterogeneously expressed cells at the concentration up to 100 microg/ml. These inhibitory effects were also confirmed by experiments on SK-N-SH cell line and synaptosomes from rats' brains. In addition, FP showed a significantly mitigating effect on 1-methyl-4-pyridinium induced injury of D8 cells. Meanwhile, FP dose-dependently reduced the binding of tritium-labeled cocaine analog (-)-2beta-carbomethoxy-3beta-(4-fluorophenyl) tropane to DAT of D8 cells, which suggests that FP may inhibit DAT activity in the same way as cocaine does. Behavioral study showed FP had a long-lasting stimulant effects on the activity of intact mice and reserpinized mice. So FP is proposed as a kind of DAT and NET inhibitor and may be involved in the process of regulating the DA and NE system, and FP or its unknown bioactive compounds may be developed into new medicines for disorders such as Parkinson's disease, depression, Attention Deficit Hyperactivity Disorder (ADHD) or cocaine addiction.

  11. Most drugs that reverse multidrug resistance also inhibit photoaffinity labeling of P-glycoprotein by a vinblastine analog

    SciTech Connect

    Akiyama, S.; Cornwell, M.M.; Kuwano, M.; Pastan, I.; Gottesman, M.M.

    1988-02-01

    Multidrug-resistant human KB carcinoma cells express a 170,000-dalton membrane glycoprotein (P-glycoprotein) that can be photoaffinity labeled with the vinblastine analog N-(p-azido-(3-/sup 125/I)salicyl)-N'-(beta-aminoethyl)vindesine. Several agents that suppress the multidrug-resistant phenotype, including N-solanesyl-N,N'-bis(3,4-dimethylbenzyl)ethylenediamine, cepharanthine, quinidine, and reserpine, were found to inhibit photolabeling of P-glycoprotein at doses comparable to those that reverse multidrug resistance. However, the phenothiazines chlorpromazine and trifluoperazine, which also effectively reverse multidrug resistance, were poor inhibitors of the photoaffinity labeling of P-glycoprotein. Chloroquine, propranolol, or atropine, which only partially reversed the drug resistance, also did not inhibit photolabeling. Naphthalene sulfonamide calmodulin inhibitors, W7 and W5, as well as many other drugs that did not circumvent multidrug resistance, did not inhibit photolabeling. These studies suggest that most, but not all, agents that phenotypically suppress multidrug resistance also inhibit drug binding to a site on P-glycoprotein with which a photoaffinity analog of vinblastine interacts.

  12. Characteristics of Ion Activation and Collision Induced Dissociation Using Digital Ion Trap Technology.

    PubMed

    Xu, Fuxing; Dang, Qiankun; Dai, Xinhua; Fang, Xiang; Wang, Yuanyuan; Ding, Li; Ding, Chuan-Fan

    2016-08-01

    Collision induced dissociation (CID) is one of the most established techniques for tandem mass spectrometry analysis. The CID of mass selected ion could be realized by ion resonance excitation with a digital rectangular waveform. The method is simple, and highly efficient CID result could be obtained by optimizing the experimental parameters, such as digital waveform voltage, frequency, and q value. In this work, the relationship between ion trapping waveform voltage and frequency at preselected q value, the relationship between waveform frequency and the q value at certain ion trapping voltage for optimum CID efficiency were investigated. Experiment results showed that the max CID efficiency of precursor reserpine ions can be obtained at different trapping waveform voltage and frequency when q and β are different. Based on systematic experimental analysis, the optimum experimental conditions for high CID efficiency can be calculated at any selected β or q. By using digital ion trap technology, the CID process and efficient fragmentation of parent ions can be realized by simply changing the trapping waveform amplitude, frequency, and the β values in the digital ion trap mass spectrometry. The technology and method are simple. It has potential use in ion trap mass spectrometry. Graphical Abstract ᅟ. PMID:27150507

  13. Tissue specific regulation of peripheral-type benzodiazepine receptor density after chemical sympathectomy

    SciTech Connect

    Basile, A.S.; Skolnick, P.

    1988-01-01

    The characteristics of (/sup 3/H)Ro 5-4864 binding to peripheral benzodiazepine receptors (PBR) in the central nervous system and peripheral tissues were examined after chemical sympathectomy with 6-hydroxydopamine (6-OHDA). One week after the intracisternal administration of 6-OHDA, the number of (/sup 3/H)Ro 5-4864 binding sites (Bmax) in the hypothalamus and striatum increased 41 and 50% respectively, concurrent with significant reductions in catecholamine content. An increase (34%) in the Bmax of (/sup 3/H)Ro 5-4864 to cardiac ventricle was observed one week after parenteral 6-OHDA administration. In contrast, the B/sub max/ of (/sup 3/H)Ro 5-4684 to pineal gland decreased 48% after 6-OHDA induced reduction in norepinephrine content. The Bmax values for (/sup 3/H)Ro 5-4864 binding to other tissues (including lung, kidney, spleen, cerebral cortex, cerebellum, hippocampus and olfactory bulbs) were unaffected by 6-OHDA administration. The density of pineal, but not cardiac PBR was also reduced after reserpine treatment, an effect reversed by isoproterenol administration. These findings demonstrate that alterations in sympathetic input may regulate the density of PBR in both the central nervous system and periphery in a tissue specific fashion. 33 references, 4 tables.

  14. Beyond reverse pharmacology: Mechanism-based screening of Ayurvedic drugs.

    PubMed

    Lele, R D

    2010-10-01

    This paper reviews the pharmacology of Indian medicinal plants, starting with the historical background of European work on the subject beginning as early as the 17th century, and tracing its history through the work of Sen and Bose in the 1930's, and Vakhil's historic 1949 paper on Sarpaghanda. The often crucial role of patient feedback in early discoveries is highlighted, as is the time lag between proof of pharmacological action and identification of the active principle, and subsequent elucidation of mechanism of action. In the case of Indian plants in the 20th century this process sometimes took almost 50 years. Reserpine and its mechanisms are given in detail, and its current relevance to public health discussed. The foundation of present day methods of pharmacology is briefly presented so the complexity of methods used to identify properties of Ayurveda derived drugs like forskolin and baicalein, and their bioavailability, may be better appreciated. Ayurveda derived anti-oxidants and their levels of action, immuno-modulators, particularly with respect to the NF-kB pathway and its implications for cancer control, are all considered. The example of curcumin derived from turmeric is explained in more detail, because of its role in cancer prevention. Finally, the paper emphasizes the importance of Ayurveda's concepts of rasayana as a form of dietary chemo-prevention; the significance of ahar, diet, in Ayurveda's aspiration to prevent disease and restore health thus becomes clear. Understood in this light, Ayurveda may transcend pharmacology as a treatment paradigm. PMID:21731372

  15. PLURIVESICULAR SECRETORY PROCESSES AND NERVE ENDINGS IN THE PINEAL GLAND OF THE RAT

    PubMed Central

    De Robertis, Eduardo; de Iraldi, Amanda Pellegrino

    1961-01-01

    The pineal body of white normal rats, 1.5 to 3 months old, was studied under the electron microscope. A single type of parenchymal cell—the pinealocyte—is recognized as the main component of the tissue, and some of the structural characteristics of the nucleus and cytoplasm are described. The main morphological characteristic of the pinealocytes is represented by club-shaped perivascular expansions connected to the cell by thin pedicles. They are found lying in a large, clear space surrounding the blood capillaries. The name plurivesicular secretory processes is proposed, to emphasize the main structural feature and the probable function of these cellular expansions. A tubulofibrillar component is mainly found in the pedicle, and within the expansion there are numerous small mitochondria and densily packed vesicles of about 425 A. Two types of vesicles, one with a homogeneous content and another with a very dense osmium deposit, are described. Between the two types there are intermediary forms. In these processes, mitochondria show profound changes which may lead to complete vacuolization. The significance of this plurivesicular secretory component is discussed in the light of recent work on the biogenic amines of the pineal body and preliminary experiments showing the release of the vesicles containing dense granules after treatment with reserpine. These vesicles are interpreted as the site of storage of some of the biogenic amines. Bundles of unmyelinated nerve fibers and endings on large blood vessels which also contain a plurivesicular content are described and tentatively interpreted as adrenergic nerve terminals. PMID:13720811

  16. [Behavioral pharmacological properties of the novel antidepressant paroxetine, a selective 5-HT uptake inhibitor].

    PubMed

    Yamamoto, T; Shibata, S; Shimazoe, T; Iwasaki, K; Ohno, M; Minamoto, Y; Furuya, Y; Miyamoto, K; Watanabe, S; Ueki, S

    1989-09-01

    The behavioral effects of paroxetine were investigated in mice and rats in comparison with imipramine and amitriptyline. 1) Locomotor activities were decreased by imipramine and amitriptyline but not by paroxetine in both animal species. 2) Paroxetine antagonized methamphetamine-induced hyperactivity in mice as did imipramine and amitriptyline. 3) Paroxetine showed a more potent antimuricidal effect in raphe-lesioned rats than imipramine and amitriptyline, and it also inhibited muricide in olfactory bulbectomized rats. 4) The immobility of rats in the forced swimming test was markedly decreased by imipramine and amitriptyline, but only slightly by paroxetine. 5) Like imipramine and amitriptyline, paroxetine potentiated the methamphetamine- or L-DOPA-induced stereotyped sniffing, and it inhibited oxotremorine-induced tremor. 6) Paroxetine antagonized reserpine-induced hypothermia, tetrabenazine-induced ptosis, and enhanced ether-induced anesthesia, all less potently than imipramine and amitriptyline. 7) The analgesic action of paroxetine was stronger than that of imipramine and amitriptyline. 8) Paroxetine did not antagonize maximal electroshock- or pentetrazol-induced convulsions and haloperidol- or THC-induced catalepsy in rats. In addition, paroxetine neither exerted muscle relaxation nor affected the shuttle-box type conditioned avoidance in rats. From these results, the behavioral effects of paroxetine, as compared with imipramine and amitriptyline, were characterized by its potent antimuricidal action in raphe-lesioned rats and its weak effect in the forced swimming test and by its less potent muscle relaxant, anticonvulsant, anticataleptic and anesthesia-potentiating actions.

  17. [Behavioral effects of a new antidepressant, setiptiline].

    PubMed

    Yamada, K; Furukawa, T

    1991-01-01

    Behavioral effects of setiptiline, a new tetracyclic compound (1,2,3,4-tetrahydro-2-methyl-9H-dibenzo [3,4:6,7] cyclohepta [1,2-C] pyridine maleate), were investigated to determine its pharmacological characteristics as an antidepressant in rats and mice, as compared with amitriptyline, a tricyclic antidepressant, and promethazine, a neuroleptic possessing an antihistaminic profile. Setiptiline exerted a weak stimulatory action on ambulation, spontaneous motor-activity, observed by the open field method in rats and potentiated the stimulatory effects of methamphetamine. Setiptiline also shortened the duration of immobility in rats forced to swim and inhibited catalepsy induced by haloperidol, yawning by physostigmine, body shaking as well as head twitch by 5-hydroxytryptophan in combination with Ro4-4602 and body shaking by morphine-withdrawal in rats. On the other hand, the drug did not exhibit an antagonistic effect on the hypothermia produced by reserpine in mice. From the results, it is suggested that setiptiline seems to have antidepressive activities that are pharmacologically dissimilar to those of tricyclic antidepressants.

  18. [Behavioral pharmacology of a new antidepressant, lopramine].

    PubMed

    Ueki, S; Fujiwara, M; Inoue, K

    1976-07-01

    The behavioral effects of lopramine [N-methyl-N-(4-chlorobenzoyl-methyl)-3-(10, 11-dihydro-5H-dibenz (b,f) azepin-5-yl) propylamine hydrochloride] were investigated in mice and rats and compared with those of amitriptyline and imipramine. Lopramine inhibited reserpine hypothermia and haloperidol catalepsy in mice and tetrabenazine ptosis in rats. In addition the drug potentiated the effects of methamphetamine, and DOPA- or apomorphine-induced stereotypy in mice, whereas it suppressed muricide of the rat induced by either olfactory bulbectomy or delta9-tetrahydrocannabinol, similar to the responses seen with imipramine and amitriptyline. On the other hand,lopramine increased spontaneous motor activity and markedly potentiated methamphetamine hyperactivity. In contrast to imipramine and amitriptyline, lopramine failed to counteract both the lethal effect of physostigmine and oxotremorine tremor in mice, indicating that the drug had no central anticholinergic effect. Lopramine, even at such a large dose as 5,000 mg/kg p.o., caused neitherimpairment of coordinated motor activity nor muscle relaxation. It is concluded that lopramine is a new type of tricyclic antidepressant with extremely low toxicity and without central anticholinergic action.

  19. Pharmacological evaluation of 2-(4-methylaminobutoxy)diphenylmethane hydrochloride (MCI-2016), a new psychotropic drug with antidepressant activity.

    PubMed

    Tobe, A; Yoshida, Y; Ikoma, H; Tonomura, S; Kikumoto, R

    1981-01-01

    Pharmacological properties of 2-(4-methylamino-butoxy)-diphenylmethane hydrochloride (MCI-2016) were examined in comparison with those of other antidepressants. MCI-2016 significantly antagonized the hypothermia and depression-like syndrome produced by reserpine injection. Furthermore, the drug exhibited such activities as antitetrabenazine and anti-cataleptic actions, and potentiation of the behavioural excitation induced by yohimbine, methamphetamine and L-dopa. MCI-2016 showed a definite suppressive effect on muricidal activity in olfactory bulb removed rats and the long-term isolation-induced fighting in mice without causing apparent motor disturbance. Judging from the effects of the drug on in vitro response to noradrenaline (NA) and serotonin (5-HT), and on p-chloramphetamine-induced hypermotility, it is suggested that MCI-2016 is a selective potentiator of NA presumably due to an inhibition of NA uptake. Anticholinergic and sedative actions of MCI-2016 were considerably weaker than those of amitriptyline and imipramine. Acute toxicity of MCI-2016 was the weakest among the drugs tested. These pharmacological profiles may suggest a potential clinical utility of MCI-2016 as a new psychotropic agent having an antidepressant activity.

  20. [General pharmacology of 6-amino-2-fluoromethyl-3-(o-tolyl)-4(3H)-quinazolinone (afloqualone), a new centrally acting muscle relaxant. I. Effects on the central nervous system (author's transl)].

    PubMed

    Ochiai, T; Yamamura, M; Kudo, Y; Ishida, R

    1981-10-01

    The general pharmacology of afloqualone, a new centrally acting muscle relaxant, in the CNS was examined in mice and rats and findings compared with those of other central muscle relaxants. Afloqualone showed relatively strong hexobarbital and barbital anesthesia potentiating action. Taking into account the dose ratio of anesthesia potentiating action to the muscle relaxing action, however, the potency of anesthesia potentiating action of afloqualone is lower than that of chlormezanone. At doses producing muscle relaxing action, afloqualone inhibited spontaneous motor activity, methamphetamine-induced hypermotility, pentylenetetrazol-, nicotine-, and maximum electroshock-convulsions, fighting episodes in foot-shocked mice, conditioned avoidance response in rat pole-climbing test, and acetic acid-induced writhing syndrome and lowered normal body temperature. The dose ratios of these pharmacological actions to muscle relaxing action of afloqualone, however, were larger than those of chlormezanone and mephenesin. This suggests that the central depressant activity of afloqualone is less potent and the specificity of muscle relaxing action of afloqualone is higher than those of climbing behaviour, physostigmine-induced death, serotonin-induced heat twitch, and reserpine-induced hypothermia, even at 50 mg/kg. Tolperisone showed neither muscle relaxing action nor other central actions when administered orally.

  1. An electrodynamic ion funnel interface for greater sensitivity and higher throughput with linear ion trap mass spectrometers

    SciTech Connect

    Page, Jason S.; Tang, Keqi; Smith, Richard D.

    2007-09-01

    An electrospray ionization interface incorporating an electrodynamic ion funnel has been designed and implemented in conjunction with a linear ion trap mass spectrometer (Thermo Electron, LTQ). We found ion transmission to be greatly improved by replacing the standard capillary-skimmer interface with the capillary-ion funnel interface. An infusion study using a serial dilution of a reserpine solution showed that ion injection times to fill the ion trap were reduced by ~90% which resulted in an ~10-fold increase in reported peak intensities. In liquid chromatography (LC)-MS and LC tandem MS (MS/MS) experiments performed using a proteomic sample from the bacterium, Shewanella oneidensis, the ion funnel interface provided an ~7-fold reduction in ion injection (accumulation) times. In a series of LC-MS/MS experiments we found that more dilute S. oneidensis samples provided more peptide and protein identifications when the ion funnel interface was used in place of the standard interface. This improvement was most pronounced at lower sample concentrations, where extended ion accumulation times are required, resulting in an ~2-fold increase in the number of protein identifications. Implementation of the ion funnel interface with a LTQ Fourier transform (FT) MS requiring much greater ion populations resulted in spectrum acquisition times reduced by ~25 to 50%.

  2. An electrodynamic ion funnel interface for greater sensitivity and higher throughput with linear ion trap mass spectrometers

    NASA Astrophysics Data System (ADS)

    Page, Jason S.; Tang, Keqi; Smith, Richard D.

    2007-09-01

    An electrospray ionization interface incorporating an electrodynamic ion funnel has been designed and implemented on a linear ion trap mass spectrometer (Thermo Electron, LTQ). We found ion transmission to be greatly improved by replacing the standard capillary-skimmer interface with the capillary-ion funnel interface. An infusion study using a serial dilution of a reserpine solution showed that ion injection (accumulation) times to fill the ion trap at a given automatic gain control (AGC) target value were reduced by ~90% which resulted in an ~10-fold increase in peak intensities. In liquid chromatography tandem MS (LC-MS/MS) experiments performed using a global protein digest sample from the bacterium, Shewanella oneidensis, more peptides and proteins were identified when the ion funnel interface was used in place of the standard interface. This improvement was most pronounced at lower sample concentrations, where extended ion accumulation times are required, resulting in an ~2-fold increase in the number of protein identifications. Implementation of the ion funnel interface on a LTQ Fourier transform (FT) mass spectrometer showed a ~25-50% reduction in spectrum acquisition time. The duty cycle improvement in this case was due to the ion accumulation event contributing a larger portion to the total spectrum acquisition time.

  3. Mephedrone, a new designer drug of abuse, produces acute hemodynamic effects in the rat.

    PubMed

    Meng, Harry; Cao, James; Kang, Jiesheng; Ying, Xiaoyou; Ji, Junzhi; Reynolds, William; Rampe, David

    2012-01-01

    Mephedrone (4-methylmethcathinone) is a new and popular drug of abuse widely available on the Internet and still legal in some parts of the world. Clinical reports are now emerging suggesting that the drug displays sympathomimetic toxicity on the cardiovascular system but no studies have yet explored its cardiovascular effects. Therefore we examined the effects of mephedrone on the cardiovascular system using a combination of in vitro electrophysiology and in vivo hemodynamic and echocardiographic measurements. Patch clamp studies revealed that mephedrone, up to 30 μM, had little effect on the major voltage-dependent ion channels of the heart or on action potentials recorded in guinea pig myocytes. Subcutaneous administration of mephedrone (3 and 15 mg/kg) to conscious telemetry-implanted rats produced dose-dependent increases in heart rate and blood pressure which persisted after pre-treatment with reserpine. Echocardiographic analysis demonstrated that intravenous injection of mephedrone (0.3 and 1mg/kg) increased cardiac function, including cardiac output, ejection fraction, and stroke volume, similar to methamphetamine (0.3mg/kg). We conclude that mephedrone is not directly pro-arrhythmic, but induces substantial increases in heart rate, blood pressure and cardiac contractility and this activity contributes to the cardiovascular toxicity in people who abuse the drug.

  4. African ethnobotany and healthcare: emphasis on mozambique.

    PubMed

    Bandeira, S O; Gaspar, F; Pagula, F P

    2001-01-01

    The relationship between common medicinal plants and major health problems in Africa, specifically Mozambique, is presented here. Emphasis is given to plant species largely used to solve or slow down diarrhoea, malaria, respiratory, and sexual complaints. These diseases, together with malnutrition/ anaemia, mental diseases, and rheumatism/arthritis are the main concern of healthcare countrywide. Diarrhoea is divided into common diarrhoea, bloody-diarrhoea, and cholera; plant species are normally used to slow down diarrhoea recurrence. Tannin is the main chemical compound with both anti-diarrhoeal and antiseptic properties. Traditional medicine seems to be rather helpful in alleviating malaria symptoms such as fever, vomiting, and diarrhoea. Special reference is made to Momordica balsamina, which is highly used to cure vomiting apparently associated with bilis and fever. Rauvolfia caffra contains reserpine, a compound used as anti-hypertension agent. This species is also used as an anti-malarial agent. Traditional medicine seems to have a role in slowing opportunistic infections related to the AIDS virus such as diarrhoea, pneumonia, and skin infections. Prostate hypertrophy is traditionally medicated using mostly Prunus africana and Hypoxis hemerocallidea, species known to contain phytosterol. Research for bioactive compounds in African plants is still in its infancy.

  5. Involvement of 5-HT2 receptors in the antinociceptive effect of Uncaria tomentosa.

    PubMed

    Jürgensen, Sofia; Dalbó, Sílvia; Angers, Paul; Santos, Adair Roberto Soares; Ribeiro-do-Valle, Rosa Maria

    2005-07-01

    Uncaria tomentosa (Willd.) DC (Rubiaceae) is a vine that grows in the Amazon rainforest. Its bark decoctions are used by Peruvian Indians to treat several diseases. Chemically, it consists mainly of oxindole alkaloids. An industrial fraction of U. tomentosa (UT fraction), containing 95% oxindole alkaloids, was used in this study in order to characterize its antinociceptive activity in chemical (acetic acid-induced abdominal writhing, formalin and capsaicin tests) and thermal (tail-flick and hot-plate tests) models of nociception in mice. UT fraction given by the i.p. route dose-dependently suppressed the behavioural response to the chemical stimuli in the models indicated and increased latencies in the thermal stimuli models. The antinociception caused by UT fraction in the formalin test was significantly attenuated by i.p. treatment of mice with ketanserin (5-HT2 receptor antagonist), but was not affected by naltrexone (opioid receptor antagonist), atropine (a nonselective muscarinic antagonist), l-arginine (precursor of nitric oxide), prazosin (alpha1-adrenoceptor antagonist), yohimbine (alpha2-adrenoceptor antagonist), and reserpine (a monoamine depleter). Together, these results indicate that UT fraction produces dose-related antinociception in several models of chemical and thermal pain through mechanisms that involve an interaction with 5-HT2 receptors.

  6. Effects of Electroacupuncture with Dominant Frequency at SP 6 and ST 36 Based on Meridian Theory on Pain-Depression Dyad in Rats.

    PubMed

    Wu, Yuan-Yuan; Jiang, Yong-Liang; He, Xiao-Fen; Zhao, Xiao-Yun; Shao, Xiao-Mei; Du, Jun-Ying; Fang, Jian-Qiao

    2015-01-01

    Epidemic investigations reveal an intimate interrelationship between pain and depression. The effect of electroacupuncture (EA) on pain or depression has been demonstrated individually, but its effect on pain-depression dyad is unknown. Our study aimed to screen a dominant EA frequency on pain-depression dyad and determine the validity of acupoint selection based on meridian theory. The pain-depression dyad rat model was induced by reserpine and treated using EA with different frequencies at identical acupoints to extract a dominant frequency and then administrated dominant-frequency EA at different acupoints in the above models. Paw withdrawal latency (PWL), emotional behavior of elevated zero maze (EZM) test, and open field (OF) test were conducted. We found that 100 Hz EA at Zusanli (ST 36) and Sanyinjiao (SP 6) (classical acupoints for spleen-deficiency syndrome) were the most effective in improving PWL, travelling distance in the EZM, and maximum velocity in OF compared to EA with other frequencies; ST 36 and SP 6 were proved more effective than other acupoints beyond the meridian theory and nonacupoints under the same administration of EA. Therefore, we concluded that 100 Hz is the dominant frequency for treating the pain-depression dyad with EA, and acupoints on spleen and stomach meridians are preferable choices.

  7. Further analysis of the neuropharmacological profile of 9-amino-1,2,3,4-tetrahydroacridine (THA), and alleged drug for the treatment of Alzheimer's disease

    SciTech Connect

    Drukarch, B.; Leysen, J.E.; Stoof, J.C.

    1988-01-01

    In a recent study the authors have documented the acetylcholinesterase and outward K+-current inhibiting activity of 9-amino-1,2,3,4-tetrahydroacridine (THA), a drug reportedly active in the treatment of Alzheimer patients. In the present study they have investigated the effects of THA on the uptake and release of radiolabeled NA, DA and 5-HT. THA concentration-dependently inhibited the uptake of these monoamines with IC-50 values of approximately 1, 7 and 2 ..mu..M respectively. Release studies of these radiolabeled monoamines from control and reserpine pretreated tissue revealed that the THA-induced uptake inhibition does not occur at the level of the axonal membrane but at the level of the monoaminergic storage granules. In addition the affinity of THA for alpha-1, alpha-2 and beta-adrenoceptors, for D-2 dopamine, S-la and S-2 serotonin and for muscarinic receptors was investigated. It appeared that in concentrations up to 1 ..mu..M THA did not display any affinity towards these receptors. It is concluded from these experiments that the effects of THA on monoaminergic neurotransmission might contribute to the alleged therapeutic action of THA in Alzheimer's disease. 17 references, 3 figures, 1 table.

  8. Self-Aspirated Atmospheric Pressure Chemical Ionization Source for Direct Sampling of Analytes on Surfaces and in Liquid Solutions

    SciTech Connect

    Asano, Keiji G; Ford, Michael J; Tomkins, Bruce A; Van Berkel, Gary J

    2005-01-01

    A self-aspirating heated nebulizer probe is described and demonstrated for use in the direct analysis of analytes on surfaces and in liquid samples by atmospheric pressure chemical ionization (APCI) mass spectrometry. Functionality and performance of the probe as a self-aspirating APCI source is demonstrated using reserpine and progesterone as test compounds. The utility of the probe to sample analytes directly from surfaces was demonstrated first by scanning development lanes of a reversed-phase thin-layer chromatography plate in which a three-component dye mixture, viz., Fat Red 7B, Solvent Green 3, and Solvent Blue 35, was spotted and the components were separated. Development lanes were scanned by the sampling probe operated under computer control (x, y plane) while full-scan mass spectra were recorded using a quadrupole ion trap mass spectrometer. In addition, the ability to sample the surface of pharmaceutical tablets (viz., Extra Strength Tylenol(reg. sign) and Evista(reg. sign) tablets) and to detect the active ingredients (acetaminophen and raloxifene, respectively) selectively was demonstrated using tandem mass spectrometry (MS/MS). Finally, the capability to sample analyte solutions from the wells of a 384-well microtiter plate and to perform quantitative analyses using MS/MS detection was illustrated with cotinine standards spiked with cotinine-d{sub 3} as an internal standard.

  9. Intestinal transport of sophocarpine across the Caco-2 cell monolayer model and quantification by LC/MS.

    PubMed

    Sun, Sen; Zhang, Hai; Sun, Fengfeng; Zhao, Liang; Zhong, Yanqiang; Chai, Yifeng; Zhang, Guoqing

    2014-06-01

    Sophocarpine is a biologically active component obtained from the foxtail-like sophora herb and seed that is often orally administered for the treatment of cancer and chronic bronchial asthma. The aim of this study was to develop a rapid and specific LC/MS method for the determination of sophocarpine and to explore its transcellular transport mechanism across the Caco-2 (the human colon adenocarcia cell lines) monolayer cell transwell model. Caco-2 cells were seeded on permeable polycarbonate membranes and incubated for 21 days. Before the experiment, the trans-epithelial electric resistance, integrity and alkaline phosphatase activity of the Caco-2 monolayers were verified and used in subsequent experiments. In the Caco-2 model constructed, many influencing factors were investigated, including time, concentration, pH and different protein inhibitors. The results suggested that sophocarpine was transported mainly by passive diffusion. The flux of sophocarpine was time- and concentration-dependent, and the pH also had an effect on its transportation. The PappBA was higher than PappAB , indicating that a polarized transport might exist for sophocarpine. MK-571 and reserpine, inhibitors of the multidrug resistance associated protein 2 and the breast cancer resistance protein, decreased the efflux of sophocarpine, while verapamil had no effect on its transport. These results revealed that sophocarpine is absorbed mainly by passive diffusion, and that a carrier-mediated mechanism is also involved in the transport of sophocarpine.

  10. Treatment resistant depression or dementia: a case report

    PubMed Central

    SHI, Zhongyong; XIAO, Shifu; LI, Xia

    2016-01-01

    Summary: The current case describes a 78-year-old female with two previous episodes of major depression who presented with both symptoms of depression (amotivation and flattened affect) and typical symptoms of dementia (impaired memory and executive functioning). Even after a detailed clinical exam and neuropsychiatric testing, it remained difficult to definitively classify the diagnosis as either treatment-resistant depression or old-age dementia. After 8 weeks of inpatient treatment, including changing her reserpine-based antihypertensive medication, adjusting her antidepressants, and providing psychotherapy, her depressive and anxiety symptoms improved, but most of her cognitive symptoms persisted. Her symptoms did not change over 7 months of post-hospitalization follow-up. She subsequently developed advanced breast cancer and started chemotherapy; at this point her depressive and cognitive symptoms became more pronounced. We conclude that it will take two-to-three years of follow-up to determine whether the cognitive symptoms are residual to her depression or a newly emerging dementia (or both). This case shows that for elderly patients who have symptoms of both depression and dementia, detailed clinical examination and neuropsychiatric testing may need to be combined with longitudinal assessment of their responsiveness to treatment before a definitive diagnosis can be assigned. PMID:27605868

  11. [Chemotherapies of negative schizophrenia].

    PubMed

    Petit, M; Dollfus, S

    1991-01-01

    Five years ago, Goldberg claimed that negative symptoms of schizophrenia do respond to neuroleptics. This apparent discovery is, in fact, a very common way of thinking for European schools of psychiatry, specially the French one guided by Delay and Deniker. Initially focused on reserpine and some alerting phenothiazines such as thioproperazine, this opinion has been extended to benzamides in the 1970s. The analysis of the publications devoted to this point indicates that several drugs are actually considered as potent disinhibitors (i.e. active on negative symptoms of schizophrenia): Phenothiazines: As shown in the controlled studies by Itil (1971), Poirier-Littré (1988), fluphenazine and pipotiazine improve the BPRS anergia factor and the SANS score. Butyrophenones: The first description of the "imipramine like" effect of trifluperidol by Janssen (1959) initiated the studies by Gallant (1960), Fox (1963). They compared trifluperidol at low doses versus haloperidol and chlorpromazine at medium and high doses, BPRS anergia factor improved only at low doses. Diphenylbutylpiperidines (DPBP): Meltzer's review (1986) concluded to the efficacy of such drugs on negative symptoms appearing as a specific biochemical relationship effect. A definite analysis about doses leads to a very different interpretation: DPBP low doses and only low doses improved negative symptoms as much as some low doses of phenothiazines. On the opposite, DPBP, phenothiazines and butyrophenones high doses are inefficient.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1683624

  12. Interactions between acetylcholine, 5-hydroxytryptamine, nicotine and morphine on isolated rabbit atria

    PubMed Central

    Chittal, S. M.; Dadkar, N. K.; Gaitondé, B. B.

    1968-01-01

    1. The effects of 5-hydroxytryptamine (5-HT) and morphine on the responses to acetylcholine and nicotine of isolated rabbit atria were studied. 2. 5-Hydroxytryptamine (10 μg/ml.) and morphine (20 μg/ml.) blocked the negative chronotropic and inotropic actions of acetylcholine. 3. Nicotine (20 μg/ml.) produced stimulation of the atria, which was blocked by dichlorisoprenaline, morphine, 5-HT, bretylium and hemicholinium. Hemicholinium block was reversed by choline. 4. In reserpinized preparations, nicotine produced inhibition of atria and this action was also blocked by atropine, 5-HT and morphine. Inhibition induced by nicotine was potentiated by physostigmine. 5. 5-Hydroxytryptamine (20 μg/ml.) produced stimulation of atria. This was blocked by bretylium and reduced by hemicholinium. Hemicholinium block was reversed by choline. 6. It is concluded that 5-HT in low concentrations acts as a weak agonist at the cholinoceptive receptors and therefore blocks the action of acetylcholine. Furthermore, nicotine and larger doses of 5-HT have actions on ganglionic structures and liberate acetylcholine, which in turn releases catecholamines. PMID:4386371

  13. Long-term stability in biomass and production of terpene indole alkaloids by hairy root culture of Rauvolfia serpentina and cost approximation to endorse commercial realism.

    PubMed

    Pandey, Pallavi; Kaur, Ranjeet; Singh, Sailendra; Chattopadhyay, Sunil Kumar; Srivastava, Santosh Kumar; Banerjee, Suchitra

    2014-07-01

    The effect of 6 years of cultivation and use of table-sugar (TS) on the biomass/terpene alkaloid productivities and rol gene expression were studied in a hairy root (HR) clone of Rauvolfia serpentina. The media cost could be reduced >94 % by replacing sucrose (SUC) with TS—an unexplored avenue for HR cultivation. The overall productivities increased over long-term cultivation with sugar proving superior to SUC for biomass (24.4 ± 2.11 g/l DW after 40 days to 17.31 % higher) and reserpine (0.094 ± 0.008 % DW after 60 days to 193.8 % more) production. The latter however revealed comparatively better yields concerning ajmaline (0.507 ± 0.048 % DW after 60 days to 61.98 % higher) and yohimbine (0.628 ± 0.062 % DW after 60 days to 38.32 % higher), respectively. PCR amplification of rol genes confirmed long-term expression stability.

  14. Quantification and characterization of alkaloids from roots of Rauwolfia serpentina using ultra-high performance liquid chromatography-photo diode array-mass spectrometry.

    PubMed

    Sagi, Satyanarayanaraju; Avula, Bharathi; Wang, Yan-Hong; Khan, Ikhlas A

    2016-01-01

    A new UHPLC-UV method has been developed for the simultaneous analysis of seven alkaloids [ajmaline (1), yohimbine (2), corynanthine (3), ajmalicine (4), serpentine (5), serpentinine (6), and reserpine (7)] from the root samples of Rauwolfia serpentina (L.) Benth. ex Kurz. The chromatographic separation was achieved using a reversed phase C18 column with a mobile phase of water and acetonitrile, both containing 0.05% formic acid. The seven compounds were completely separated within 8 min at a flow rate of 0.2 mL/min with a 2-μL injection volume. The method is validated for linearity, accuracy, repeatability, limits of detection (LOD), and limits of quantification (LOQ). Seven plant samples and 21 dietary supplements claiming to contain Rauwolfia roots were analyzed and content of total alkaloids (1-7) varied, namely, 1.57-12.1 mg/g dry plant material and 0.0-4.5 mg/day, respectively. The results indicated that commercial products are of variable quality. The developed analytical method is simple, economic, fast, and suitable for quality control analysis of Rauwolfia samples and commercial products. The UHPLC-QToF-mass spectrometry with electrospray ionization (ESI) interface method is described for the confirmation and characterization of alkaloids from plant samples. This method involved the detection of [M + H](+) or M(+) ions in the positive mode.

  15. Spiperone: evidence for uptake into secretory granules.

    PubMed Central

    Dannies, P S; Rudnick, M S; Fishkes, H; Rudnick, G

    1984-01-01

    Spiperone, a dopamine antagonist widely used as a specific ligand for dopamine and serotonin receptors, is actively accumulated into the F4C1 strain of rat pituitary tumor cells. The accumulation of 10 nM [3H]spiperone was linear for 3 min and reached a steady state after 10 min. Spiperone accumulation was reduced 50% by preincubation with 5 microM reserpine, an inhibitor of biogenic amine transport into secretory granules, and was also blocked by monensin and ammonium chloride, both of which increase the pH of intracellular storage organelles. Uptake was not affected by replacing sodium in the buffer with lithium at equimolar concentrations. Spiperone at 1 microM inhibited by over 50% serotonin transport into membrane vesicles isolated from platelet dense granules; this concentration inhibited the Na+-dependent plasma membrane transport system less than 10%. The data indicate spiperone specifically interacts with the secretory granule amine transport system and suggest that this transport system is found in the F4C1 pituitary cell strain as well as in platelets and neurons. The data also suggest that experiments utilizing spiperone to measure dopamine and serotonin receptors be interpreted with caution. PMID:6584920

  16. Traditional knowledge and formulations of medicinal plants used by the traditional medical practitioners of bangladesh to treat schizophrenia like psychosis.

    PubMed

    Ahmed, Md Nasir; Kabidul Azam, Md Nur

    2014-01-01

    Schizophrenia is a subtle disorder of brain development and plasticity; it affects the most basic human processes of perception, emotion, and judgment. In Bangladesh the traditional medical practitioners of rural and remote areas characterized the schizophrenia as an insanity or a mental problem due to possession by ghosts or evil spirits and they have used various plant species' to treat such symptoms. The aim of the present study was to conduct an ethnomedicinal plant survey and documentation of the formulations of different plant parts used by the traditional medical practitioners of Rangamati district of Bangladesh for the treatment of schizophrenia like psychosis. It was observed that the traditional medical practitioners used a total of 15 plant species to make 14 formulations. The plants were divided into 13 families, used for treatment of schizophrenia and accompanying symptoms like hallucination, depression, oversleeping or insomnia, deterioration of personal hygiene, forgetfulness, and fear due to evil spirits like genies or ghost. A search of the relevant scientific literatures showed that a number of plants used by the medicinal practitioners have been scientifically validated in their uses and traditional medicinal knowledge has been a means towards the discovery of many modern medicines. Moreover, the antipsychotic drug reserpine, isolated from the dried root of Rauvolfia serpentina species, revolutionized the treatment of schizophrenia. So it is very much possible that formulations of the practitioner, when examined scientifically in their entireties, can form discovery of lead compounds which can be used as safe and effective antipsychotic drug to treat schizophrenia.

  17. Bystander effects of ionizing radiation can be modulated by signaling amines

    SciTech Connect

    Poon, R.C.C.; Agnihotri, N.; Seymour, C.; Mothersill, C.

    2007-10-15

    Actual risk and risk management of exposure to ionizing radiation are among the most controversial areas in environmental health protection. Recent developments in radiobiology especially characterization of bystander effects have called into question established dogmas and are thought to cast doubt on the scientific basis of the risk assessment framework, leading to uncertainty for regulators and concern among affected populations. In this paper we test the hypothesis that small signaling molecules widely used throughout the animal kingdom for signaling stress or environmental change, such as 5-Hydroxytryptamine (5-HT, serotonin), L-DOPA, glycine or nicotine are involved in bystander signaling processes following ionizing radiation exposure. We report data which suggest that nano to micromolar concentrations of these agents can modulate bystander-induced cell death. Depletion of 5-HT present in tissue culture medium, occurred following irradiation of cells. This suggested that 5-HT might be bound by membrane receptors after irradiation. Expression of 5-HT type 3 receptors which are Ca{sup 2+} ion channels was confirmed in the cells using immunocytochemistry and receptor expression could be increased using radiation or 5-HT exposure. Zofran and Kitryl, inhibitors of 5-HT type 3 receptors, and reserpine a generic serotonin antagonist block the bystander effect induced by radiation or by serotonin. The results may be important for the mechanistic understanding of how low doses of radiation interact with cells to produce biological effects.

  18. Interactions between acetylcholine, 5-hydroxytryptamine, nicotine and morphine on isolated rabbit atria.

    PubMed

    Chittal, S M; Dadkar, N K; Gaitondé, B B

    1968-09-01

    1. The effects of 5-hydroxytryptamine (5-HT) and morphine on the responses to acetylcholine and nicotine of isolated rabbit atria were studied.2. 5-Hydroxytryptamine (10 mug/ml.) and morphine (20 mug/ml.) blocked the negative chronotropic and inotropic actions of acetylcholine.3. Nicotine (20 mug/ml.) produced stimulation of the atria, which was blocked by dichlorisoprenaline, morphine, 5-HT, bretylium and hemicholinium. Hemicholinium block was reversed by choline.4. In reserpinized preparations, nicotine produced inhibition of atria and this action was also blocked by atropine, 5-HT and morphine. Inhibition induced by nicotine was potentiated by physostigmine.5. 5-Hydroxytryptamine (20 mug/ml.) produced stimulation of atria. This was blocked by bretylium and reduced by hemicholinium. Hemicholinium block was reversed by choline.6. It is concluded that 5-HT in low concentrations acts as a weak agonist at the cholinoceptive receptors and therefore blocks the action of acetylcholine. Furthermore, nicotine and larger doses of 5-HT have actions on ganglionic structures and liberate acetylcholine, which in turn releases catecholamines.

  19. Inhibitory action of acetylcholine on the smooth muscle from the lower esophageal sphincter.

    PubMed

    Velkova, V; Papasova, M; Boev, K; Bonev, A

    1979-01-01

    The effect of acetylcholine (Ach) on smooth-muscle strips isolated along the transversal axis of cat lower esophageal sphincter (LES) is studied. Ach in low concentrations (10(-11)--10(-9) g/ml) causes contraction of the muscle strips. Increase of the concentration to 10(-8) g/ml leads to biphasic effect: contraction with relaxation. Inhibitory response predominates at Ach 10(-6) and 10(-5) g/ml. Atropine (10(-6) M) eliminates the excitatory phase but it has no effect on the second relaxation phase. Propranolol (10(-6), 2 X 10(-6) M) as well as phentolamine turn the inhibitory response to Ach into contraction. Noradrenaline leads to LES contraction while isoprenaline induces relaxation. In smooth-muscle LES strips from cats pretreated with reserpine (1 mg/kg for 3 days), Ach in the concentrations used (10(-5), 10(-6) g/ml) leads to contraction. The changes observed are membrane-dependent -- the contraction is accompanied by depolarization, relaxation by hyperpolarization. The inhibitory effect of Ach on LES smooth muscle is discussed in the light of the hypothesis of Burn and Rand (1960) about the release of noradrenaline under the effect of Ach.

  20. Active uptake and extravesicular storage of m-iodobenzylguanidine in human neuroblastoma SK-N-SH cells

    SciTech Connect

    Smets, L.A.; Loesberg, C.; Janssen, M.; Metwally, E.A.; Huiskamp, R.

    1989-06-01

    Radioiodinated m-iodobenzylguanidine (MIBG), an analogue of the neurotransmitter norepinephrine (NE), is increasingly used in the diagnosis and treatment of neural crest tumors. Active uptake and subsequent retention of MIBG and NE was studied in human neuroblastoma SK-N-SH cells. Neuron-specific uptake of (125I)MIBG and (3H)NE saturated at extracellular concentration of 10(-6) M and exceeded by 20-30-fold that by passive diffusion alone. A minimum of 50% of accumulated MIBG remained permanently stored but the SK-N-SH cells were incapable of retaining recaptured (3H)NE. (125I)MIBG was displaced from intracellular binding sites by unlabeled MIBG with 10-fold higher potency than by unlabeled NE. MIBG stored in SK-N-SH cells was insensitive to depletion by the inhibitor of granular uptake reserpine (RSP) and was not precipitated in a granular fraction by differential centrifugation. Only few electron-dense granules were found in these cells by electron microscopy. In contrast, MIBG storage in PC-12 pheochromocytoma cells which contained many storage granules, was sensitive to RSP and part of accumulated drug was recovered in a granular fraction. Accordingly, storage of MIBG in the SK-N-SH neuroblastoma cells is predominantly extravesicular and thus essentially different from that of biogenic amines in normal adrenomedullary tissue or in pheochromocytoma tumors, while sharing with these tissues a common mechanism of active uptake.

  1. Dual aminergic regulation of central beta adrenoceptors. Effect of atypical antidepressants and 5-hydroxytryptophan

    SciTech Connect

    Manier, D.H.; Gillespie, D.D.; Sulser, F.

    1989-06-01

    Nonlinear regression analysis of agonist competition binding curves reveals that the (/sup 3/H)-dihydroalprenolol-labeled receptor population with low affinity for isoproterenol is increased by p-chlorophenylalanine (PCPA) and this increase is abolished by 5-hydroxytryptophan (5-HTP) in vivo. Desipramine (DMI) decreased the beta adrenoceptor population with high agonist affinity to the same degree in PCPA-treated animals as in control animals, thus explaining the reported discrepancy between beta adrenoceptor number and responsiveness of the beta adrenoceptor-coupled adenylate cyclase system. Mianserin also selectively reduced the beta adrenoceptor population with high agonist affinity in membrane preparations of normal animals, whereas fluoxetine selectively abolished the upregulation of the low affinity sites in reserpinized animals and had no effect on either receptor population from brain of normal animals. The results emphasize the importance of nonlinear regression analysis of agonist competition binding for the interpretation of drug action and encourage the pursuit of the molecular neurobiology of the serotonin (5-HT)/norepinephrine (NE) link in brain.

  2. Myocardial effects of flavonoids from Crataegus species.

    PubMed

    Schüssler, M; Hölzl, J; Fricke, U

    1995-08-01

    The influence of the main flavonoids from Crataegus species (hawthorn, Rosaceae) on coronary flow, heart rate and left ventricular pressure as well as on the velocity of contraction and relaxation was investigated in Langendorff perfused isolated guinea pig hearts at a constant pressure of 70 cmH2O. Drug action was evaluated in a concentration range of 10(-7) to 5 x 10(-4) mol/l. An increase of coronary flow caused by the O-glycosides luteolin-7-glucoside (186%), hyperoside (66%) and rutin (66%) as well as an increase of the relaxation velocity (positive lusitropism) by luteolin-7-glucoside (104%), hyperoside (62%) and rutin (73%) were the major effects observed at a maximum concentration of 0.5 mmol/l. Furthermore, slight positive inotropic effects and a rise in heart rate were seen. Similar but less intensive actions were found with the C-glycosides vitexin, vitexin-rhamnoside and monoacetyl-vitexin-rhamnoside. Possible beta-adrenergic activities of the flavonoids could be excluded by the addition of propranolol in fixed concentrations of 10(-8) to 10(-5) mol/l. Moreover, pretreatment of the animals with reserpine (7 mg/kg) did not influence myocardial activity of hyperoside (10(-4) mol/l). As previous experiments showed an inhibition of the 3',5'-cyclic adenosine monophosphate phosphodiesterase, the results suggest an inhibition of this enzyme as the possible underlying mechanism of cardiac action of flavonoids from Crataegus species.

  3. Myocardial imaging with a radioiodinated norepinephrine storage analog

    SciTech Connect

    Wieland, D.M.; Brown, L.E.; Rogers, W.L.; Worthington, K.C.; Wu, J.L.; Clinthorne, N.H.; Otto, C.A.; Swanson, D.P.; Beierwaltes, W.H.

    1981-01-01

    Meta-iodobenzylguanidine (M-IBG), an iodinated aromatic analog of the hypotensive drug guanethidine, localizes in the heart of the rat, dog, and rhesus monkey. A comparative study of tissue distribution in the dog has been performed with five myocardiophilic agents: thallium-201, I-125 16-iodohexadecanoic acid, H-3 norepinephrine, C-14 guanethidine and I-125 M-IBG. The last two compounds give heart concentrations and heart-to-blood concentration ratios similar to those of thallium-201. Planar and tomographic images of the hearts of the dog and rhesus monkey were obtained using I-131 or I-123 labeled M-IBG. Blocking studies with reserpine suggest that a major component of myocardial retention of M-IBG is sequestration within the norepinephrine storage vesicles of the adrenergic nerves. The localization of M-IBG in other organs with rich sympathetic innervation and the relative insensitivity of myocardial uptake to a wide range of loading doses lend additional support for a neuronal mode of retention.

  4. The antidepressant-like effect of bacopaside I: possible involvement of the oxidative stress system and the noradrenergic system.

    PubMed

    Liu, Xiaojun; Liu, Fang; Yue, Rongcai; Li, Yuanyuan; Zhang, Jigang; Wang, Shuping; Zhang, Shoude; Wang, Rui; Shan, Lei; Zhang, Weidong

    2013-09-01

    In the present study, the antidepressant-like effect of bacopaside I, a saponin compound present in the Bacopa monniera plant, was evaluated by behavioral and neurochemical methods. Bacopaside I (50, 15 and 5 mg/kg) was given to mice via oral gavage for 7 successive days. The treatment significantly decreased the immobility time in mouse models of despair tests, but it did not influence locomotor activity. Neurochemical assays suggested that treatment by bacopaside I (50, 15 and 5 mg/kg) improved brain antioxidant activity to varying degrees after the behavioral despair test. Bacopaside I (15 and 5 mg/kg) significantly reversed reserpine-induced depressive-like behaviors, including low temperature and ptosis. Conversely, bacopaside I did not affect either brain MAO-A or MAO-B activity after the behavioral despair test in mice. Additionally, 5-hydroxytryptophan (a precursor of 5-serotonin) was not involved in the antidepressant-like effect of bacopaside I. These findings indicated that the antidepressant-like effect of bacopaside I might be related to both antioxidant activation and noradrenergic activation, although the exact mechanism remains to be further elucidated.

  5. Positron emission tomographic imaging of cardiac sympathetic innervation and function

    SciTech Connect

    Goldstein, D.S.; Chang, P.C.; Eisenhofer, G.; Miletich, R.; Finn, R.; Bacher, J.; Kirk, K.L.; Bacharach, S.; Kopin, I.J. )

    1990-05-01

    Sites of uptake, storage, and metabolism of ({sup 18}F)fluorodopamine and excretion of ({sup 18}F)fluorodopamine and its metabolites were visualized using positron emission tomographic (PET) scanning after intravenous injection of the tracer into anesthetized dogs. Radioactivity was concentrated in the renal pelvis, heart, liver, spleen, salivary glands, and gall bladder. Uptake of 18F by the heart resulted in striking delineation of the left ventricular myocardium. Pretreatment with desipramine markedly decreased cardiac positron emission, consistent with dependence of the heart on neuronal uptake (uptake-1) for removal of circulating catecholamines. In reserpinized animals, cardiac positron emission was absent within 30 minutes after injection of ({sup 18}F)-6-fluorodopamine, demonstrating that the emission in untreated animals was from radioactive labeling of the sympathetic storage vesicles. Decreased positron emission from denervated salivary glands confirmed that the tracer was concentrated in sympathetic neurons. Radioactivity in the gall bladder and urinary system depicted the hepatic and renal excretion of the tracer and its metabolites. Administration of tyramine or nitroprusside increased and ganglionic blockade with trimethaphan decreased the rate of loss of myocardial radioactivity. The results show that PET scanning after administration of ({sup 18}F)fluorodopamine can be used to visualize sites of sympathetic innervation, follow the metabolism and renal and hepatic excretion of catecholamines, and examine cardiac sympathetic function.

  6. C2 Arylated Benzo[b]thiophene Derivatives as Staphylococcus aureus NorA Efflux Pump Inhibitors.

    PubMed

    Liger, François; Bouhours, Pascale; Ganem-Elbaz, Carine; Jolivalt, Claude; Pellet-Rostaing, Stéphane; Popowycz, Florence; Paris, Jean-Marc; Lemaire, Marc

    2016-02-01

    An innovative and straightforward synthesis of second-generation 2-arylbenzo[b]thiophenes as structural analogues of INF55 and the first generation of our laboratory-made molecules was developed. The synthesis of C2-arylated benzo[b]thiophene derivatives was achieved through a method involving direct arylation, followed by simple structural modifications. Among the 34 compounds tested, two of them were potent NorA pump inhibitors, which led to a 16-fold decrease in the ciprofloxacin minimum inhibitory concentration (MIC) against the SA-1199B strain at concentrations of 0.25 and 0.5 μg mL(-1) (1 and 1.5 μm, respectively). This is a promising result relative to that obtained for reserpine (MIC=20 μg mL(-1)), a reference compound amongst NorA pump inhibitors. These molecules thus represent promising candidates to be used in combination with ciprofloxacin against fluoroquinolone-resistant strains.

  7. Involvement of the Cerebral Monoamine Neurotransmitters System in Antidepressant-Like Effects of a Chinese Herbal Decoction, Baihe Dihuang Tang, in Mice Model

    PubMed Central

    Chen, Meng-Li; Gao, Jie; He, Xin-Rong; Chen, Qian

    2012-01-01

    Baihe Dihuang Tang (BDT) is a renowned Chinese herbal formula which is commonly used for treating patients with mental instability, absentmindedness, insomnia, deficient dysphoria, and other psychological diseases. These major symptoms closely associated with the depressive disorders. BDT was widely popular use for treating emotion-thought disorders for many years in China. In the present study, the antidepressant-like effect of BDT in mice was investigated by using the forced swim test (FST) and the tail suspension test (TST). The underlying mechanism was explored by determining the effect of BDT on the level of cerebral monoamine neurotransmitters. BDT (9 and 18 g/kg, p.o. for 14 days) administration significantly reduced the immobility time in both the FST and the TST without changing locomotion in the open field-test (OFT). Moreover, BDT treatment at the dose of 18 g/kg inhibited reserpine-induced ptosis. Meanwhile, BDT enhanced 5-HT and NA levels in mouse cerebrum as well as decreased the ratio of 5-HT compared to its metabolite, 5-HIAA, (turnover, 5-HIAA/5-HT) after TST. The results demonstrated that the antidepressant-like effect of BDT is mediated, at least partially, via the central monoaminergic neurotransmitter system. PMID:22956973

  8. [Mechanism of action of clonidine in the forced-swimming test in mice].

    PubMed

    Malinge, M; Colombel, M C; Bourin, M

    1989-01-01

    Clonidine displays immobility-reducing effects in the mouse swimming model at doses (0.06-16 mg/kg IP) which decrease spontaneous motility. Tricyclic antidepressants evoke a similar dissociation in motor activity. The immobility-reducing effect of clonidine (1 mg/kg at 30 min pretesting) was reversed by yohimbine (4 mg/kg) but was unaffected by prazosin (2 mg/kg) or alpha-methyl-paratyrosine (100 mg/kg), and was enhanced by reserpine (2.5 mg/kg). Mediation by alpha-2 postjunctional receptors was thus suggested. However, two 5-HT receptor blockers--methysergide (2 mg/kg) and ketanserin (8 mg/kg)--increased this effect of clonidine whereas the non selective agonist 5-MeODMT (1 mg/kg) reduced clonidine action. Conversely, pretreatment with a subthreshold dose of clonidine (0.06 mg/kg at 45 min pretesting) made effective subthreshold doses of three 5-HT uptake inhibitors (citalopram 2 mg/kg, indalpine and fluvoxamine 4 mg/kg) and of the 5-HT1 receptor agonist 8-OH-DPAT (0.5 mg/kg). According to these data, the mouse swimming model would trigger functional relationships between central alpha-noradrenergic and serotonergic mechanisms.

  9. Development of antimicrobial resistance in Campylobacter jejuni and Campylobacter coli adapted to biocides.

    PubMed

    Mavri, Ana; Smole Možina, Sonja

    2013-01-01

    The potential for adaptive resistance of Campylobacter jejuni and Campylobacter coli after step-wise exposure to increasing sub-inhibitory concentrations of five biocides as triclosan, benzalkonium chloride, cetylpyridinium chloride, chlorhexidine diacetate and trisodium phosphate, was investigated, to identify the mechanisms underlying resistance. The biocide resistance and cross-resistance to the antimicrobials erythromycin and ciprofloxacin, and to sodium dodecyl sulphate, were examined according to the broth microdilution method. The presence of active efflux was studied on the basis of restored sensitivity in the presence of the efflux pump inhibitors phenylalanine-arginine beta-naphthylamide, 1-(1-naphthylmethyl)-piperazine, cyanide 3-chlorophenylhydrazone, verapamil and reserpine. Changes in the outer membrane protein profiles and morphological changes in adapted strains were studied, as compared with the parent strains. Repeated exposure of C. jejuni and C. coli to biocides resulted in partial increases in tolerance to biocides itself, to other biocides and antimicrobial compounds. The developed resistance was stable for up to 10 passages in biocide-free medium. More than one type of active efflux was identified in adapted strains. These adapted strains showed different alterations to their outer membrane protein profiles, along with morphological changes. The data presented here suggest that different mechanisms are involved in adaptation to biocides and that this adaptation is unique to each strain of Campylobacter and does not result from a single species-specific mechanism.

  10. Alkaloids Modulate Motility, Biofilm Formation and Antibiotic Susceptibility of Uropathogenic Escherichia coli

    PubMed Central

    Dusane, Devendra H.; Hosseinidoust, Zeinab; Asadishad, Bahareh; Tufenkji, Nathalie

    2014-01-01

    Alkaloid-containing natural compounds have shown promise in the treatment of microbial infections. However, practical application of many of these compounds is pending a mechanistic understanding of their mode of action. We investigated the effect of two alkaloids, piperine (found in black pepper) and reserpine (found in Indian snakeroot), on the ability of the uropathogenic bacterium Escherichia coli CFT073 to colonize abiotic surfaces. Sub-inhibitory concentrations of both compounds (0.5 to 10 µg/mL) decreased bacterial swarming and swimming motilities and increased biofilm formation. qRT-PCR revealed a decrease in the expression of the flagellar gene (fliC) and motility genes (motA and motB) along with an increased expression of adhesin genes (fimA, papA, uvrY). Interestingly, piperine increased penetration of the antibiotics ciprofloxacin and azithromycin into E. coli CFT073 biofilms and consequently enhanced the ability of these antibiotics to disperse pre-established biofilms. The findings suggest that these alkaloids can potentially affect bacterial colonization by hampering bacterial motility and may aid in the treatment of infection by increasing antibiotic penetration in biofilms. PMID:25391152

  11. SOS induction of selected naturally occurring substances in Escherichia coli (SOS chromotest).

    PubMed

    Kevekordes, S; Mersch-Sundermann, V; Burghaus, C M; Spielberger, J; Schmeiser, H H; Arlt, V M; Dunkelberg, H

    1999-09-15

    Naturally occurring substances were tested for genotoxicity using a modified laboratory protocol of the Escherichia coli PQ37 genotoxicity assay (SOS chromotest) in the presence and in the absence of an exogenous metabolizing system from rat liver S9-mix. Aristolochic acid I, II, the plant extract aristolochic acid and psoralene were genotoxic; cycasine, emodine, monocrotaline and retrorsine were classified as marginal genotoxic in the SOS chromotest in the absence of S9-mix. In the presence of an exogenous metabolizing system from rat liver S9-mix aristolochic acid I, the plant extract, beta-asarone, cycasin, monocrotaline, psoralen and retrorsine showed genotoxic effects; aristolochic acid II marginal genotoxic effects. Arecoline, benzyl acetate, coumarin, isatidine dihydrate, reserpine, safrole, sanguinarine chloride, senecionine, senkirkine, tannin and thiourea revealed no genotoxicity in the SOS chromotest either in the presence or in the absence of an exogenous metabolizing system from rat liver S9-mix. For 17 of 20 compounds, the results obtained in the SOS chromotest could be compared to those obtained in the Ames test. It was found that 12 (70.6%) of these compounds give similar responses in both tests (6 positive and 6 negative responses). The present investigation and those reported earlier, the SOS chromotest, using E. coli PQ37, was able to detect correctly most of the Salmonella mutagens and non-mutagens.

  12. Treatment resistant depression or dementia: a case report.

    PubMed

    Shi, Zhongyong; Xiao, Shifu; Li, Xia

    2016-04-25

    The current case describes a 78-year-old female with two previous episodes of major depression who presented with both symptoms of depression (amotivation and flattened affect) and typical symptoms of dementia (impaired memory and executive functioning). Even after a detailed clinical exam and neuropsychiatric testing, it remained difficult to definitively classify the diagnosis as either treatment-resistant depression or old-age dementia. After 8 weeks of inpatient treatment, including changing her reserpine-based antihypertensive medication, adjusting her antidepressants, and providing psychotherapy, her depressive and anxiety symptoms improved, but most of her cognitive symptoms persisted. Her symptoms did not change over 7 months of post-hospitalization follow-up. She subsequently developed advanced breast cancer and started chemotherapy; at this point her depressive and cognitive symptoms became more pronounced. We conclude that it will take two-to-three years of follow-up to determine whether the cognitive symptoms are residual to her depression or a newly emerging dementia (or both). This case shows that for elderly patients who have symptoms of both depression and dementia, detailed clinical examination and neuropsychiatric testing may need to be combined with longitudinal assessment of their responsiveness to treatment before a definitive diagnosis can be assigned. PMID:27605868

  13. A review of the gastroprotective effects of ginger (Zingiber officinale Roscoe).

    PubMed

    Haniadka, Raghavendra; Saldanha, Elroy; Sunita, Venkatesh; Palatty, Princy L; Fayad, Raja; Baliga, Manjeshwar Shrinath

    2013-06-01

    The rhizomes of Zingiber officinale Roscoe (Zingiberaceae), commonly known as ginger is an important kitchen spice and also possess a myriad health benefits. The rhizomes have been used since antiquity in the various traditional systems of medicine to treat arthritis, rheumatism, sprains, muscular aches, pains, sore throats, cramps, hypertension, dementia, fever, infectious diseases, catarrh, nervous diseases, gingivitis, toothache, asthma, stroke and diabetes. Ginger is also used as home remedy and is of immense value in treating various gastric ailments like constipation, dyspepsia, belching, bloating, gastritis, epigastric discomfort, gastric ulcerations, indigestion, nausea and vomiting and scientific studies have validated the ethnomedicinal uses. Ginger is also shown to be effective in preventing gastric ulcers induced by nonsteroidal anti-inflammatory drugs [NSAIDs like indomethacin, aspirin], reserpine, ethanol, stress (hypothermic and swimming), acetic acid and Helicobacter pylori-induced gastric ulcerations in laboratory animals. Various preclinical and clinical studies have also shown ginger to possess anti-emetic effects against different emetogenic stimuli. However, conflicting reports especially in the prevention of chemotherapy-induced nausea and vomiting and motion sickness prevent us from drawing any firm conclusion on its effectiveness as a broad spectrum anti-emetic. Ginger has been shown to possess free radical scavenging, antioxidant; inhibition of lipid peroxidation and that these properties might have contributed to the observed gastroprotective effects. This review summarizes the various gastroprotective effects of ginger and also emphasizes on aspects that warranty future research to establish its activity and utility as a gastroprotective agent in humans. PMID:23612703

  14. Treatment resistant depression or dementia: a case report

    PubMed Central

    SHI, Zhongyong; XIAO, Shifu; LI, Xia

    2016-01-01

    Summary: The current case describes a 78-year-old female with two previous episodes of major depression who presented with both symptoms of depression (amotivation and flattened affect) and typical symptoms of dementia (impaired memory and executive functioning). Even after a detailed clinical exam and neuropsychiatric testing, it remained difficult to definitively classify the diagnosis as either treatment-resistant depression or old-age dementia. After 8 weeks of inpatient treatment, including changing her reserpine-based antihypertensive medication, adjusting her antidepressants, and providing psychotherapy, her depressive and anxiety symptoms improved, but most of her cognitive symptoms persisted. Her symptoms did not change over 7 months of post-hospitalization follow-up. She subsequently developed advanced breast cancer and started chemotherapy; at this point her depressive and cognitive symptoms became more pronounced. We conclude that it will take two-to-three years of follow-up to determine whether the cognitive symptoms are residual to her depression or a newly emerging dementia (or both). This case shows that for elderly patients who have symptoms of both depression and dementia, detailed clinical examination and neuropsychiatric testing may need to be combined with longitudinal assessment of their responsiveness to treatment before a definitive diagnosis can be assigned.

  15. Design, fabrication and test of a microfluidic nebulizer chip for desorption electrospray ionization mass spectrometry

    PubMed Central

    Sen, A K; Darabi, J; Knapp, D R

    2009-01-01

    This paper presents design, microfabrication, and test of a microfluidic nebulizer chip for desorption electrospray ionization mass spectrometry (DESI-MS) in proteomic analysis. The microfluidic chip is fabricated using cyclic olefin copolymer (COC) substrates. The fluidic channels are thermally embossed onto a base substrate using a nickel master and then a top substrate is thermally bonded to seal the channels. Carbon ink embossed into the top COC substrate is used to established electrical connection between the external power supply and the liquid in the channel. The microfluidic chip to external capillary connection is fabricated using Nanoport™ interconnection system. Preliminary leakage test was performed to demonstrate the interconnection system is leak-free and pressure test was performed to evaluate the burst pressure. Finally, the nebulizer chip was used to perform DESI-MS for analyzing peptides (BSA and bradykinin) and reserpine on the nanoporous alumina surface. DESI-MS performance of the microfluidic nebulizer chip is compared with that obtained using a conventional DESI nebulizer. PMID:20161284

  16. Characteristics of Ion Activation and Collision Induced Dissociation Using Digital Ion Trap Technology

    NASA Astrophysics Data System (ADS)

    Xu, Fuxing; Dang, Qiankun; Dai, Xinhua; Fang, Xiang; Wang, Yuanyuan; Ding, Li; Ding, Chuan-Fan

    2016-08-01

    Collision induced dissociation (CID) is one of the most established techniques for tandem mass spectrometry analysis. The CID of mass selected ion could be realized by ion resonance excitation with a digital rectangular waveform. The method is simple, and highly efficient CID result could be obtained by optimizing the experimental parameters, such as digital waveform voltage, frequency, and q value. In this work, the relationship between ion trapping waveform voltage and frequency at preselected q value, the relationship between waveform frequency and the q value at certain ion trapping voltage for optimum CID efficiency were investigated. Experiment results showed that the max CID efficiency of precursor reserpine ions can be obtained at different trapping waveform voltage and frequency when q and β are different. Based on systematic experimental analysis, the optimum experimental conditions for high CID efficiency can be calculated at any selected β or q. By using digital ion trap technology, the CID process and efficient fragmentation of parent ions can be realized by simply changing the trapping waveform amplitude, frequency, and the β values in the digital ion trap mass spectrometry. The technology and method are simple. It has potential use in ion trap mass spectrometry.

  17. Minimizing analyte electrolysis in electrospray ionization mass spectrometry using a redox buffer coated emitter electrode

    SciTech Connect

    Peintler-Krivan, Emese; Van Berkel, Gary J; Kertesz, Vilmos

    2010-01-01

    An emitter electrode with an electroactive poly(pyrrole) (PPy) polymer film coating was constructed for use in electrospray ionization mass spectrometry (ESI-MS). The PPy film acted as a surface-attached redox buffer limiting the interfacial potential of the emitter electrode. While extensive oxidation of selected analytes (reserpine and amodiaquine) was observed in positive ion mode ESI using a bare metal (gold) emitter electrode, the oxidation was suppressed for these same analytes when using the PPy-coated electrode. A semi-quantitative relationship between the rate of oxidation observed and the interfacial potential of the emitter electrode was shown. The redox buffer capacity, and therefore the lifetime of the redox buffering effect, correlated with the oxidation potential of the analyte and with the magnitude of the film charge capacity. Online reduction of the PPy polymer layer using negative ion mode ESI between analyte injections was shown to successfully restore the redox buffering capacity of the polymer film to its initial state.

  18. Investigation of the enzymology and pharmacology of novel substrates and inhibitors of dopamine beta-monooxygenase

    SciTech Connect

    Roberts, S.F.

    1987-01-01

    Dopamine beta-monooxygenase (DBM) was shown to catalyze the selenoxidation of 2-(phenylseleno)ethylamines, selenium-containing analogues of dopamine, by the normal monooxygenase pathway. The compounds 2-(phenylseleno)-ethylamine (PAESe), 2-(4'-hydroxyphenylseleno)ethylamine (pOH PAESe), and 1-(phenylseleno)-2-propylamine (Me PAESe) were synthesized and fully characterized as DBM substrates. Two other classes of compounds were investigated as potential alternate substrates for DBM. The possibility of stereoselective sulfonylation of 2-(phenylsulfenyl)- ethylamine (PAESO) was considered. A unique class of compounds, 2-(phenylthio)ethanols were designed and synthesized as DBM substrates but were found to be a novel class of potent competitive inhibitors of DBM with respect to tyramine. Preliminary experiments were also performed in an effort to demonstrate that the potent antihypertensive and indirect-acting sympathomimetic activity of 2-(phenylthio)ethylamine (PAES) was a result of DBM-oxygenation of this compound in vivo. The specific reserpine-sensitive uptake of (/sup 3/H)-norepinephrine into rat brain synaptosomes was demonstrated as was the synaptosomal conversion of (/sup 3/H)-dopamine to (/sup 3/H)-norepinephrine.

  19. Angiotensin converting enzyme in the brain, testis, epididymis, pituitary gland and adrenal gland

    SciTech Connect

    Strittmatter, S.M.

    1986-01-01

    (/sup 3/H)Captopril binds to angiotensin converting enzyme (ACE) in rat tissue homogenates. The pharmacology, regional distribution and copurification of (/sup 3/H)captopril binding with enzymatic activity demonstrate the selectivity of (/sup 3/H)captopril labeling of ACE. (/sup 3/H)Captopril binding to purified ACE reveals differences in cationic dependence and anionic regulation between substrate catalysis and inhibitor recognition. (/sup 3/H)Captopril association with ACE is entropically driven. The selectivity of (/sup 3/H)captopril binding permits autoradiographic localization of the ACE in the brain, male reproductive system, pituitary gland and adrenal gland. In the brain, ACE is visualized in a striatonigral neuronal pathway which develops between 1 and 7 d after birth. In the male reproductive system, (/sup 3/H)captopril associated silver grains are found over spermatid heads and in the lumen of seminiferous tubules in stages I-VIII and XII-XIV. In the pituitary gland, ACE is localized to the posterior lobe and patches of the anterior lobe. The adrenal medulla contains moderate ACE levels while low levels are found in the adrenal cortex. Adrenal medullary ACE is increased after hypophysectomy and after reserpine treatment. The general of ligand binding techniques for the study of enzymes is demonstrated by the specific labeling of another enzyme, enkephaline convertase, in crude tissue homogenates by the inhibitor (/sup 3/H)GEMSA.

  20. Myocardial effects of flavonoids from Crataegus species.

    PubMed

    Schüssler, M; Hölzl, J; Fricke, U

    1995-08-01

    The influence of the main flavonoids from Crataegus species (hawthorn, Rosaceae) on coronary flow, heart rate and left ventricular pressure as well as on the velocity of contraction and relaxation was investigated in Langendorff perfused isolated guinea pig hearts at a constant pressure of 70 cmH2O. Drug action was evaluated in a concentration range of 10(-7) to 5 x 10(-4) mol/l. An increase of coronary flow caused by the O-glycosides luteolin-7-glucoside (186%), hyperoside (66%) and rutin (66%) as well as an increase of the relaxation velocity (positive lusitropism) by luteolin-7-glucoside (104%), hyperoside (62%) and rutin (73%) were the major effects observed at a maximum concentration of 0.5 mmol/l. Furthermore, slight positive inotropic effects and a rise in heart rate were seen. Similar but less intensive actions were found with the C-glycosides vitexin, vitexin-rhamnoside and monoacetyl-vitexin-rhamnoside. Possible beta-adrenergic activities of the flavonoids could be excluded by the addition of propranolol in fixed concentrations of 10(-8) to 10(-5) mol/l. Moreover, pretreatment of the animals with reserpine (7 mg/kg) did not influence myocardial activity of hyperoside (10(-4) mol/l). As previous experiments showed an inhibition of the 3',5'-cyclic adenosine monophosphate phosphodiesterase, the results suggest an inhibition of this enzyme as the possible underlying mechanism of cardiac action of flavonoids from Crataegus species. PMID:7575743

  1. The effects of paraoxon on blood pressure in the anaesthetized and in the conscious rat

    PubMed Central

    de Neef, J.H.; Jordaan, K.M.; Porsius, A.J.

    1982-01-01

    1 Intravenous administration of paraoxon (150-825 μg/kg) to anaesthetized rats induced long-lasting, dose-dependent pressor effects. Only after injection of 825 μg/kg paraoxon was the pressor response followed by a depressor effect and a bradycardia that could be blocked by N-methylatropine. Intracerebroventricular injection of paraoxon into anaesthetized rats also induced pressor effects. 2 In order to elucidate the mechanism of the pressor action rats were given dexetimide, N-methylatropine, mecamylamine, phentolamine, prazosin, yohimbine, atenolol and metoprolol. If treatment with these drugs resulted in a low initial blood pressure, vasopressin was infused to elevate blood pressure to normal levels. The influence of adrenalectomy, pretreatment with reserpine and midcollicular transection was also examined. 3 The pressor effect of paraoxon was not influenced by N-methylatropine or mecamylamine. However, a combination of these drugs as well as dexetimide, phentolamine or prazosin combined with yohimbine, reduced or prevented the pressor effect. 4 In conscious rats the effects of paraoxon and the action of antimuscarinic drugs upon the pressor response were similar to those observed in anaesthetized animals. 5 Acetylcholinesterase activities were measured in various brain regions and in whole blood. Paraoxon concentrations within the CNS were also measured. 6 It is concluded that the pressor effect of paraoxon in anaesthetized and conscious rats is mediated by a central mechanism, although a contribution of peripheral acetylcholinesterase inhibition in sympathetic ganglia to this pressor effect cannot be ruled out. PMID:7139183

  2. Structural Modifications of Neuroprotective Anti-Parkinsonian (−)-N6-(2-(4-(Biphenyl-4-yl)piperazin-1-yl)-ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (D-264): An Effort toward the Improvement of in Vivo Efficacy of the Parent Molecule

    PubMed Central

    2015-01-01

    In our overall goal to develop multifunctional dopamine D2/D3 agonist drugs for the treatment of Parkinson’s disease (PD), we previously synthesized potent D3 preferring agonist D-264 (1a), which exhibited neuroprotective properties in two animal models of PD. To enhance the in vivo efficacy of 1a, a structure–activity relationship study was carried out. Competitive binding and [35S]GTPγS functional assays identified compound (−)-9b as one of the lead molecules with preferential D3 agonist activity (EC50(GTPγS); D3 = 0.10 nM; D2/D3 (EC50): 159). Compounds (−)-9b and (−)-8b exhibited high in vivo activity in two PD animal models, reserpinized and 6-hydroxydopamine (OHDA)-induced unilateral lesioned rats. On the other hand, 1a failed to show any in vivo activity in these models unless the compound was dissolved in 5–10% beta-hydroxy propyl cyclodextrin solution. Lead compounds exhibited appreciable radical scavenging activity. In vitro experiments with dopaminergic MN9D cells indicated neuroprotection by both 1a and (−)-9b from toxicity of MPP+. PMID:24471976

  3. Liquid Microjunction Surface Sampling Probe Electrospray Mass Spectrometry for Detection of Drugs and Metabolites in Thin Tissue Sections

    SciTech Connect

    Van Berkel, Gary J; Kertesz, Vilmos; Koeplinger, Kenneth A.; Vavek, Marissa; Kong, Ah-Ng Tony

    2008-01-01

    A self-aspirating, liquid micro-junction surface sampling probe/electrospray emitter mass spectrometry system was demonstrated for use in the direct analysis of spotted and dosed drugs and their metabolites in thin tissue sections. Proof-of-principle sampling and analysis directly from tissue without the need for sample preparation was demonstrated first by raster scanning a region on a section of rat liver onto which reserpine was spotted. The mass spectral signal from selected reaction monitoring was used to develop a chemical image of the spotted drug on the tissue. The probe was also used to selectively spot sample areas of sagittal whole mouse body tissue sections that had been dosed orally (90 mg/kg) with R,S-sulforaphane 3 hrs prior to sacrifice. Sulforaphane and its glutathione and N-acetyl cysteine conjugates were monitored with selected reaction monitoring and detected in the stomach and various other tissues from the dosed mouse. No signal for these species was observed in the tissue from a control mouse. The same dosed tissue section was used to illustrate the possibility of obtaining a line scan across the whole body section. In total these results illustrate the potential for rapid screening of the distribution of drugs and metabolites in tissue sections with the micro-liquid junction surface sampling probe/electrospray mass spectrometry approach.

  4. Expediting the method development and quality control of reversed-phase liquid chromatography electrospray ionization mass spectrometry for pharmaceutical analysis by using an LC/MS performance test mix.

    PubMed

    Tang, L; Fitch, W L; Alexander, M S; Dolan, J W

    2000-11-01

    Mass spectrometry combined with liquid chromatography (LC/MS) has become an important analytical methodology in both pharmaceutical and biomolecule analyses. LC/MS, especially with reversed-phase HPLC (RP-LC), is extensively used in the separation and structural identification of pharmaceutical samples. However, many parameters have to be considered when a new LC/MS method is developed for either separation and structural analysis of unknown mixtures or quantitative analysis of a set of known compounds in an assay. The optimization of a new LC/MS method can be a time-consuming process. A novel kit-LC/MS performance test mix-composed of aspartame, cortisone, reserpine, and dioctyl phthalate has been developed to accelerate the process of establishing a new RP-LC/MS method. The LC/MS mix makes the evaluation and validation of an LC/MS method more efficient and easier. It also simplifies the quality control procedure for an LC/MS method in use.

  5. Effect of mealing on plasma and brain amino acid, and brain monoamine in rats after oral aspartame.

    PubMed

    Torii, K; Mimura, T; Takasaki, Y; Ichimura, M

    1986-01-01

    Aspartame (APM; L-aspartyl-L-phenylalanine methyl ester) was investigated for its ability to alter brain amino acids and monoamines in overnight fasted rats allowed to consume commercial diets for 60 minutes. In addition, the effects of mealing on the changes in plasma and brain amino acids and brain monoamines induced by glucose and/or insulin, and known pharmacologically active compounds, were studied. The consumption of the commercial chow largely prevented changes in blood glucose and amino acids, and brain amino acids and the monoamines dopamine, norepinephrine and serotonin that might be expected to occur following glucose with or without insulin. Feeding failed to prevent changes in the above parameters when 5-hydroxy-tryptophan, p-chlorophenylalanine and reserpine were administered. The oral administration of up to 250 mg/kg BW APM with water or glucose followed by free feeding failed to alter brain monoamines. These studies demonstrate the potent ability of food to normalize biochemical parameters in blood and brain that otherwise might occur, and clearly show the lack of effect on brain monoamine levels of abuse doses of APM when administered with food.

  6. Neurotoxic compound N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP4) depletes endogenous norepinephrine and enhances release of (/sup 3/H)norepinephrine from rat cortical slices

    SciTech Connect

    Landa, M.E.; Rubio, M.C.; Jaim-Etcheverry, G.

    1984-10-01

    The alkylating compound N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP4) injected to rodents blocks norepinephrine (NE) uptake and reduces endogenous NE levels in the central nervous system and in the periphery. To investigate the processes leading to these alterations, rat cortical slices were incubated in the presence of DSP4. Cortical NE was depleted by 40% after incubation of slices in 10(-5) M DSP4 for 60 min and this was blocked by desipramine. The spontaneous outflow of radioactivity from cortical slices labeled previously with (/sup 3/H)NE was enhanced markedly both during exposure to DSP4 and during the subsequent washings, suggesting that NE depletion could be due to this stimulation of NE release. The radioactivity released by DSP4 was accounted for mainly by NE and its deaminated metabolite 3,4-dihydroxyphenylglycol. The enhanced release, independent of external Ca++, apparently originated from the vesicular pool as it was absent after reserpine pretreatment. Activities of the enzymes related to NE synthesis were not altered by DSP4 in vitro and only monoamine oxidase activity was inhibited at high concentrations. Thus, the depletion of endogenous NE produced by DSP4 is probably due to a persistent enhancement of its release from the vesicular pool. Fixation of DSP4 to the NE transport system is necessary but not sufficient to produce the acute NE depletion and the characteristic long-term actions of the compound.

  7. Wild Edible Fruit of Prunus nepalensis Ser. (Steud), a Potential Source of Antioxidants, Ameliorates Iron Overload-Induced Hepatotoxicity and Liver Fibrosis in Mice

    PubMed Central

    Panja, Sourav; Das, Abhishek; Mandal, Nripendranath

    2015-01-01

    The antioxidant and restoration potentials of hepatic injury by Prunus nepalensis Ser. (Steud), a wild fruit plant from the Northeastern region of India, were investigated. The fruit extract (PNME) exhibited excellent antioxidant and reducing properties and also scavenged the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical (IC50 = 30.92 ± 0.40 μg/ml). PNME demonstrated promising scavenging potency, as assessed by the scavenging of different reactive oxygen and nitrogen species. Moreover, the extract revealed an exceptional iron chelation capacity with an IC50 of 25.64 ± 0.60 μg/ml. The extract induced significant improvement of hepatic injury and liver fibrosis against iron overload induced hepatotoxicity in mice in a dose-dependent manner, and this effect was supported by different histopathological studies. The phytochemical constitutions and their identification by HPLC confirmed the presence of purpurin, tannic acid, methyl gallate, reserpine, gallic acid, ascorbic acid, catechin and rutin. The identified compounds were investigated for their individual radical scavenging and iron chelation activity; some compounds exhibited excellent radical scavenging and iron chelation properties, but most were toxic towards normal cells (WI-38). On the other hand, crude PNME was found to be completely nontoxic to normal cells, suggesting its feasibility as a safe oral drug. The above study suggests that different phytochemicals in PNME contributed to its free radical scavenging and iron chelation activity; however, further studies are required to determine the pathway in which PNME acts to treat iron-overload diseases. PMID:26633891

  8. Unexpected Analyte Oxidation during Desorption Electrospray Ionization - Mass Spectrometry

    SciTech Connect

    Pasilis, Sofie P; Kertesz, Vilmos; Van Berkel, Gary J

    2008-01-01

    During the analysis of surface spotted analytes using desorption electrospray ionization mass spectrometry (DESI-MS), abundant ions are sometimes observed that appear to be the result of oxygen addition reactions. In this investigation, the effect of sample aging, the ambient lab environment, spray voltage, analyte surface concentration, and surface type on this oxidative modification of spotted analytes, exemplified by tamoxifen and reserpine, during analysis by desorption electrospray ionization mass spectrometry was studied. Simple exposure of the samples to air and to ambient lighting increased the extent of oxidation. Increased spray voltage lead also to increased analyte oxidation, possibly as a result of oxidative species formed electrochemically at the emitter electrode or in the gas - phase by discharge processes. These oxidative species are carried by the spray and impinge on and react with the sampled analyte during desorption/ionization. The relative abundance of oxidized species was more significant for analysis of deposited analyte having a relatively low surface concentration. Increasing spray solvent flow rate and addition of hydroquinone as a redox buffer to the spray solvent were found to decrease, but not entirely eliminate, analyte oxidation during analysis. The major parameters that both minimize and maximize analyte oxidation were identified and DESI-MS operational recommendations to avoid these unwanted reactions are suggested.

  9. Traditional knowledge and formulations of medicinal plants used by the traditional medical practitioners of bangladesh to treat schizophrenia like psychosis.

    PubMed

    Ahmed, Md Nasir; Kabidul Azam, Md Nur

    2014-01-01

    Schizophrenia is a subtle disorder of brain development and plasticity; it affects the most basic human processes of perception, emotion, and judgment. In Bangladesh the traditional medical practitioners of rural and remote areas characterized the schizophrenia as an insanity or a mental problem due to possession by ghosts or evil spirits and they have used various plant species' to treat such symptoms. The aim of the present study was to conduct an ethnomedicinal plant survey and documentation of the formulations of different plant parts used by the traditional medical practitioners of Rangamati district of Bangladesh for the treatment of schizophrenia like psychosis. It was observed that the traditional medical practitioners used a total of 15 plant species to make 14 formulations. The plants were divided into 13 families, used for treatment of schizophrenia and accompanying symptoms like hallucination, depression, oversleeping or insomnia, deterioration of personal hygiene, forgetfulness, and fear due to evil spirits like genies or ghost. A search of the relevant scientific literatures showed that a number of plants used by the medicinal practitioners have been scientifically validated in their uses and traditional medicinal knowledge has been a means towards the discovery of many modern medicines. Moreover, the antipsychotic drug reserpine, isolated from the dried root of Rauvolfia serpentina species, revolutionized the treatment of schizophrenia. So it is very much possible that formulations of the practitioner, when examined scientifically in their entireties, can form discovery of lead compounds which can be used as safe and effective antipsychotic drug to treat schizophrenia. PMID:25101175

  10. Wild Edible Fruit of Prunus nepalensis Ser. (Steud), a Potential Source of Antioxidants, Ameliorates Iron Overload-Induced Hepatotoxicity and Liver Fibrosis in Mice.

    PubMed

    Chaudhuri, Dipankar; Ghate, Nikhil Baban; Panja, Sourav; Das, Abhishek; Mandal, Nripendranath

    2015-01-01

    The antioxidant and restoration potentials of hepatic injury by Prunus nepalensis Ser. (Steud), a wild fruit plant from the Northeastern region of India, were investigated. The fruit extract (PNME) exhibited excellent antioxidant and reducing properties and also scavenged the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical (IC50 = 30.92 ± 0.40 μg/ml). PNME demonstrated promising scavenging potency, as assessed by the scavenging of different reactive oxygen and nitrogen species. Moreover, the extract revealed an exceptional iron chelation capacity with an IC50 of 25.64 ± 0.60 μg/ml. The extract induced significant improvement of hepatic injury and liver fibrosis against iron overload induced hepatotoxicity in mice in a dose-dependent manner, and this effect was supported by different histopathological studies. The phytochemical constitutions and their identification by HPLC confirmed the presence of purpurin, tannic acid, methyl gallate, reserpine, gallic acid, ascorbic acid, catechin and rutin. The identified compounds were investigated for their individual radical scavenging and iron chelation activity; some compounds exhibited excellent radical scavenging and iron chelation properties, but most were toxic towards normal cells (WI-38). On the other hand, crude PNME was found to be completely nontoxic to normal cells, suggesting its feasibility as a safe oral drug. The above study suggests that different phytochemicals in PNME contributed to its free radical scavenging and iron chelation activity; however, further studies are required to determine the pathway in which PNME acts to treat iron-overload diseases.

  11. The antidepressant-like effect of bacopaside I: possible involvement of the oxidative stress system and the noradrenergic system.

    PubMed

    Liu, Xiaojun; Liu, Fang; Yue, Rongcai; Li, Yuanyuan; Zhang, Jigang; Wang, Shuping; Zhang, Shoude; Wang, Rui; Shan, Lei; Zhang, Weidong

    2013-09-01

    In the present study, the antidepressant-like effect of bacopaside I, a saponin compound present in the Bacopa monniera plant, was evaluated by behavioral and neurochemical methods. Bacopaside I (50, 15 and 5 mg/kg) was given to mice via oral gavage for 7 successive days. The treatment significantly decreased the immobility time in mouse models of despair tests, but it did not influence locomotor activity. Neurochemical assays suggested that treatment by bacopaside I (50, 15 and 5 mg/kg) improved brain antioxidant activity to varying degrees after the behavioral despair test. Bacopaside I (15 and 5 mg/kg) significantly reversed reserpine-induced depressive-like behaviors, including low temperature and ptosis. Conversely, bacopaside I did not affect either brain MAO-A or MAO-B activity after the behavioral despair test in mice. Additionally, 5-hydroxytryptophan (a precursor of 5-serotonin) was not involved in the antidepressant-like effect of bacopaside I. These findings indicated that the antidepressant-like effect of bacopaside I might be related to both antioxidant activation and noradrenergic activation, although the exact mechanism remains to be further elucidated. PMID:23872136

  12. Presynaptic recording of quanta from midbrain dopamine neurons and modulation of the quantal size.

    PubMed

    Pothos, E N; Davila, V; Sulzer, D

    1998-06-01

    The observation of quantal release from central catecholamine neurons has proven elusive because of the absence of evoked rapid postsynaptic currents. We adapted amperometric methods to observe quantal release directly from axonal varicosities of midbrain dopamine neurons that predominantly contain small synaptic vesicles. Quantal events were elicited by high K+ or alpha-latrotoxin, required extracellular Ca2+, and were abolished by reserpine. The events indicated the release of 3000 molecules over 200 microsec, much smaller and faster events than quanta associated with large dense-core vesicles previously recorded in vertebrate preparations. The number of dopamine molecules per quantum increased as a population to 380% of controls after glial-derived neurotrophic factor (GDNF) exposure and to 350% of controls after exposure to the dopamine precursor L-dihydroxyphenylalanine (L-DOPA). These results introduce a means to measure directly the number of transmitter molecules released from small synaptic vesicles of CNS neurons. Moreover, quantal size was not an invariant parameter in CNS neurons but could be modulated by neurotrophic factors and altered neurotransmitter synthesis.

  13. The effects of anticoagulants and other drugs on cellular and cutaneous reactions to antigen in guinea-pigs with delayed-type hypersensitivity

    PubMed Central

    Nelson, D. S.

    1965-01-01

    Delayed-type hypersensitivity to tuberculin was induced in guinea-pigs by vaccination with BCG. The effects of several drugs on the responses of peritoneal exudate cells to tuberculin (PPD) and on delayed skin reactions to PPD were investigated. In untreated animals intraperitoneal injections of PPD were followed by the virtually complete loss of macrophages from the exudates (the macrophage disappearance reaction), the partial loss of lymphocytes and a marked increase in the number of polymorphs in the exudates. The macrophage disappearance reaction was markedly or completely inhibited in animals treated with the anticoagulant drugs heparin or sodium warfarin, very slightly inhibited in animals treated with cortisone acetate or promethazine and not inhibited in animals treated with reserpine. The other peritoneal cellular responses were variably but only slightly affected by these drugs. Delayed skin reactions to PPD were partly inhibited in animals treated with heparin, sodium warfarin or cortisone acetate and more strongly inhibited in animals treated with a combination of sodium warfarin and cortisone acetate. Histological examination of the skin test sites of untreated animals and of animals treated with sodium warfarin and/or cortisone acetate showed that the accumulation of macrophages was more markedly inhibited in animals treated with sodium warfarin than in animals treated with cortisone alone. No correlation could be established between the effect of treatment with sodium warfarin on the macrophage disappearance reaction, on blood coagulation and on serum complement levels. ImagesFIGS. 2-5 PMID:5838197

  14. Identification of a mammalian vesicular polyamine transporter

    PubMed Central

    Hiasa, Miki; Miyaji, Takaaki; Haruna, Yuka; Takeuchi, Tomoya; Harada, Yuika; Moriyama, Sawako; Yamamoto, Akitsugu; Omote, Hiroshi; Moriyama, Yoshinori

    2014-01-01

    Spermine and spermidine act as neuromodulators upon binding to the extracellular site(s) of various ionotropic receptors, such as N-methyl-d-aspartate receptors. To gain access to the receptors, polyamines synthesized in neurons and astrocytes are stored in secretory vesicles and released upon depolarization. Although vesicular storage is mediated in an ATP-dependent, reserpine-sensitive fashion, the transporter responsible for this process remains unknown. SLC18B1 is the fourth member of the SLC18 transporter family, which includes vesicular monoamine transporters and vesicular acetylcholine transporter. Proteoliposomes containing purified human SLC18B1 protein actively transport spermine and spermidine by exchange of H+. SLC18B1 protein is predominantly expressed in the hippocampus and is associated with vesicles in astrocytes. SLC18B1 gene knockdown decreased both SLC18B1 protein and spermine/spermidine contents in astrocytes. These results indicated that SLC18B1 encodes a vesicular polyamine transporter (VPAT). PMID:25355561

  15. Self-aspirating atmospheric pressure chemical ionization source for direct sampling of analytes on surfaces and in liquid solutions.

    PubMed

    Asano, Keiji G; Ford, Michael J; Tomkins, Bruce A; Van Berkel, Gary J

    2005-01-01

    A self-aspirating heated nebulizer probe is described and demonstrated for use in the direct analysis of analytes on surfaces and in liquid samples by atmospheric pressure chemical ionization (APCI) mass spectrometry. Functionality and performance of the probe as a self-aspirating APCI source is demonstrated using reserpine and progesterone as test compounds. The utility of the probe to sample analytes directly from surfaces was demonstrated first by scanning development lanes of a reversed-phase thin-layer chromatography plate in which a three-component dye mixture, viz., Fat Red 7B, Solvent Green 3, and Solvent Blue 35, was spotted and the components were separated. Development lanes were scanned by the sampling probe operated under computer control (x, y plane) while full-scan mass spectra were recorded using a quadrupole ion trap mass spectrometer. In addition, the ability to sample the surface of pharmaceutical tablets (viz., Extra Strength Tylenol and Evista tablets) and to detect the active ingredients (acetaminophen and raloxifene, respectively) selectively was demonstrated using tandem mass spectrometry (MS/MS). Finally, the capability to sample analyte solutions from the wells of a 384-well microtiter plate and to perform quantitative analyses using MS/MS detection was illustrated with cotinine standards spiked with cotinine-d3 as an internal standard.

  16. Traditional Knowledge and Formulations of Medicinal Plants Used by the Traditional Medical Practitioners of Bangladesh to Treat Schizophrenia Like Psychosis

    PubMed Central

    Kabidul Azam, Md. Nur

    2014-01-01

    Schizophrenia is a subtle disorder of brain development and plasticity; it affects the most basic human processes of perception, emotion, and judgment. In Bangladesh the traditional medical practitioners of rural and remote areas characterized the schizophrenia as an insanity or a mental problem due to possession by ghosts or evil spirits and they have used various plant species' to treat such symptoms. The aim of the present study was to conduct an ethnomedicinal plant survey and documentation of the formulations of different plant parts used by the traditional medical practitioners of Rangamati district of Bangladesh for the treatment of schizophrenia like psychosis. It was observed that the traditional medical practitioners used a total of 15 plant species to make 14 formulations. The plants were divided into 13 families, used for treatment of schizophrenia and accompanying symptoms like hallucination, depression, oversleeping or insomnia, deterioration of personal hygiene, forgetfulness, and fear due to evil spirits like genies or ghost. A search of the relevant scientific literatures showed that a number of plants used by the medicinal practitioners have been scientifically validated in their uses and traditional medicinal knowledge has been a means towards the discovery of many modern medicines. Moreover, the antipsychotic drug reserpine, isolated from the dried root of Rauvolfia serpentina species, revolutionized the treatment of schizophrenia. So it is very much possible that formulations of the practitioner, when examined scientifically in their entireties, can form discovery of lead compounds which can be used as safe and effective antipsychotic drug to treat schizophrenia. PMID:25101175

  17. Antidepressant Effects of Mallotus oppositifolius in Acute Murine Models

    PubMed Central

    Kukuia, Kennedy K. E.; Mante, Priscilla K.; Ameyaw, Elvis O.; Adongo, Donatus W.

    2014-01-01

    Objective. Hydroalcoholic extract of leaves of Mallotus oppositifolius (MOE), a plant used for CNS conditions in Ghana, was investigated for acute antidepressant effects in the forced swimming (FST) and tail suspension tests (TST). Results. In both FST and TST, MOE (10, 30, and 100 mg kg−1) significantly decreased immobility periods and frequencies. A 3-day pretreatment with 200 mg kg−1, i.p., para-chlorophenylalanine (PCPA), a tryptophan hydroxylase inhibitor, reversed the decline in immobility and the increase of swimming score induced by MOE in the modified FST. Pretreatment with reserpine alone (1 mg kg−1), α-methyldopa alone (400 mg kg−1, i.p.), or a combination of both drugs failed to reverse the decline in immobility or the increase in swimming score caused by the extract in the modified FST. The extract potentiated the frequency of head twitch responses induced by 5-hydroxytryptamine. Pretreatment with d-serine (600 mg kg−1, i.p.), glycine/NMDA agonist, abolished the behavioural effects of MOE while d-cycloserine (2.5 mg kg−1, i.p.), a glycine/NMDA partial agonist, potentiated it in both TST and modified FST. Conclusion. The extract exhibited antidepressant effects in mice which is mediated by enhancement of serotoninergic neurotransmission and inhibition of glycine/NMDA receptor activation. PMID:25045543

  18. Cytochrome P450 mediates dopamine formation in the brain in vivo.

    PubMed

    Bromek, Ewa; Haduch, Anna; Gołembiowska, Krystyna; Daniel, Władysława A

    2011-09-01

    The cytochrome P450-mediated synthesis of dopamine from tyramine has been shown in vitro. The aim of the present study was to demonstrate the ability of rat cytochrome P450 (CYP) 2D to synthesize dopamine from tyramine in the brain in vivo. We employed two experimental models using reserpinized rats with a blockade of the classical pathway of dopamine synthesis from tyrosine. Model A estimated dopamine production from endogenous tyramine in brain structures in vivo (ex vivo measurement of a tissue dopamine level), while Model B measured extracellular dopamine produced from exogenous tyramine (an in vivo microdialysis). In Model A, quinine (a CYP2D inhibitor) given intraperitoneally caused a significant decrease in dopamine level in the striatum and nucleus accumbens and tended to fall in the substantia nigra and frontal cortex. In Model B, an increase in extracellular dopamine level was observed after tyramine given intrastructurally (the striatum). After joint administration of tyramine and quinine, the amount of the dopamine formed was significantly lower compared to the group receiving tyramine only. The results of the two complementary experimental models indicate that the hydroxylation of tyramine to dopamine may take place in rat brain in vivo, and that CYP2D catalyzes this reaction.

  19. Breathing in Parkinsonism in the Rat.

    PubMed

    Bialkowska, Monika; Boguszewski, Paweł; Pokorski, Mieczyslaw

    2016-01-01

    Parkinsonism is underlain by dopamine (DA) deficiency in the mid-brain, a neurotransmitter innately involved with respiratory regulation. However, the state of respiration in parkinsonism is an unsettled issue. In this study we seek to determine ventilation and its responses to hypoxia in a reserpine--alpha-methyl-tyrosine model of parkinsonism in the rat. We also attempted to differentiate between the role of discrete brain and carotid body DA stores in the modulation of the hypoxic ventilatory response (HVR). To this end we used domperidone, a peripheral D2 receptor antagonist, and levodopa, a central D2 receptor agonist. The HVRs to acute 12% and 8% hypoxia were studied in a whole body plethysmograph in the same rats before and after the induction of parkinsonic symptoms in conscious rats. We found that resting ventilation and the HVR were distinctly reduced in parkinsonism. The reduction was particularly evident in the peak hypoxic hyperpneic augmentation. Domperidone, which enhanced ventilation in the control healthy condition, failed to reverse the reduced parkinsonic HVR. In contrast, levodopa, which did not appreciably affected ventilation in the healthy condition, caused the parkinsonic HVR to return to and above the baseline healthy level. The findings demonstrate the predominance of a lack of the central DA stimulatory element and minimize the role of carotid body DA in the ventilatory impediment of parkinsonism. In conclusion, the study provides the pathophysiological savvy concerning the respiratory insufficiency of parkinsonism, a sequela which carries a risk of chronically impaired blood oxygenation, which may drive the disease worsening.

  20. Behavioral effects of β-phenylethylamine and various monomethylated and monohalogenated analogs in mice are mediated by catecholaminergic mechanisms.

    PubMed

    Mosnaim, Aron D; Hudzik, Thomas; Wolf, Marion E

    2015-01-01

    The effects of the administration [intraperitoneally, 15 and 75 mg/kg, except α-MePEA (amphetamine, AMPH) at 5 and 10 mg/kg] of β-phenylethylamine (PEA), its methylated (o-Me-, p-Me-, α-Me-, β-Me-, N-Me-, p-OMe-, N,N-di-Me-, and 3,4-diOH-N-Me-), para-halogenated (Br-, Cl-, F-, and I-), and other derivatives for example, p-OHPEA (p-tyramine), on Swiss male albino mice caged behavior fall into 3 broad categories. (1) N,N-diMe-, 3,4-diOH-N-Me-, and o-MePEA tend to reduce the behavioral activity, (2) p-OH and p-IPEA were without noticeable effects, and (3) the remaining compounds increased locomotor activity, produced hyperexcitability and fighting, jumping and vocalization, and convulsion in a graded manner (listed in increasing order p-OMe-, β-Me-, p-Cl-, p-Br-, p-F-, p-Me-, and N-MePEA, PEA itself and α-MePEA). The latter compound (amphetamine) being the most potent among them; equieffective but with lower potency were p-MePEA, N-MePEA, and PEA itself. The effects of PEAs upon group cage behavior were increased by pretreatment with pargyline (1.5 hours; 15 mg/kg) and decreased after reserpine or haloperidol [4 hours and/or 24 hours (2.5 and/or 2.5 mg/kg) and 1 hour (1 mg/kg), respectively], reaching full suppression with the double-dose regimen of reserpine and single dose of haloperidol. As expected, none of these substances by themselves were noticeable changed group mice activity or stereotypic behavior. The effects of test amines and catecholamine-modulating agents on stereotypy were assessed by rating the sequentially occurring behaviors: increased exploratory behavior with increased sniffing; occasional side-to-side head weaving; paw-licking and other grooming; gnawing, fighting and continuous side-to-side head weaving, and periodic episodes of "popcorn" behavior, during which all mice in the cage ran, jumped, and vocalized. In general, rank efficacy in eliciting stereotype aligned with rank efficacy in affecting group cage behavior. Our results show

  1. Behavioral effects of β-phenylethylamine and various monomethylated and monohalogenated analogs in mice are mediated by catecholaminergic mechanisms.

    PubMed

    Mosnaim, Aron D; Hudzik, Thomas; Wolf, Marion E

    2015-01-01

    The effects of the administration [intraperitoneally, 15 and 75 mg/kg, except α-MePEA (amphetamine, AMPH) at 5 and 10 mg/kg] of β-phenylethylamine (PEA), its methylated (o-Me-, p-Me-, α-Me-, β-Me-, N-Me-, p-OMe-, N,N-di-Me-, and 3,4-diOH-N-Me-), para-halogenated (Br-, Cl-, F-, and I-), and other derivatives for example, p-OHPEA (p-tyramine), on Swiss male albino mice caged behavior fall into 3 broad categories. (1) N,N-diMe-, 3,4-diOH-N-Me-, and o-MePEA tend to reduce the behavioral activity, (2) p-OH and p-IPEA were without noticeable effects, and (3) the remaining compounds increased locomotor activity, produced hyperexcitability and fighting, jumping and vocalization, and convulsion in a graded manner (listed in increasing order p-OMe-, β-Me-, p-Cl-, p-Br-, p-F-, p-Me-, and N-MePEA, PEA itself and α-MePEA). The latter compound (amphetamine) being the most potent among them; equieffective but with lower potency were p-MePEA, N-MePEA, and PEA itself. The effects of PEAs upon group cage behavior were increased by pretreatment with pargyline (1.5 hours; 15 mg/kg) and decreased after reserpine or haloperidol [4 hours and/or 24 hours (2.5 and/or 2.5 mg/kg) and 1 hour (1 mg/kg), respectively], reaching full suppression with the double-dose regimen of reserpine and single dose of haloperidol. As expected, none of these substances by themselves were noticeable changed group mice activity or stereotypic behavior. The effects of test amines and catecholamine-modulating agents on stereotypy were assessed by rating the sequentially occurring behaviors: increased exploratory behavior with increased sniffing; occasional side-to-side head weaving; paw-licking and other grooming; gnawing, fighting and continuous side-to-side head weaving, and periodic episodes of "popcorn" behavior, during which all mice in the cage ran, jumped, and vocalized. In general, rank efficacy in eliciting stereotype aligned with rank efficacy in affecting group cage behavior. Our results show

  2. NMDA receptor complex blockade by oral administration of magnesium: comparison with MK-801.

    PubMed

    Decollogne, S; Tomas, A; Lecerf, C; Adamowicz, E; Seman, M

    1997-09-01

    The ion channel of the N-methyl-D-aspartate (NMDA) receptor complex is subject to a voltage-dependent regulation by Mg2+ cations. Under physiological conditions, this channel is supposed to be blocked by a high concentration of magnesium in extracellular fluids. A single dose of magnesium organic salts (i.e., aspartate, pyroglutamate, and lactate) given orally to normal mice rapidly increases the plasma Mg2+ level and reveals a significant dose-dependent antagonist effect of magnesium on the latency of NMDA-induced convulsions; this effect is similar to that seen after administration of the dizocilpine (MK-801) channel blocker. An anticonvulsant effect of Mg2+ treatment is also observed with strychnine-induced convulsions but not with bicuculline-, picrotoxin-, or pentylenetetrazol-induced convulsions. In the forced swimming test, Mg2+ salts reduce the immobility time in a way similar to imipramine and thus resemble the antidepressant-like activity of MK-801. This activity is masked at high doses of magnesium by a myorelaxant effect that is comparable to MK-801-induced ataxia. Potentiation of yohimbine fatal toxicity is another test commonly used to evaluate putative antidepressant drugs. Administration of Mg2+ salts, like administration of imipramine strongly potentiates yohimbine lethality in contrast to MK-801, which is only poorly active in this test. Neither Mg2+ nor MK-801 treatment can prevent reserpine-induced hypothermia. These data demonstrate that oral administration of magnesium to normal animals can antagonize NMDA-mediated responses and lead to antidepressant-like effects that are comparable to those of MK-801. This important regulatory role of Mg2+ in the central nervous system needs further investigation to evaluate the potential therapeutic advantages of magnesium supplementation in psychiatric disorders. PMID:9264101

  3. Ambient Mass Spectrometry Imaging with Picosecond Infrared Laser Ablation Electrospray Ionization (PIR-LAESI).

    PubMed

    Zou, Jing; Talbot, Francis; Tata, Alessandra; Ermini, Leonardo; Franjic, Kresimir; Ventura, Manuela; Zheng, Jinzi; Ginsberg, Howard; Post, Martin; Ifa, Demian R; Jaffray, David; Miller, R J Dwayne; Zarrine-Afsar, Arash

    2015-12-15

    A picosecond infrared laser (PIRL) is capable of cutting through biological tissues in the absence of significant thermal damage. As such, PIRL is a standalone surgical scalpel with the added bonus of minimal postoperative scar tissue formation. In this work, a tandem of PIRL ablation with electrospray ionization (PIR-LAESI) mass spectrometry is demonstrated and characterized for tissue molecular imaging, with a limit of detection in the range of 100 nM for reserpine or better than 5 nM for verapamil in aqueous solution. We characterized PIRL crater size using agar films containing Rhodamine. PIR-LAESI offers a 20-30 μm vertical resolution (∼3 μm removal per pulse) and a lateral resolution of ∼100 μm. We were able to detect 25 fmol of Rhodamine in agar ablation experiments. PIR-LAESI was used to map the distribution of endogenous methoxykaempferol glucoronide in zebra plant (Aphelandra squarrosa) leaves producing a localization map that is corroborated by the literature. PIR-LAESI was further used to image the distribution inside mouse kidneys of gadoteridol, an exogenous magnetic resonance contrast agent intravenously injected. Parallel mass spectrometry imaging (MSI) using desorption electrospray ionization (DESI) and matrix assisted laser desorption ionization (MALDI) were performed to corroborate PIR-LAESI images of the exogenous agent. We further show that PIR-LAESI is capable of desorption ionization of proteins as well as phospholipids. This comparative study illustrates that PIR-LAESI is an ion source for ambient mass spectrometry applications. As such, a future PIRL scalpel combined with secondary ionization such as ESI and mass spectrometry has the potential to provide molecular feedback to guide PIRL surgery. PMID:26561279

  4. Continuous dopaminergic stimulation by pramipexole is effective to treat early morning akinesia in animal models of Parkinson's disease: A pharmacokinetic-pharmacodynamic study using in vivo microdialysis in rats.

    PubMed

    Ferger, Boris; Buck, Kerstin; Shimasaki, Makoto; Koros, Eliza; Voehringer, Patrizia; Buerger, Erich

    2010-07-01

    Short-acting dopamine (DA) agonists are usually administered several times a day resulting in fluctuating plasma and brain levels. DA agonists providing continuous dopaminergic stimulation may achieve higher therapeutic benefit for example by alleviating nocturnal disturbances as well as early morning akinesia. In the present study continuous release (CR) of pramipexole (PPX) was maintained by subcutaneous implantation of Alzet minipumps, whereas subcutaneous PPX injections were used to mimic PPX immediate release (IR) in male Wistar rats. In the catalepsy bar test, PPX-CR (1 mg/kg/day) reversed the haloperidol-induced motor impairment in the morning and over the whole observation period of 12h. In contrast, PPX-IR (tid 1 mg/kg, pre-treatment the day before) was not effective in the morning but catalepsy was reduced for 6 h after PPX-IR (1 mg/kg) injection. In the reserpine model, early morning akinesia indicated by the first motor activity measurement in the morning was significantly reversed by PPX-CR (2 mg/kg/day). Again, PPX-IR (tid 0.3 mg/kg, pre-treatment the day before) was not able to antagonise early morning akinesia. These results are in agreement with in vivo microdialysis measurements showing a continuous decrease of extracellular DA levels and a continuous PPX exposure in the PPX-CR (1 mg/kg/day) group. In contrast, PPX-IR (0.3 mg/kg) produced a transient decrease of extracellular DA levels over 6 h and showed maximum PPX levels 2 h after dosing which decreased over the following 6-8 h. The present study demonstrates that PPX-CR may offer a higher therapeutic benefit than PPX-IR on early morning akinesia and confirms earlier reports that PPX-IR reverses motor impairment for several hours. PMID:20196139

  5. Vmat2 Heterozygous Mutant Mice Display a Depressive-Like Phenotype

    PubMed Central

    Fukui, Masato; Rodriguiz, Ramona M.; Zhou, Jiechun; Jiang, Sara X.; Phillips, Lindsey E.; Caron, Marc G.; Wetsel, William C.

    2010-01-01

    The vesicular monoamine transporter 2 (VMAT2) is localized primarily within the CNS and is responsible for transporting monoamines from the cytoplasm into secretory vesicles. Because reserpine (a VMAT inhibitor) can precipitate depressive-like symptoms in humans, we investigated whether Vmat2 heterozygous (HET) mice present with depressive-like behaviors. The mutants showed locomotor and rearing retardation in the open field and appeared anhedonic to 1 and 1.5% sucrose solutions. Immobility times for Vmat2 heterozygotes were prolonged in forced swim and imipramine normalized this behavior. HET animals also showed enhanced immobility in tail suspension and this response was alleviated by fluoxetine, reboxetine, and bupropion. Stimulated GTPγS binding indicated that α2-adrenergic receptors in HET hippocampus were more sensitive to UK 14,304 (5-bromo-N-(4,5-dihydro-1-H-imidazol-2-yl)-6-quinoxalinamine) stimulation than in wild type (WT) mice. In learned helplessness, mice were exposed to a shuttle box for 4 d or were given inescapable foot-shocks for the same time period. On day 5, all animals were tested in shock escape. Failure rates and the latency to escape were similar for WT and HET mice that were only pre-exposed to the test apparatus. In foot-shock groups, learned helplessness was more robust in heterozygotes than in WT controls. Basal secretion of serum corticosterone was not distinguished by genotype; however, corticosterone levels in mutants were more responsive to stress. Anxiety-like responses of WT and HET animals in the open field, light-dark exploration, zero maze, and novelty-suppressed feeding tests were indistinguishable. Collectively, these findings suggest that Vmat2 heterozygotes display a depressive-like phenotype that is devoid of anxiety-like behavior. PMID:17898223

  6. An examination of the cardiovascular effects of an 'Irukandji' jellyfish, Alatina nr mordens.

    PubMed

    Winter, Kelly L; Isbister, Geoffrey K; Schneider, Jennifer J; Konstantakopoulos, Nicki; Seymour, Jamie E; Hodgson, Wayne C

    2008-07-10

    Irukandji syndrome is usually characterized by delayed severe abdominal, back and chest pain associated with autonomic effects including diaphoresis, hypertension and, in severe cases, myocardial injury and pulmonary oedema. It is most often associated with envenoming by the jellyfish Carukia barnesi, but a number of other jellyfish, including Alatina mordens, are now known to produce Irukandji syndrome. In the present study, nematocyst-derived venom from A. nr mordens (150-250 microg/kg, i.v.) produced a long-lasting pressor effect in anaesthetised rats. This pressor response (250 microg/kg, i.v.) was significantly inhibited by prior administration of the alpha-adrenoceptor antagonist prazosin (200 microg/kg, i.v.) but not by CSL box jellyfish antivenom (300 U/kg, i.v.). A. nr mordens venom 250 microg/kg (i.v.) caused marked increases in plasma adrenaline and noradrenaline concentrations following administration in anaesthetised rats. The venom did not contain appreciable amounts of either adrenaline or noradrenaline. A. nr mordens venom (25 microg/ml) produced a contractile response in rat electrically stimulated vas deferens which was markedly reduced in tissues pre-treated with reserpine (0.1mM) or guanethidine (0.1mM). Sodium dodecyl sulphate (SDS)-PAGE analysis showed that A. nr mordens venom is comprised of multiple protein bands ranging from 10 to 200 kDa. Western blot analysis using CSL box jellyfish antivenom indicated several antigenic proteins in A. nr mordens venom, however, it did not detect all proteins present in the venom. This study characterizes the in vitro and in vivo effects of A. nr mordens venom and indicates that the cardiovascular effects are at least partially mediated by endogenous catecholamine release. PMID:18547753

  7. Tandem action of exercise training and food restriction completely preserves ischemic preconditioning in the aging heart.

    PubMed

    Abete, P; Testa, G; Galizia, G; Mazzella, F; Della Morte, D; de Santis, D; Calabrese, C; Cacciatore, F; Gargiulo, G; Ferrara, N; Rengo, G; Sica, V; Napoli, C; Rengo, F

    2005-01-01

    Ischemic preconditioning (IP) has been proposed as an endogenous form of protection against ischemia reperfusion injury. IP, however, does not prevent post-ischemic dysfunction in the aging heart but may be partially corrected by exercise training and food restriction. We investigated the role of exercise training combined with food restriction on restoring IP in the aging heart. Effects of IP against ischemia-reperfusion injury in isolated hearts from adult (A, 6 months old), sedentary 'ad libitum' fed (SL), trained ad libitum fed (TL), sedentary food-restricted (SR), trained- and food-restricted senescent rats (TR) (24 months old) were investigated. Norepinephrine release in coronary effluent was determined by high performance liquid cromatography. IP significantly improved final recovery of percent developed pressure in hearts from A (p<0.01) but not in those from SL (p=NS) vs unconditioned controls. Developed pressure recovery was partial in hearts from TL and SR (64.3 and 67.3%, respectively; p<0.05 vs controls) but it was total in those from TR (82.3%, p=NS vs A; p<0.05 vs hearts from TL and SR). Similarly, IP determined a similar increase of norepinephrine release in A (p<0.001) and in TR (p<0.001, p=NS vs adult). IP was abolished by depletion of myocardial norepinephrine stores by reserpine in all groups. Thus, IP reduces post-ischemic dysfunction in A but not in SL. Moreover, IP was preserved partially in TR and SR and totally in TR. Complete IP maybe due to full restoration of norepinephrine release in response to IP stimulus.

  8. A multifunctional microfluidic droplet-array chip for analysis by electrospray ionization mass spectrometry.

    PubMed

    Su, Yuan; Zhu, Ying; Fang, Qun

    2013-05-21

    This paper describes a multifunctional semi-closed droplet-array chip coupled with electrospray ionization mass spectrometry (ESI-MS) detection for multiple sample pretreatment and analysis. A novel interfacing method for coupling droplet system with ESI-MS was proposed using a sampling probe-two-dimensional (2D) droplet-array strategy. The 2D droplet-array system was composed of an 8 × 8 microwell array chip for droplet storage and a layer of oil covering the droplets served as a "virtual wall" to avoid droplet evaporation or cross-contamination. An L-shaped capillary was adopted as the interface of the droplet array and ESI-MS, using its inlet end as a sampling probe for droplets and its outlet with a tip size of ~20 μm as an electrospray emitter, without the need for any droplet extraction device. The droplet analysis was performed by moving the droplet-array chip to allow the capillary sampling probe to sequentially enter into the droplets through the oil and introduce the sample solution into the capillary emitter for MS detection. The MS analysis time for each droplet sample was 40 s with a sample consumption of ca. 13 nL. A good repeatability of 5.7% (RSD, n = 9) was obtained for 10(-6) M reserpine droplet analysis. The uses of the semi-closed 2D droplet array and off-line interfacing mode provide the system with the substantial flexibility and controllability in droplet indexing, multi-step manipulating, and on-demand sampling for MS analysis. We applied the present system in multi-step pretreatment and identification of small amounts of proteomic samples of myoglobin and cytochrome C, including in-droplet protein reduction, alkylation, digestion, and purification based on solid-phase extraction, matrix modification, sample droplet introduction under flow injection mode, and ESI-MS detection. PMID:23525283

  9. Half a century of antipsychotics and still a central role for dopamine D2 receptors.

    PubMed

    Kapur, Shitij; Mamo, David

    2003-10-01

    A review of the history of antipsychotics reveals that while the therapeutic effects of chlorpromazine and reserpine were discovered and actively researched almost concurrently, subsequent drug development has been restricted to drugs acting on postsynaptic receptors rather than modulation of dopamine release. The fundamental property of atypical antipsychotics is their ability to produce an antipsychotic effect in the absence of extrapyramidal side effects (EPS) or prolactin elevation. Modulation of the dopamine D2 receptor remains both necessary and sufficient for antipsychotic drug action, with affinity to the D2-receptor being the single most important discriminator between a typical and atypical drug profile. Most antipsychotics, including atypical antipsychotics, show a dose-dependent threshold of D2 receptor occupancy for their therapeutic effects, although the precise threshold is different for different drugs. Some atypical antipsychotics do not appear to reach the threshold for EPS and prolactin elevation, possibly accounting for their atypical nature. To link the biological theories of antipsychotics to their psychological effects, a hypothesis is proposed wherein psychosis is a state of aberrant salience of stimuli and ideas, and antipsychotics, via modulation of the mesolimbic dopamine system, dampen the salience of these symptoms. Thus, antipsychotics do not excise psychosis: they provide the neurochemical platform for the resolution of symptoms. Future generations of antipsychotics may need to move away from a "one-size-fits-all polypharmacy-in-a-pill" approach to treat all the different aspects of schizophrenia. At least in theory a preferred approach would be the development of specific treatments for the different dimensions of schizophrenia (e.g., positive, negative, cognitive, and affective) that can be flexibly used and titrated in the service of patients' presenting psychopathology. PMID:14642968

  10. General pharmacological properties of cilostazol, a new antithrombotic drug. Part I: Effects on the central nervous system.

    PubMed

    Shintani, S; Toba, Y; Suzuki, S; Ninomiya, S; Umezato, M; Hiyama, T

    1985-01-01

    The pharmacological effects of the new platelet aggregation inhibitor cilostazol (6-(4-(1-cyclohexyl-1 H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, OPC-13013) on the central nervous system were studied. Cilostazol had little effect on the general behavior of mice up to a dose of 1000 mg/kg p.o. and caused disappearance of pinna reflex, alertness and startle response and slight ptosis in only one of 6 rats at a dose of 1000 mg/kg p.o. Cilostazol had little effect on spontaneous movement and motor coordination in mice and did not potentiate hexobarbital-induced hypnosis, antagonize methamphetamine-induced hypermotor activity, cause muscle relaxation or have an anticonvulsant effect. Cilostazol did not affect normal body temperature but slightly antagonized reserpine-induced hypothermia at 300 mg/kg p.o. in mice. Cilostazol did not show an analgesic effect by Haffner's method, but it did slightly inhibit acetic acid-induced writhing at doses higher than 300 mg/kg p.o. in mice. The inhibitory effect was considered to be due to its peripheral effect. Cilostazol had little effect on discriminated avoidance response in rats, EEG arousal response in rabbits or spinal reflex in cats. However, it did slightly increase the slow wave until about 2 h after administration at 1000 mg/kg p.o., but the slow-wave sleep period did not tend to persist for a long period. These results suggest that cilostazol had little effect on the central nervous system.

  11. [Behavior pharmacology of maprotiline, a new antidepressant].

    PubMed

    Ueki, S; Fujiwara, M; Inoue, K; Kataoka, Y; Ibii, N

    1975-11-01

    The effect of maprotiline (N-methyl-9, 10-ethanoanthracene-9 (10H)-propylamine) on animal behavior was investigated in mice and rats and compared with those of amitriptyline and imipramine. Maprotiline inhibited reserpine hypothermia in mice and tetrabenazine ptosis in rats, while it potentiated the effects of methamphetamine, L-DOPA and apomorphine in mice, in a similar manner to that of amitriptyline and imipramine. Maprotiline was more potent than anitriptyline and imipramine in antagonizing haloperidol-induced catalepsy as well as in suppressing muricide induced by either olfactory bulbectomy or delta-9-tetrahydrocannabinol in rats. Maprotiline potentiated anesthesia induced by thiopental or ether in mice to a lesser degree than did amitriptyline, and failed to counteract the lethal effect of physostigmine or oxotremorine tremor in mice, indicating that this drug has no central anti-cholinergic effect. Maprotiline markedly inhibited hyperemotionality of the rat with either septal lesions or olfactory bulb ablations, suggesting that it does have a tranquilizing effect. Inhibition of conditioned avoidance response of the rat in the shuttle box and reduction of methamphetamine group toxicity with maprotiline were similar to those with amitriptyline. Maprotiline exaggerated pentetrazol convulsion, decreased muscle tone and impaired coordinated motor activity in mice to a much lesser degree than amitriptyline and imipramine. LD50 of maprotiline was approximately twice that of imipramine and three times that of amitriptyline. These results indicate that maprotiline is a new type of antidepressant, has a low toxicity and shares both potent antidepressant and some tranquilizing effect, without possessing central anticholinergic action.

  12. Dopamine D(1) receptor deletion strongly reduces neurotoxic effects of methamphetamine.

    PubMed

    Ares-Santos, S; Granado, N; Oliva, I; O'Shea, E; Martin, E D; Colado, M I; Moratalla, R

    2012-02-01

    Methamphetamine (METH) is a potent, highly addictive psychostimulant consumed worldwide. In humans and experimental animals, repeated exposure to this drug induces persistent neurodegenerative changes. Damage occurs primarily to dopaminergic neurons, accompanied by gliosis. The toxic effects of METH involve excessive dopamine (DA) release, thus DA receptors are highly likely to play a role in this process. To define the role of D(1) receptors in the neurotoxic effects of METH we used D(1) receptor knock-out mice (D(1)R(-/-)) and their WT littermates. Inactivation of D(1)R prevented METH-induced dopamine fibre loss and hyperthermia, and increases in gliosis and pro-inflammatory molecules such as iNOS in the striatum. In addition, D(1)R inactivation prevented METH-induced loss of dopaminergic neurons in the substantia nigra. To explore the relationship between hyperthermia and neurotoxicity, METH was given at high ambient temperature (29 °C). In this condition, D(1)R(-/-) mice developed hyperthermia following drug delivery and the neuroprotection provided by D(1)R inactivation at 23 °C was no longer observed. However, reserpine, which empties vesicular dopamine stores, blocked hyperthermia and strongly potentiated dopamine toxicity in D(1)R(-/-) mice, suggesting that the protection afforded by D(1)R inactivation is due to both hypothermia and higher stored vesicular dopamine. Moreover, electrical stimulation evoked higher DA overflow in D(1)R(-/-) mice as demonstrated by fast scan cyclic voltammetry despite their lower basal DA content, suggesting higher vesicular DA content in D(1)R(-/-) than in WT mice. Altogether, these results indicate that the D(1)R plays a significant role in METH-induced neurotoxicity by mediating drug-induced hyperthermia and increasing the releasable cytosolic DA pool.

  13. Serotonin storage pools in basophil leukemia and mast cells: characterization of two types of serotonin binding protein and radioautographic analysis of the intracellular distribution of (/sup 3/H)serotonin

    SciTech Connect

    Tamir, H.; Theoharides, T.C.; Gershon, M.D.; Askenase, P.W.

    1982-06-01

    The binding of serotonin to protein(s) derived from rat basophil leukemia (RBL) cells and mast cells was studied. Two types of serotonin binding protein in RBL cells was found. These proteins differed from one another in molecular weight and eluted in separate peaks from sephadex G-200 columns. Peak I protein (KD = 1.9 x 10/sup -6/ M) was a glycoprotein that bound to concanavalin A (Con A); Peak II protein (KD/sub 1/ = 4.5 x 10/sup -/8 M; KD/sub 2/ = 3.9 x 10/sup -6/ M) did not bind to Con A. Moreover, binding of (/sup 3/H)serotonin to protein of Peak I was sensitive to inhibition by reserpine, while binding of (/sup 3/H)serotonin to protein of Peak II resisted inhibition by that drug. Other differences between the two types of binding protein were found, the most significant of which was the far more vigorous conditions of homogenization required to extract Peak I than Peak II protein. Electron microscope radioautographic analysis of the intracellular distribution of (/sup 3/H) serotonin taken up in vitro by RBL cells or in vivo by murine mast cells indicated that essentially all of the labeled amine was located in cytoplasmic granules.No evidence for a pool in the cytosol was found and all granules were capable of becoming labeled. The presence of two types of intracellular serotonin binding proteins in these cells may indicate that there are two intracellular storage compartments for the amine. Both may be intragranular, but Peak I protein may be associated with the granular membrane while Peak II protein may be more free within the granular core. Different storage proteins may help to explain the differential release of amines from mast cell granules.

  14. Interaction of cannabis and general anaesthetic agents in mice.

    PubMed

    Chesher, G B; Jackson, D M; Starmer, G A

    1974-04-01

    1 A cannabis extract (I) (in a concentration equivalent to 10 mg Delta(9)-tetrahydro-cannabinol(THC)/kg) prolonged pentobarbitone anaesthesia in mice maximally 20 min to 2 h after medication. The effect was still significant after 8 h, but less than at 2 hours.2 The cannabis extract (I) (equivalent to 10 mg Delta(9)-THC/kg) prolonged both pentobarbitone and ether anaesthesia in mice when administered 20 min before the anaesthetic. After eight consecutive daily doses of cannabis, the pentobarbitone anaesthesia was still significantly longer than a control group, while ether anaesthesia was not significantly prolonged.3 A second cannabis extract (II) with a different ratio of cannabinoids (also administered in dosage equivalent to 10 mg Delta(9)-THC/kg) failed to affect pentobarbitone anaesthesia in mice. This extract presented about 4% the dose of cannabidiol as extract I.4 Delta(8)-THC, Delta(9)-THC and cannabidiol prolonged pentobarbitone anaesthesia with cannabidiol being generally more active than Delta(9)-THC. Cannabinol (10 mg/kg) was inactive.5 The effects of cannabidiol and Delta(9)-THC were found to be additive, and there was a consistent trend for cannabinol to reduce the effectiveness of Delta(9)-THC and cannabidiol when given in combination.6 Premedication with phenoxybenzamine, phentolamine, propranolol, iproniazid, protriptyline, desipramine, reserpine, alpha-methyl tyrosine or parachlorophenylalanine did not affect the extract I-induced prolongation of pentobarbitone anaesthesia.7 It is concluded that cannabis may affect pentobarbitone and ether anaesthesia in mice at least partially by a direct depressant effect, and that the cannabis-induced prolongation of anaesthesia is probably unrelated to any effect on central 5-hydroxytryptamine or catecholamine neurones.

  15. Occurrence of a unique protein toxin from the Indian King Cobra (Ophiophagus hannah) venom.

    PubMed

    Gomes, A; De, P; Dasgupta, S C

    2001-01-01

    A unique (lethal-cardiotoxic-hemorrhagic) protein toxin (Toxin CM55) was isolated and purified from Indian King Cobra (Ophiophagus hannah) venom by CM-sephadex ion exchange chromatography and reverse phase HPLC. The purified toxin had an SDS-molecular weight of 22 +/- 0.5 kD. UV absorption spectra of Toxin CM55 showed a peak at 280 nm, whereas when excited at 280 nm fluorescence, Toxin CM55 showed an E(max) at 333.4 nm. Toxin CM55 had an LD(50) of 28.28 microg/20 g (i. v.) in albino mice. The cardiotoxic action of the toxin was established on isolated guinea pig/rabbit heart and guinea pig auricle. In rats, Toxin CM55 caused ECG abnormalities including widened QRS complex and monomorphic ventricular tachycardia suggesting that the possible site of action of Toxin CM55 was the ventricle. Toxin CM55 produced significant vasoconstriction on peripheral blood vessels. It produced significant contraction of isolated guinea pig ileum, rat fundus and rat uterus, which was completely antagonised by methysergide. The toxin was found to release a significant amount of serotonin from rabbit platelets. Toxin CM55 produced cutaneous hemorrhage in albino mice, which was also produced in reserpine and p-chloro phenylalanine pretreated animals. Rabbit antiserum was raised against Toxin CM55, which gave prominent bands in immunogel diffusion and immunoelectrophoresis. The antiserum provided 2 LD(50) protection against Toxin CM55-induced lethality in mice and also neutralised 3 MHD hemorrhagic dose of the toxin.

  16. Comparative neurochemical profile of 3,4-methylenedioxymethamphetamine and its metabolite alpha-methyldopamine on key targets of MDMA neurotoxicity.

    PubMed

    Escubedo, E; Abad, S; Torres, I; Camarasa, J; Pubill, D

    2011-01-01

    The neurotoxicity of MDMA or "Ecstasy" in rats is selectively serotonergic, while in mice it is both dopaminergic and serotonergic. MDMA metabolism may play a key role in this neurotoxicity. The function of serotonin and dopamine transporter and the effect of MDMA and its metabolites on them are essential to understand MDMA neurotoxicity. The aim of the present study was to investigate and compare the effects of MDMA and its metabolite alpha-methyldopamine (MeDA) on several molecular targets, mainly the dopamine and serotonin transporter functionality, to provide evidence for the role of this metabolite in the neurotoxicity of MDMA in rodents. MeDA had no affinity for the serotonin transporter but competed with serotonin for its uptake. It had no persistent effects on the functionalism of the serotonin transporter, in contrast to the effect of MDMA. Moreover, MeDA inhibited the uptake of dopamine into the serotonergic terminal and also MAO(B) activity. MeDA inhibited dopamine uptake with a lower IC(50) value than MDMA. After drug washout, the inhibition by MeDA persisted while that of MDMA was significantly reduced. The effect of MDMA on the dopamine transporter is related with dopamine release from vesicular stores, as this inhibition disappeared in reserpine-treated animals. However, the effect of MeDA seems to be a persistent conformational change of this transporter. Moreover, in contrast with MDMA, MeDA did not show affinity for nicotinic receptors, so no effects of MeDA derived from these interactions can be expected. The metabolite reduced cell viability at lower concentrations than MDMA. Apoptosis plays a key role in MDMA induced cellular toxicity but necrosis is the major process involved in MeDA cytotoxicity. We conclude that MeDA could protect against the serotonergic lesion induced by MDMA but potentiate the dopaminergic lesion as a result of the persistent blockade of the dopamine transporter induced this metabolite.

  17. Integration of Multiple Components in Polystyrene-based Microfluidic Devices Part 2: Cellular Analysis

    PubMed Central

    Anderson, Kari B.; Halpin, Stephen T.; Johnson, Alicia S.; Martin, R. Scott; Spence, Dana M.

    2012-01-01

    In Part II of this series describing the use of polystyrene (PS) devices for microfluidic-based cellular assays, various cellular types and detection strategies are employed to determine three fundamental assays often associated with cells. Specifically, using either integrated electrochemical sensing or optical measurements with a standard multi-well plate reader, cellular uptake, production, or release of important cellular analytes are determined on a PS-based device. One experiment involved the fluorescence measurement of nitric oxide (NO) produced within an endothelial cell line following stimulation with ATP. The result was a four-fold increase in NO production (as compared to a control), with this receptor-based mechanism of NO production verifying the maintenance of cell receptors following immobilization onto the PS substrate. The ability to monitor cellular uptake was also demonstrated by optical determination of Ca2+ into endothelial cells following stimulation with the Ca2+ ionophore A20317. The result was a significant increase (42%) in the calcium uptake in the presence of the ionophore, as compared to a control (17%) (p < 0.05). Finally, the release of catecholamines from a dopaminergic cell line (PC 12 cells) was electrochemically monitored, with the electrodes being embedded into the PS-based device. The PC 12 cells had better adherence on the PS devices, as compared to use of PDMS. Potassium-stimulation resulted in the release of 114 ± 11 µM catecholamines, a significant increase (p < 0.05) over the release from cells that had been exposed to an inhibitor (reserpine, 20 ± 2 µM of catecholamines). The ability to successfully measure multiple analytes, generated in different means from various cells under investigation, suggests that PS may be a useful material for microfluidic device fabrication, especially considering the enhanced cell adhesion to PS, its enhanced rigidity/amenability to automation, and its ability to enable a wider range of

  18. Fundamental studies with a monodisperse aerosol-based liquid chromatography/mass spectrometry interface (MAGIC-LC/MS): Progress report, September 1, 1985-August 31, 1988

    SciTech Connect

    Browner, R.F.

    1988-05-01

    Technical advances have been made through a number of careful and detailed studies of fundamental processes occurring within the interface. These have led to great improvements in the performance of the interface, many of which are detailed below. Of particular importance has been an improvement in detection capabilities, allowing full-scan (40--400 daltons) electron impact mass spectra to be obtained with only approximately 5 ng of material injected on column. Selected ion monitoring gives detection limits in the range of 100 pg. These figures are particularly noteworthy because they represent values within a factor of 3 of the lowest detection limits possible with the same instrument when used in a GC/MS mode. The full range of compound types accessible with the MAGIC-LC/MS interface has not been fully investigated. In general terms, all compounds which are known to be capable of generating EI and CI spectra and which have been tried with the interface have generated good quality spectra. These include carbamate and triazine pesticides, phenyl urea herbicides, polynuclear aromatic hydrocarbons, plant alkaloids, antioxidants and EPA Appendix 8 compounds. Compounds known not to generate EI spectra, such as simple sugars and certain azo dyes, predictably do not generate spectra with the current system. The primary mode of ion formation appears to be through a flash vaporization step in the ion source, followed by EI or CI ionization, as selected. It is possible to generate good searchable EI spectra with strong molecular ions even for quite involatile species. An example is provided by reserpine, with a molecular weight of 608 daltons, which generates a searchable EI spectrum with a strong molecular ion at m/z 608. 11 refs.

  19. Monoamine receptor agonists, acting preferentially at presynaptic autoreceptors and heteroreceptors, downregulate the cell fate adaptor FADD in rat brain cortex.

    PubMed

    García-Fuster, M Julia; García-Sevilla, Jesús A

    2015-02-01

    FADD is a crucial adaptor of death receptors that can engage apoptosis or survival actions (e.g. neuroplasticity) through its phosphorylated form (p-FADD). Although FADD was shown to participate in receptor mechanisms related to drugs of abuse, little is known on its role in the signaling of classic neurotransmitters (dopamine, noradrenaline, and serotonin) in brain. This study assessed the modulation of FADD (and p-FADD/FADD ratio, as an index of neuroplasticity) and FLIP-L (a neuroprotective FADD interacting partner), as well as the role of MEK-ERK signaling, after activation of monoamine auto/heteroreceptors by selective agonists in rat cortex. Acute depletion of monoamines with reserpine, but not with AMPT or PCPA, reduced FADD (28%) and increased p-FADD/FADD ratio (1.34-fold). Activation of presynaptic α2A-adrenoceptors (UK-14304 and clonidine), 5-HT1A receptors (8-OH-DPAT), and D2 dopamine receptor (bromocriptine) dose-dependently decreased FADD (up to 54%) and increased p-FADD (up to 29%) and p-FADD/FADD ratios (up to 2.93-fold), through specific receptor mechanisms. Activation of rat 5-HT1B autoreceptor in axon terminals by CP-94253 did not modulate FADD forms. Activation of postsynaptic D1 dopamine receptor by SKF-81297 also reduced FADD (25%) and increased p-FADD (32%). Disruption of MEK-ERK activation with SL327 did not modify clonidine (α2A-adrenoceptor)-induced FADD inhibition, indicating that agonist effect was not dependent on ERK signaling. The various monoamine receptor agonists and antagonists did not alter FLIP-L content, or the activation of executioner caspase-3 and PARP-1 cleavage, indicating that the agonists attenuated apoptotic signals and promoted neuroplasticity through FADD regulation. These novel results indicate that inhibition of pro-apoptotic FADD adaptor could function as a common signaling step in the initial activation of monoamine receptors in the brain.

  20. Effect of Saraswatarishta in animal models of behavior despair

    PubMed Central

    Parekar, Reshma R.; Jadhav, Kshitij S.; Marathe, Padmaja A.; Rege, Nirmala N.

    2014-01-01

    Background: Saraswatarishta (SA) is a herbo-mineral formulation consisting of 18 plants some of which are Medhyarasayanas. It has been claimed to be useful in treating central nervous system disorders. Objective: To evaluate antidepressant effect of ‘Saraswatarishta’(SA) alone and in combination with imipramine and fluoxetine in animal models of depression. Materials and Methods: After obtaining IAEC permission, 144 rats (n = 36/part) were randomized into 6 groups- Group 1: Distilled water (1 mL), Group 2: Imipramine (30 mg/kg), Group 3: Fluoxetine (10 mg/kg), Group 4: SA (1.8 mL/kg), Group 5: Imipramine + SA, Group 6: Fluoxetine + SA. Effects of study drugs were evaluated in forced swim test (FST) with single exposure to FST (Part 1) and repeated exposure for 14 days (Part 2). In Part 3, reserpine was used with FST and effects of study drugs were evaluated against single exposure to FST. Same model was used with repeated exposures to FST (Part 4). In each part, rats were subjected to open field test (OFT) for 5 min prior to final FST. The variables measured: Immobility time in FST; line crossing, rearing and defecation in the OFT. Results: In all four parts, individual drugs and combinations thereof produced significant decrease in immobility time as compared to control, and extent of decrease was comparable amongst these groups. However, values for combination of fluoxetine with SA group were found to be lesser than that for individual agents in Parts 2 and 3. Combination of SA with imipramine did not enhance its anti-depressant effect in any of the parts. OFT findings did not vary significantly amongst the study groups. Conclusion: Decreased immobility in FST and absence of generalized stimulation or depression of motor activity in OFT point towards potential antidepressant effect of Saraswatarishta. Its co-administration with fluoxetine showed more promising effects. PMID:25336844

  1. Early Treatment With Olmesartan Prevents Juxtamedullary Glomerular Podocyte Injury and the Onset of Microalbuminuria in Type 2 Diabetic Rats

    PubMed Central

    Sofue, Tadashi; Kiyomoto, Hideyasu; Kobori, Hiroyuki; Urushihara, Maki; Nishijima, Yoko; Kaifu, Kumiko; Hara, Taiga; Matsumoto, Sachiko; Ichimura, Atsuhiko; Ohsaki, Hiroyuki; Hitomi, Hirofumi; Kawachi, Hiroshi; Hayden, Melvin R.; Whaley-Connell, Adam; Sowers, James R.; Ito, Sadayoshi; Kohno, Masakazu; Nishiyama, Akira

    2012-01-01

    Background Studies were performed to determine if early treatment with an angiotensin II (Ang II) receptor blocker (ARB), olmesartan, prevents the onset of microalbuminuria by attenuating glomerular podocyte injury in Otsuka Long-Evans Tokushima Fatty (OLETF) rats with type 2 diabetes mellitus. Methods OLETF rats were treated with either a vehicle, olmesartan (10 mg/kg/day) or a combination of nonspecific vasodilators (hydralazine 15 mg/kg/day, hydrochlorothiazide 6 mg/kg/day, and reserpine 0.3 mg/kg/day; HHR) from the age of 7–25 weeks. Results OLETF rats were hypertensive and had microalbuminuria from 9 weeks of age. At 15 weeks, OLETF rats had higher Ang II levels in the kidney, larger glomerular desmin-staining areas (an index of podocyte injury), and lower gene expression of nephrin in juxtamedullary glomeruli, than nondiabetic Long-Evans Tokushima Otsuka (LETO) rats. At 25 weeks, OLETF rats showed overt albuminuria, and higher levels of Ang II in the kidney and larger glomerular desmin-staining areas in superficial and juxtamedullary glomeruli compared to LETO rats. Reductions in mRNA levels of nephrin were also observed in superficial and juxtamedullary glomeruli. Although olmesartan did not affect glucose metabolism, it decreased blood pressure and prevented the renal changes in OLETF rats. HHR treatment also reduced blood pressure, but did not affect the renal parameters. Conclusions This study demonstrated that podocyte injury occurs in juxtamedullary glomeruli prior to superficial glomeruli in type 2 diabetic rats with microalbuminuria. Early treatment with an ARB may prevent the onset of albuminuria through its protective effects on juxtamedullary glomerular podocytes. PMID:22318512

  2. Memantine, amantadine, and L-deprenyl potentiate the action of L-dopa in monoamine-depleted rats.

    PubMed

    Skuza, G; Rogoz, Z; Quack, G; Danysz, W

    1994-01-01

    Some treatments used for Parkinson's disease attenuate locomotor depression in rats treated with reserpine and alpha-methyl-p-tyrosine. In the present study memantine (2.5, 5.0 mg/kg), amantadine (10, 20 mg/kg) (both uncompetitive NMDA antagonists), and L-deprenyl (1.0, 5.0 mg/kg; MAO-B inhibitor) were tested for possible synergistic interactions with the dopamine agonists: bromocriptine (2.5, 5.0 mg/kg) and L-dopa (50, 100 mg/kg, +benserazide, 100 mg/kg). At higher doses, memantine (10 mg/kg), amantadine (40 mg/kg), bromocriptine (5 and 10 mg/kg) and L-dopa (100, 200 mg/kg) but not L-deprenyl (up to 10 mg/kg) produced a pronounced increase in locomotor activity when given alone. The combination of memantine, amantadine and L-deprenyl with bromocriptine did not result in synergism of action and, at best, an additive effect was seen. On the other hand the combination of these agents with L-dopa produced a pronounced synergistic effect. Hence, the clinical observation that coadministration of L-dopa with either memantine or amantadine results in enhancement of their action is also reflected in an animal model of Parkinson's disease. Such a combination therapy should allow the use of lower doses of both drugs which may reduce the occurrence of side effects and may also be predicted to have additional benefits related to the neuroprotective properties of memantine, amantadine, and L-deprenyl.

  3. Contribution of mdr1b-type P-glycoprotein to okadaic acid resistance in rat pituitary GH3 cells.

    PubMed

    Ritz, V; Marwitz, J; Sieder, S; Ziemann, C; Hirsch-Ernst, K I; Quentin, I; Steinfelder, H J

    1999-08-01

    Okadaic acid as well as other, structurally different, inhibitors of serine/threonine phosphatases 1 and 2A induce apoptosis in pituitary GH3 cells. Incubation with stepwise raised concentrations of okadaic acid resulted in the isolation of cells that were increasingly less sensitive to the cytotoxic effect of this agent. After about 18 months cells were selected that survived at 300 nM okadaic acid, which is about 30 times the initially lethal concentration. This study revealed that a major pharmacokinetic mechanism underlying cell survival was the development of a P-glycoprotein-mediated multidrug resistance (MDR) phenotype. The increase in mRNA levels of the mdr1b P-glycoprotein isoform correlated with the extent of drug resistance. Functional assays revealed that increasing drug resistance was paralleled by a decreased accumulation of rhodamine 123, a fluorescent dye which is a substrate of mdr1-mediated efflux activity. Resistance could be abolished by structurally different chemosensitizers of P-glycoprotein function like verapamil and reserpine but not by the leukotriene receptor antagonist MK571 which is a modulator of the multidrug resistance-associated protein (MRP). Okadaic acid resistance included cross-resistance to other cytotoxic agents that are substrates of mdr1-type P-glycoproteins, like doxorubicin and actinomycin D, but not to non-substrates of mdr1, e.g. cytosine arabinoside. Thus, functional as well as biochemical features support the conclusion that okadaic acid is a substrate of the mdr1-mediated efflux activity in rat pituitary GH3 cells. Maintenance of resistance after withdrawal of okadaic acid as well as metaphase spreads of 100 nM okadaic acid-resistant cells suggested a stable MDR genotype without indications for the occurrence of extrachromosomal amplifications, e.g. double minute chromosomes.

  4. Mechanism of dexamphetamine-induced mydriasis in the anaesthetized rat.

    PubMed Central

    Hey, J. A.; Ito, T.; Koss, M. C.

    1989-01-01

    1. The effect of intravenous administration of dexamphetamine [+)-Amp) on rat pupil diameter was investigated. In all experiments, the vagosympathetic trunks were sectioned bilaterally at the cervical level. 2. In rats anaesthetized with urethane, (+)-Amp (0.1-0.3 mg kg-1, i.v.) produced a dose-related increase in pupil size. The mydriatic effects of (+)-Amp were evident immediately after administration. 3. Pretreatment with the alpha 2-adrenoceptor antagonists yohimbine (1.5 mg kg-1 i.v.) or idazoxan (0.5 mg kg-1, i.v.) blocked the pupillary response to (+)-Amp. Yohimbine caused about a 30 fold shift to the right in the dose-response curve whereas idazoxan almost completely abolished the mydriatic response to (+)-Amp. 4. In contrast, pretreatment with the alpha 1-adrenoceptor antagonist phenoxybenzamine (2 mg kg-1, i.v.), failed to alter significantly the pupillary response to (+)-Amp. 5. Depletion of central nervous system (CNS) monoamines with reserpine (5 mg kg-1, i.p.) and alpha-methyl-p-tyrosine (2 x 300 mg kg-1, i.p.) prevented the pupillary response to (+)-Amp. 6. The mydriatic effect of (+)-Amp was present only in preparations that had intact parasympathetic neural tone to the iris. Central preganglionic denervation of the oculomotor nerve abolished the mydriatic response of (+)-Amp. 7. These results indicate the (+)-Amp acts in the CNS to produce mydriasis in the anaesthetized rat by stimulating CNS postsynaptic alpha 2-adrenoceptors, findings that are consistent with the hypothesis that (+)-Amp acts predominantly as an indirect sympathomimetic agent to release endogenous stores of a monoaminergic neurotransmitter (perhaps noradrenaline). PMID:2564290

  5. The effect of lithium administration in animal models of depression: a short review.

    PubMed

    Redrobe, J P; Bourin, M

    1999-01-01

    The aim of this short review was to collate the data involving the effects of lithium alone, or in combination, with antidepressant drugs in several animal models of depression. It has been shown that lithium administration reduced immobility in the mouse forced swimming test when given 30 min, but not 45 min, before testing. Further studies indicated that this activity was probably a result of an activity on serotonin (5-HT) 1A and 1B receptor subtypes. Lithium treatment has been shown to reverse helpless behaviour in the learned helplessness model of depression after chronic treatment (30 days), where lithium was administered in the drinking water. Further studies showed that acute (5 days) administration of lithium failed to reverse behavioural deficits. In the olfactory bulbectomised rat model of depression, several immunological and enzymatic functions have been shown to be altered and these changes are regularised by antidepressant treatment as well as lithium administration for 15 days. Hypokinesia (reduced locomotor activity) is a phenomenon observed following immobilisation stress in rats. This behavioural deficit was attenuated by lithium together with a wide range of antidepressant drugs used in the treatment of unipolar depression at non-stimulant doses. In addition, a single administration of lithium slightly inhibited midbrain raphe lesion-induced muricidal behaviour (25%); however, repeated treatment (5 days) significantly attenuated this behavioural deficit. Lithium treatment has also been shown to reverse behavioural and biochemical deficits induced by reserpine together with those induced by acute administration of single intracerebroventricular (i.c.v.) dose of the Na, K-ATPase-inhibiting compound, ouabain. Long-term studies of lithium augmentation have not been performed, so that no clear recommendations for the duration of this therapy can be made. The points raised in this short review endorse the commencement of such studies.

  6. Additive effects of clonidine and antidepressant drugs in the mouse forced-swimming test.

    PubMed

    Malinge, M; Bourin, M; Colombel, M C; Larousse, C

    1988-01-01

    In the mouse forced-swimming model, dose-dependent reversal of immobility was induced by the alpha-agonist clonidine given IP 30 min before testing. In addition, three preferential inhibitors of 5-HT uptake (citalopram, indalpine and fluvoxamine) had similar activity in the dose range 8-16 mg/kg as did the 5-HT1 agonist 8-OH-DPAT (1-4 mg/kg). Pretreatment with alpha-methyl-paratyrosine (100 mg/kg) did not prevent clonidine (1 mg/kg) action, suggesting that there was mediation by alpha post-junctional receptors. The effect of clonidine was unaltered by prazosin (2 mg/kg) and reversed by yohimbine (4 mg/kg) and 5-MeODMT (1 mg/kg), whereas it was potentiated by reserpine (2.5 mg/kg), methysergide (2 mg/kg) and ketanserin (8 mg/kg). Moreover, an ineffective dose of clonidine (0.06 mg/kg at 45 min pre-testing) made active subthreshold doses of various antidepressants (given at 30 min pre-testing): imipramine (4 mg/kg), amitriptyline (1 mg/kg), maprotiline (8 mg/kg), citalopram (2 mg/kg), indalpine, fluvoxamine and mianserin (4 mg/kg), viloxazine (2 mg/kg). Similar interactions were found with iprindole and nialamide (32 mg/kg), which were inactive alone up to 64 mg/kg, and 8-OH-DPAT (0.5 mg/kg) but not with major and minor tranquillizers. It is suggested that one effect of antidepressants might be the triggering of different relationships between alpha-2 and 5-HT mechanisms.

  7. Calcium modulatory properties of 2,6-dibutylbenzylamine (B25) in rat isolated vas deferens, cardiac and smooth muscle preparations.

    PubMed Central

    Pirisino, R.; Banchelli, G.; Ignesti, G.; Mantelli, L.; Matucci, R.; Raimondi, L.; Buffoni, F.

    1993-01-01

    1. In rat isolated vas deferens the new compound 2,6-dibutylbenzylamine (B25) evoked a series of repeating rhythmic contractions. Concentration-response curves constructed for this effect were bell-shaped, indicating a biphasic effect for this compound. By contrast, B25 depressed heart contractility without any visible positive inotropic or chronotropic activity. 2. Experiments with tetrodotoxin, reserpine, capsaicin, alpha-adrenoceptor blocking compounds and other agents permit us to exclude a release of neuromediators or a direct stimulation of post-synaptic receptors to account for the rhythmic effect of B25 in the rat vas deferens. 3. In the same tissue, the increase in 45Ca2+ uptake, the voltage-dependency as well as the dependence of the B25-induced rhythmic activity upon the external calcium concentration indicate a direct activation of voltage-sensitive calcium channels (VSCC). 4. Verapamil paradoxically stimulated the rhythmic effect of B25 in the rat vas deferens. La3+ was inactive while nifedipine was a weak inhibitor. By contrast Ni2+ and Mn2+ ions were good inhibitors (IC50 < 10(-4) M), suggesting that a possible opening of T-type VSCC underlies rhythmic effect of B25. 5. In radioligand binding studies competition experiments with [3H]-nitrendipine indicated that only at high concentrations was B25 able to interact with dihydropyridine-sensitive binding sites of heart and vas deferens smooth muscle. 6. B25 (3-30 microM) counteracted the inhibitory effects of omega-conotoxin GVIA in field-stimulated rat vas deferens. PMID:8401916

  8. Identification of active ingredients in Wuzhuyu decoction improving migraine in mice by spectral efficiency association.

    PubMed

    Pan, Xueqiang; Wang, Manyuan; Wu, Yanchuan; Lu, Xuran; Shang, Yawen; Xu, Yongsong; Zhai, Yongsong; Li, Jing; Li, Zhaoxia; Gong, Muxin

    2015-07-01

    Wuzhuyu decoction is a traditional Chinese medicine used for the effective treatment of migraines, termed 'Jueyin headache', in China. However, there have been few investigations to clarify the composition of Wuzhuyu decoction for the treatment of migraines. In the present study, 10 types of Wuzhuyu decoction were analyzed by chromatograms. 5-hydroxytryptamine (5-HT)-depletion mouse models of migraine were prepared by subcutaneous injection of reserpine and placement of autologous blood clots in the cerebral cortex. The levels of 5-HT, noradrenaline (NE), dopamine (DA), nitric oxide (NO) and nitric oxide synthase (NOS) in the brain tissues and sera of the mice were determined. The ingredients and pharmacodynamic indices of the Wuzhuyu decoctions were analyzed using spectral efficiency association by partial least squares regression. The levels of 5-HT, NE and DA in the mouse brain tissues were reduced to 337.785 ± 84.504, 171.173 ± 65.172 and 242.075 ± 158.621 mg/g brain tissue, respectively. The level of NO in the brain tissues increased to 0.425 ± 0.184 µmol/g protein and the activities of NOS in the brain tissues and sera increased to 0.719 ± 0.477 U/mg and 50.688 ± 8.132 U/ml, respectively. Regarding the ingredients of the Wuzhuyu decoction, those with significant regression coefficients were ginsenoside-Rg1, Re, Rb1, rutaevine (Rv), limonin (Li), evodiamine (Ev), rutaecarpine (Ru) and substance X (awaiting identification). Rg1, Re, Rb1, Rv, Li, Ev, Ru and X in the Wuzhuyu decoction were observed to yield the pharmacological effects, whereas Rb1, Rv and Ev were important in index improvement.

  9. Renoprotection by nitric oxide donor and lisinopril in the remnant kidney model.

    PubMed

    Benigni, A; Zoja, C; Noris, M; Corna, D; Benedetti, G; Bruzzi, I; Todeschini, M; Remuzzi, G

    1999-04-01

    Previous studies showed a renoprotective effect of l-arginine in experimental uremia. Whether this was caused by an increased nitric oxide (NO) release or depended on l-arginine per se is not clear. Here, we evaluated whether chronic administration of an NO donor, molsidomine, controlled systemic blood pressure and renal disease progression and prolonged survival in rats with renal mass reduction (RMR). Rats with RMR received the following daily in the drinking water: group 1 (n = 21), no specific therapy (vehicle); group 2 (n = 12), molsidomine, 120 mg/L; group 3 (n = 9), lisinopril, 25 mg/L; and group 4 (n = 12), reserpine, 5 mg/L, hydralazine, 80 mg/L, and hydrochlorothiazide, 25 mg/L, from day 21 after surgery, when rats had hypertension and proteinuria, until the death of the vehicle-treated rats. Molsidomine normalized systemic hypertension, only partially reduced proteinuria and serum creatinine levels, but significantly prolonged animal survival, particularly in the early stage of the disease. Lisinopril at a similar systemic blood pressure was even better than molsidomine in limiting proteinuria, preserving renal function, and prolonging survival, but triple therapy, despite being effective on blood pressure, offered no renoprotection or prolonged survival. Endothelin-1 (ET-1) levels, formed in excessive amounts by the kidneys of these animals, were reduced by molsidomine and lisinopril, but not by triple therapy. The prolongation of survival by NO donor could be attributed to its effect of reducing ET levels, which in turn may limit the smooth muscle cell proliferation and matrix accumulation responsible for organ and, especially, myocardial fibrosis in uremia.

  10. Animal models of depression: are there any?

    PubMed

    O'Neil, Michael F; Moore, Nicholas A

    2003-06-01

    Simple tests for antidepressant-like activity, such as 5-HTP-induced syndrome or reserpine-induced hypomotility, are often mechanism-based tests, pharmacologically specific for certain known classes of therapeutically successful antidepressant agents. Many of these behavioural assays have been superseded by neurochemical techniques such as in vivo microdialysis. In contrast to these mechanistic-based models, investigators have also endeavoured to reproduce in the laboratory, factors that are believed to precipitate depression in people. It is a strong assumption in this approach that depression is a response to stress. This strategy profiles the consequences of chronic stress particularly psychosocial stress or early life events, in order to reproduce in animals the behavioural signs and pathologies associated with depression. The advances in the social psychological, clinical pathological and new areas such as neuroimaging research offer the possibility of establishing more sophisticated models for depression in animals with a broader range of biomarkers from the immunological and endocrinological to neurochemical and behavioural. Combining these novel insights with more traditional tests of depression may not only increase our understanding of the neurobiology of depression but also afford more precise and predictive preclinical models of depression. The responsiveness of different strains or genetically modified animals to stress is likely to be a key area of study. Furthermore we must look to individual differences in subjects, even within the same strain, to more fully understand why some individuals show pathological responses to stress whereas others appear unaffected. Conversely in validating our models using currently available treatments we must include the concept of non-responders so as not to disregard models that may extend therapeutic possibilities in these patients. PMID:12766928

  11. Two types of receptors for 5-hydroxytryptamine on the cholinergic nerves of the guinea-pig myenteric plexus.

    PubMed Central

    Kilbinger, H.; Pfeuffer-Friederich, I.

    1985-01-01

    The effects of 5-hydroxytryptamine (5-HT) on spontaneous and electrically-evoked release of [3H]-acetylcholine (ACh) from guinea-pig myenteric plexus preparations preincubated with [3H]-choline have been investigated in the absence of cholinesterase inhibitors. 5-HT caused a transient increase in spontaneous release and an inhibition of the electrically-evoked release of [3H]-ACh. The 5-HT-induced contractions of the longitudinal muscle were clearly related to the increase in spontaneous release. The inhibitory effect was not due to activation of alpha-adrenoceptors since it was also observed in the presence of tolazoline and on strips from reserpine-pretreated guinea-pigs. After desensitization of the excitatory 5-HT receptors with 5-HT or metoclopramide the effects of 5-HT on spontaneous [3H]-ACh release were largely reduced. A variety of established antagonists at neuronal 5-HT receptors (i.e. metitepine 0.1-1 microM; methysergide 1 microM; ketanserin 0.1-1 microM; MDL 72222 0.1 microM; tropacocaine 1 microM) failed to block the excitation. The inhibition by 5-HT of the electrically evoked [3H]-ACh release was competitively antagonized by metitepine (pA2 7.6) and methysergide (pA2 7.0) but not by ketanserin. Tachyphylaxis to the inhibitory action of 5-HT did not occur. The results suggest that the excitatory 5-HT receptor ('M'-receptor) differs in its pharmacological properties from other neuronal 5-HT receptors. The presynaptically located inhibitory receptor may roughly correspond to the 5-HT1 receptor subtype but probably differs from the 5-HT autoreceptor. PMID:3161573

  12. Anatomical Transcriptome of G Protein-Coupled Receptors Leads to the Identification of a Novel Therapeutic Candidate GPR52 for Psychiatric Disorders

    PubMed Central

    Yao, Shuuhei; Shinohara, Tokuyuki; Sakuma, Kensuke; Imaichi, Sachiko; Chikatsu, Tomoko; Kuniyeda, Kanako; Siu, Foo Kok; Peng, Lam Sock; Zhuo, Katherine; Mun, Lay Sock; Han, Tan Min; Matsumoto, Yoshio; Hashimoto, Tadatoshi; Miyajima, Nobuyuki; Itoh, Yasuaki; Ogi, Kazuhiro; Habata, Yugo; Mori, Masaaki

    2014-01-01

    Many drugs of abuse and most neuropharmacological agents regulate G protein-coupled receptors (GPCRs) in the central nervous system (CNS)_ENREF_1. The striatum, in which dopamine D1 and D2 receptors are enriched, is strongly innervated by the ventral tegmental area (VTA), which is the origin of dopaminergic cell bodies of the mesocorticolimbic dopamine system_ENREF_3 and plays a central role in the development of psychiatric disorders_ENREF_4. Here we report the comprehensive and anatomical transcript profiling of 322 non-odorant GPCRs in mouse tissue by quantitative real-time PCR (qPCR), leading to the identification of neurotherapeutic receptors exclusively expressed in the CNS, especially in the striatum. Among them, GPR6, GPR52, and GPR88, known as orphan GPCRs, were shown to co-localize either with a D2 receptor alone or with both D1 and D2 receptors in neurons of the basal ganglia. Intriguingly, we found that GPR52 was well conserved among vertebrates, is Gs-coupled and responsive to the antipsychotic drug, reserpine. We used three types of transgenic (Tg) mice employing a Cre-lox system under the control of the GPR52 promoter, namely, GPR52-LacZ Tg, human GPR52 (hGPR52) Tg, and hGPR52-GFP Tg mice. Detailed histological investigation suggests that GPR52 may modulate dopaminergic and glutamatergic transmission in neuronal circuits responsible for cognitive function and emotion. In support of our prediction, GPR52 knockout and transgenic mice exhibited psychosis-related and antipsychotic-like behaviors, respectively. Therefore, we propose that GPR52 has the potential of being a therapeutic psychiatric receptor. This approach may help identify potential therapeutic targets for CNS diseases. PMID:24587241

  13. Half a century of antipsychotics and still a central role for dopamine D2 receptors.

    PubMed

    Kapur, Shitij; Mamo, David

    2003-10-01

    A review of the history of antipsychotics reveals that while the therapeutic effects of chlorpromazine and reserpine were discovered and actively researched almost concurrently, subsequent drug development has been restricted to drugs acting on postsynaptic receptors rather than modulation of dopamine release. The fundamental property of atypical antipsychotics is their ability to produce an antipsychotic effect in the absence of extrapyramidal side effects (EPS) or prolactin elevation. Modulation of the dopamine D2 receptor remains both necessary and sufficient for antipsychotic drug action, with affinity to the D2-receptor being the single most important discriminator between a typical and atypical drug profile. Most antipsychotics, including atypical antipsychotics, show a dose-dependent threshold of D2 receptor occupancy for their therapeutic effects, although the precise threshold is different for different drugs. Some atypical antipsychotics do not appear to reach the threshold for EPS and prolactin elevation, possibly accounting for their atypical nature. To link the biological theories of antipsychotics to their psychological effects, a hypothesis is proposed wherein psychosis is a state of aberrant salience of stimuli and ideas, and antipsychotics, via modulation of the mesolimbic dopamine system, dampen the salience of these symptoms. Thus, antipsychotics do not excise psychosis: they provide the neurochemical platform for the resolution of symptoms. Future generations of antipsychotics may need to move away from a "one-size-fits-all polypharmacy-in-a-pill" approach to treat all the different aspects of schizophrenia. At least in theory a preferred approach would be the development of specific treatments for the different dimensions of schizophrenia (e.g., positive, negative, cognitive, and affective) that can be flexibly used and titrated in the service of patients' presenting psychopathology.

  14. Cardiovascular effects of the South American medicinal plant Cecropia pachystachya (ambay) on rats.

    PubMed

    Consolini, Alicia E; Migliori, Graciela N

    2005-01-15

    Cecropia pachystachya is used in South America for relieving cough and asthma. In Argentina it is known as "ambay" and grows in the neotropical forests (Ntr C.p.) and in temperate hilly regions (Tp C.p.). To evaluate their cardiovascular profile, the effect of extracts obtained from plants growing in the neotropical region as well as in temperate areas were compared by i.v. administration in normotensive rats. The following parameters were measured: blood pressure (BP) and heart rate (HR). The hypotensive effect was stronger for Ntr C.p., which aqueous extract decreased BP at doses between 90 and 300 mg lyophilised/kg until 46.2 +/- 12% of basal. The extract of Tp C.p. reduced BP to 86.1 +/- 11% of basal (p < 0.05 respect to Ntr C.p.) at 180 mg/kg, but increased HR at 90 and 180 mg/kg (until 133.6 +/- 10.8% of basal, p < 0.05) and produced death by respiratory paralysis at 320 mg/kg (about 3g dry leaves/kg). The hypotensive effects, but not the chronotropic ones, were attenuated by pretreatment with reserpine (5 mg/kg). The plant extracts had not diuretic activity by oral administration in conscious rats, nor produced vasodilation of perfused hindquarters arterial bed precontracted with high-[K] or 100 microM phenylephrine. The results suggest that neotropical ambay is more hypotensive than the one from the temperate hilly region. When it reaches plasma, it could produce hypotension (by central blockade of sympathic innervation of vessels) and tachycardia (by central cholinergic inhibition of heart), although it happens at doses higher than the oral ethnotherapeutic (about 340 mg dried leaves/kg).

  15. Discovery, characterization, and antiparkinsonian effect of novel positive allosteric modulators of metabotropic glutamate receptor 4

    PubMed Central

    Niswender, Colleen M.; Johnson, Kari A.; Weaver, C. David; Jones, Carrie K.; Xiang, Zixiu; Luo, Qingwei; Rodriguez, Alice L.; Marlo, Joy E.; de Paulis, Tomas; Thompson, Analisa D.; Days, Emily L.; Nalywajko, Tasha; Aust, Cheryl A.; Williams, Michael Baxter; Ayala, Jennifer E.; Williams, Richard; Lindsley, Craig W.; Conn, P. Jeffrey

    2008-01-01

    Parkinson's disease (PD) is caused by the death of dopamine neurons in the basal ganglia and results in motor symptoms such as tremor and bradykinesia. Activation of metabotropic glutamate receptor 4 (mGluR4) has been shown to modulate neurotransmission in the basal ganglia and results in antiparkinsonian effects in rodent PD models. PHCCC is a positive allosteric modulator (PAM) of mGluR4 which has been used to further validate the role of mGluR4 in PD, but the compound suffers from a lack of selectivity, relatively low potency and poor solubility. Via high-throughput screening, we discovered over 400 novel PAMs of mGluR4. Compounds derived from a novel chemical scaffold were characterized in vitro at both rat and human mGluR4 using two distinct assays of mGluR4 function. The lead compound was approximately 8-fold more potent than PHCCC, enhanced the potency of glutamate at mGluR4 by 8-fold, and did not show any significant potentiator or antagonist activity at other mGluR subtypes. Resolution of the regioisomers of the lead revealed that the cis regioisomer, VU0155041, contained the majority of the mGluR4 PAM activity and also exhibited partial agonist activity at mGluR4 at a site that was distinct from the glutamate binding site, suggesting that this compound is a mixed allosteric agonist/PAM of mGluR4. VU0155041 was soluble in an aqueous vehicle and intracerebroventricular administration of 31 to 316 nmol of VU0155041 dose-dependently decreased haloperidol-induced catalepsy and reserpine-induced akinesia in rats. These exciting results provide continued support for mGluR4 as a therapeutic target in PD. PMID:18664603

  16. Overexpression of VMAT-2 and DT-diaphorase protects substantia nigra-derived cells against aminochrome neurotoxicity

    PubMed Central

    Muñoz, Patricia; Paris, Irmgard; Sanders, Laurie H.; Greenamyre, J. Timothy; Segura-Aguilar, Juan

    2013-01-01

    We tested the hypothesis that both VMAT-2 and DT-diaphorase are an important cellular defense against aminochrome-dependent neurotoxicity during dopamine oxidation. A cell line with VMAT-2 and DT-diaphorase over-expressed was created. The transfection of RCSN-3 cells with a bicistronic plasmid coding for VMAT-2 fused with GFP-IRES-DT-diaphorase cDNA induced a significant increase in protein expression of VMAT-2 (7-fold; P<0.001) and DT-diaphorase (9-fold; P<0.001), accompanied by a 4- and 5.5-fold significant increase in transport and enzyme activity, respectively. Studies with synaptic vesicles from rat substantia nigra revealed that VMAT-2 uptake of 3H-aminochrome 6.3 ± 0.4nmol/min/mg was similar to dopamine uptake 6.2 ± 0.3 nmol/min/mg that which were dependent on ATP. Interestingly, aminochrome uptake was inhibited by 2 μM lobeline but not reserpine (1 and 10 μM). Incubation of cells overexpressing VMAT-2 and DT-diaphorase with 20 μM aminochrome resulted in (i) a significant decrease in cell death (6-fold, P<0.001); (ii) normal ultra structure determined by transmission electron microscopy contrasting with a significant increase of autophagosome and a dramatic remodeling of the mitochondrial inner membrane in wild type cells; (iii) normal level of ATP (256 ± 11 μM) contrasting with a significant decrease in wild type cells (121 ± 11 μM, P<0.001); and (iv) a significant decrease in DNA laddering (21 ± 8 pixels, P<0.001) cells in comparison with wild type cells treated with 20 μM aminochrome (269 ± 9). These results support our hypothesis that VMAT-2 and DT-diaphorase are an important defense system against aminochrome formed during dopamine oxidation. PMID:22483869

  17. Evidence that ibogaine releases dopamine from the cytoplasmic pool in isolated mouse striatum.

    PubMed

    Harsing, L G; Sershen, H; Lajtha, A

    1994-01-01

    We measured the effect of ibogaine on the tritium efflux from isolated mouse striatum preloaded with [3H]dopamine ([3H]DA). Ibogaine increased the basal tritium outflow in a concentration-dependent manner, but it was without effect on electrical stimulation-induced tritium overflow. Separation of the released radioactivity after ibogaine administration showed that this drug increased the release of [3H]DA and [3H]-dihydroxyphenylacetic acid ([3H]DOPAC), but the efflux of O-methylated-deaminated metabolites was not changed. The dopamine (DA)-releasing effect of ibogaine was reduced by the DA uptake inhibitors cocaine and nomifensine. The tritium efflux evoked by ibogaine was not altered by omission of Ca2+ from the perfusion buffer or by inhibition of the voltage-sensitive Na+ channels with tetrodotoxin. Ibogaine maintained its effect on release from superfused striatum prepared from reserpine-pretreated mice. The ibogaine-induced tritium release measured from mouse striatum that was preloaded with [3H]DA was not affected by the D-2 DA receptor ligands (-)-quinpirole and (+/-)-sulpiride, indicating that the ibogaine-induced release is not subject to presynaptic autoreceptor regulation. Ibogaine failed to affect [3H]DA uptake and retention in mouse striatum. These data indicate that at the nerve terminal level ibogaine releases DA, and the primary source for the release is probably the cytoplasmic pool. The DA-releasing effect of ibogaine may have importance in mediation of its hallucinogenic action, as seen in a frequent practice in African cults. PMID:7826572

  18. Design and Performance Evaluation of a Linear Ion Trap Mass Analyzer Featuring Half Round Rod Electrodes

    NASA Astrophysics Data System (ADS)

    Li, Xiaoxu; Zhang, Xiaohua; Yao, Rujiao; He, Yang; Zhu, Yongyong; Qian, Jie

    2015-05-01

    A novel linear ion trap mass analyzer featuring half round rod electrodes (HreLIT) has been built. It is mainly composed of two pairs of stainless steel electrodes which have a cross-section of half round rod and a pair of end electrodes. The HreLIT has a simple structure and so it could be assembled by hand with relatively high mechanical accuracy. The external dimension of HreLIT is 50 mm × 29.5 mm × 28 mm (length × width × height) and its internal volume is about 3.8 cm3. A home-made HreLIT mass spectrometer with three-stage vacuum system was built and the performance of HreLIT was characterized using reserpine solution and PPG standard solution. When the scan rate was 254 u/s, mass peak with FWHM of 0.14 u was achieved for ions with m/z 609, which corresponds to a mass resolution of 4350. The HreLIT was also operated at a low q value of 0.28 to extend its mass range. The experiment result showed a mass range of over 2800 u and the amplitude of radio frequency (rf) signal was only 1560 V (0-p). Three-stage tandem mass spectrometry was successfully performed in the HreLIT, and the collision-induced dissociation (CID) efficiencies of MS2 (CID of ions with m/z 609) and MS3 (CID of ions with m/z 448) were 78% and 59%, respectively.

  19. Attenuation by alpha,beta-methylenadenosine-5'-triphosphate of periarterial nerve stimulation-induced renal vasoconstriction is not due to desensitization of purinergic receptors.

    PubMed

    Sehic, E; Ruan, Y; Malik, K U

    1994-11-01

    We investigated in the isolated rat kidney the modulation of vasoconstrictor responses to ATP (0.05-0.5 mumol), renal nerve stimulation (RNS) (0.5-10.0 Hz), norepinephrine (NE) (0.15-0.9 nmol), angiotensin II (2 pmol) and arginine vasopressin (3 pmol) by alpha,beta-methylenadenosine-5'-triphosphate (alpha beta mATP) infused at 6 microM (Procedure I) or for short intervals (5 min) at a low concentration (60 nM) gradually increased to 6 microM to reduce the dramatic initial vasoconstriction (Procedure II). Infusion of alpha beta mATP (Procedure I) produced a marked, transient rise in perfusion pressure of 146 to 198 mm Hg that returned to basal level within 10 min and thereafter inhibited the vasoconstrictor response to ATP, RNS (0.5-6.0 Hz), NE, angiotensin II and arginine vasopressin. Infusion of alpha beta mATP by Procedure II produced a smaller maximal transient increase in perfusion pressure (< 100 mm Hg) and reduced the vasoconstrictor responses to RNS at 0.5 to 2.0 Hz and to the lower dose of NE (0.15 nmol) only. ATP infusion reduced the vasoconstrictor response to both RNS and NE. In animals pretreated with reserpine, the effect of RNS to produce vasoconstriction was inhibited. These data suggest that ATP does not contribute to the renal vasoconstrictor response elicited by RNS, and that attenuation of renal vasoconstrictor responses by alpha beta mATP is not due to desensitization of purinergic receptors. PMID:7965821

  20. Selective response of rat peripheral sympathetic nervous system to various stimuli

    PubMed Central

    Ulus, I. H.; Wurtman, R. J.

    1979-01-01

    1. We utilized the induction of tyrosine hydroxylase, a catecholamine-synthesizing enzyme, in sympathetic ganglia and adrenal medullae to explore the central and peripheral mechanisms through which choline, various environmental stresses, and drugs that alter blood pressure or central neurotransmission affect various portions of the sympathetic nervous system. Animals received each treatment chronically, and enzyme activity was measured in the superior cervical, stellate, and coeliac ganglia and in the adrenal medullae. 2. Choline administration increased tyrosine hydroxylase activity in all four tissues, probably by increasing the release of acetylcholine from preganglionic sympathetic neurones that synapse on catecholamine-producing ganglion and chromaffin cells; carbachol and nicotine had similar effects. 3. Insulin enhanced tyrosine hydroxylase activity primarily in the coeliac ganglion and the adrenal medullae, but not in the superior cervical ganglia. 4. Reserpine and phenoxybenzamine increased the activity of the enzyme in all four tissues. 5. Prolonged exposure to a cold environment increased enzyme activity in all four tissues, but especially in the stellate and coeliac ganglia; forced swimming affected tyrosine hydroxylase only in these two ganglia. 6. Several drugs known to modify central neurotransmission were found to increase tyrosine hydroxylase activity in some portions of the sympathetic nervous system but not in others. 5,7-Dihydroxytryptamine, which destroys terminals of serotoninergic neurones, enhanced enzyme activity in all four tissues, but primarily in the coeliac ganglion and adrenal medullae. ET-495 (a dopaminergic agonist), D-amphetamine, and morphine induced tyrosine hydroxylase activity in the adrenal medullae and the coeliac ganglion, but not in the superior cervical ganglia. Oxotremorine, a centrally acting muscarinic agonist, increased tyrosine hydroxylase activity only in the adrenal medullae; its effect was not blocked by

  1. Calcium-dependent contractile response of arterial smooth muscle to a jellyfish toxin (pCrTX: Carybdea rastonii).

    PubMed Central

    Azuma, H.; Ishikawa, M.; Nakajima, T.; Satoh, A.; Sekizaki, S.

    1986-01-01

    The purpose of the present experiments was to investigate the pharmacological mechanisms of the vasoconstriction caused by the toxin (pCrTX) which had been partially purified from the tentacles of the jellyfish Carybdea rastonii ('Andonkurage'). pCrTX (0.1 to 10 micrograms ml-1) produced a tonic contraction of rabbit aortic strips, which was nearly abolished in Ca2+-free medium and was significantly reduced by verapamil or diltiazem. pCrTX stimulated 45Ca2+-influx and this effect was markedly attenuated by verapamil. pCrTX-induced vasoconstriction was significantly attenuated by phentolamine, 6-hydroxydopamine (6-OHDA) and in low Na+-medium, but not by bretylium, guanethidine, reserpinization or tetrodotoxin (TTX). pCrTX continuously and significantly increased the 3H-efflux from [3H]-noradrenaline preloaded aortic strips and this effect was completely inhibited by pretreatment with 6-OHDA and in Ca2+-free medium, but not by phentolamine, bretylium, guanethidine or TTX. A single exposure to pCrTX for 30 min greatly reduced the contractile responses to tyramine, nicotine and transmural electrical stimulation, but not those to noradrenaline or KC1. In addition, incorporation of [3H]-noradrenaline was reduced. Pretreatments with chlorphenylamine or indomethacin failed to modify the contractile response to pCrTX. These results suggest that the pCrTX-induced vasoconstriction is caused by a presynaptic action, releasing noradrenaline from the intramural adrenergic nerve terminals, and by a postsynaptic action, which consists at least in part of stimulation of the transmembrane calcium influx. Both pre- and postsynaptic actions depend on the external calcium concentration. The data further suggest that pCrTX damages the noradrenaline uptake and/or storage mechanisms without damaging postsynaptic contractile systems. PMID:2874856

  2. Array of Chemically Etched Fused Silica Emitters for Improving the Sensitivity and Quantitation of Electrospray Ionization Mass Spectrometry

    SciTech Connect

    Kelly, Ryan T.; Page, Jason S.; Tang, Keqi; Smith, Richard D.

    2007-06-01

    An array of emitters has been developed for increasing the sensitivity of electrospray ionization mass spectrometry (ESI-MS). The linear array consists of 19 chemically etched fused silica capillaries arranged with 500 µm (center-to-center) spacing. The multi-emitter device has a low dead volume to facilitate coupling to capillary liquid chromatography (LC) separations. The high aspect ratio of the emitters enables operation at flow rates as low as 20 nL/min/emitter, effectively extending the benefits of nanoelectrospray to higher flow rate analyses. To accommodate the larger ion current produced by the emitter array, a multi-capillary inlet to the mass spectrometer was also constructed. The inlet, which matched the dimensions of the emitter array, effectively preserved ion transmission efficiency. Standard reserpine solutions of varying concentration were electrosprayed at 1 µL/min using the multi-emitter/multi-inlet combination, and compared to a standard, single emitter configuration. A nine-fold sensitivity enhancement was observed for the multi-emitter relative to the single emitter. A bovine serum albumin tryptic digest was also analyzed and resulted in a sensitivity increase ranging from 2.4 to 12.3-fold for the detected tryptic peptides; the varying response was attributed to reduced ion suppression under the nano-ESI conditions afforded by the emitter array. An equimolar mixture of leucine enkephalin and maltopentaose was studied to verify that ion suppression is indeed reduced for the multi-ESI array relative to a single emitter over a range of flow rates.

  3. Characterization of MDL 73005EF as a 5-HT1A selective ligand and its effects in animal models of anxiety: comparison with buspirone, 8-OH-DPAT and diazepam.

    PubMed Central

    Moser, P. C.; Tricklebank, M. D.; Middlemiss, D. N.; Mir, A. K.; Hibert, M. F.; Fozard, J. R.

    1990-01-01

    1. With radioligand binding techniques, MDL 73005 EF (8-[2-(2,3-dihydro-1,4-benzodioxin-2-yl-methylamino)ethyl]-8-az aspiro[4, 5]decane-7,9-dione methyl sulphonate) shows high affinity (pIC50 8.6) and selectivity (greater than 100 fold compared to other monoamine and benzodiazepine receptor sites) for the 5-hydroxytryptamine (5-HT)1A recognition site; it was both more potent and more selective than buspirone in this respect. 2. In rats pretreated with reserpine, 8-hydroxy-2-(di-n-propyl-amino) tetralin (8-OH-DPAT) induced forepaw treading and flat body posture; in the same model, MDL 73005EF and buspirone showed minimal agonist activity and at high doses MDL 73005EF inhibited responses to 8-OH-DPAT. 3. In rats trained to discriminate 8-OH-DPAT from saline in a drug discrimination paradigm, both MDL 73005EF and buspirone generalized dose-dependently and completely to the 8-OH-DPAT cue. 4. To define the anxiolytic potential of MDL 73005EF, it was examined in the elevated plus-maze test and in the water-lick conflict test in comparison with diazepam and buspirone. In both tests MDL 73005EF induced effects similar to those seen following diazepam. Buspirone had similar effects to both MDL 73005EF and diazepam in the water-lick conflict test but opposite effects in the elevated plus-maze. 8-OH-DPAT also had opposite effects in the elevated plus-maze test to MDL 73005EF and diazepam. 5. The anti-conflict effects of MDL 73005EF were reversed by low doses of the 5-HT1A receptor agonist, 8-OH-DPAT; those of buspirone were neither antagonised nor mimicked by 8-OH-DPAT.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1970269

  4. Antidepressant Potential of 5-HT3 Receptor Antagonist, N-n- propyl-3-ethoxyquinoxaline-2-carboxamide (6n)

    PubMed Central

    Mahesh, R; Bhatt, S; Devadoss, T; Jindal, AK; Gautam, BK; Pandey, DK

    2012-01-01

    The present study was designed to evaluate the antidepressant potential of 5-HT3 receptor antagonist N-n-propyl-3-ethoxyquinoxaline-2-carboxamide (6n). The compound ‘6n’ with optimum log P and pA2 value identified from a series of compounds synthesized in our laboratory was subjected to forced Swim Test (FST) (1, 2, and 4 mg/kg, i.p) and Tail Suspension Test (TST) (1, 2, and 4 mg/kg, i.p.). The compound ‘6n’ significantly reduced the duration of immobility in mice without affecting the baseline locomotion. Moreover, ‘6n’ (2 mg/kg, i.p.) potentiated the 5-hydroxytryptophan (5-HTP)-induced head twitch responses in mice and ‘6n’ at tested dose (1 and 2 mg/kg, i.p.) reversed the reserpine-induced hypothermia in rats. In interaction studies of ‘6n’ with various standard drugs/ligands using FST, ‘6n’ (1 mg/kg, i.p.) potentiated the antidepressant effect of venlafaxine (4 and 8 mg/kg, i.p.) and fluoxetine (10 and 20 mg/kg, i.p.). Additionally, ‘6n’ (1 and 2 mg/kg, i.p.) influenced the effect of harmane (5 mg/ kg, i.p.) as well as reversed the effect of parthenolide (1 mg/kg, i.p.) by reducing the duration of immobility in FST. Furthermore, ‘6n’ (1 mg/kg, i.p.) potentiated the effect of bupropion (10 and 20 mg/kg, i.p.) in TST. Chronic ‘6n’ (1 and 2 mg/kg, i.p.) treatment attenuated the behavioral abnormalities in olfactory bulbectomized rats. In conclusion, these various findings reiterated the antidepressant-like effects of ‘6n’ in behavioral models of depression. PMID:23493308

  5. Monoamine receptor agonists, acting preferentially at presynaptic autoreceptors and heteroreceptors, downregulate the cell fate adaptor FADD in rat brain cortex.

    PubMed

    García-Fuster, M Julia; García-Sevilla, Jesús A

    2015-02-01

    FADD is a crucial adaptor of death receptors that can engage apoptosis or survival actions (e.g. neuroplasticity) through its phosphorylated form (p-FADD). Although FADD was shown to participate in receptor mechanisms related to drugs of abuse, little is known on its role in the signaling of classic neurotransmitters (dopamine, noradrenaline, and serotonin) in brain. This study assessed the modulation of FADD (and p-FADD/FADD ratio, as an index of neuroplasticity) and FLIP-L (a neuroprotective FADD interacting partner), as well as the role of MEK-ERK signaling, after activation of monoamine auto/heteroreceptors by selective agonists in rat cortex. Acute depletion of monoamines with reserpine, but not with AMPT or PCPA, reduced FADD (28%) and increased p-FADD/FADD ratio (1.34-fold). Activation of presynaptic α2A-adrenoceptors (UK-14304 and clonidine), 5-HT1A receptors (8-OH-DPAT), and D2 dopamine receptor (bromocriptine) dose-dependently decreased FADD (up to 54%) and increased p-FADD (up to 29%) and p-FADD/FADD ratios (up to 2.93-fold), through specific receptor mechanisms. Activation of rat 5-HT1B autoreceptor in axon terminals by CP-94253 did not modulate FADD forms. Activation of postsynaptic D1 dopamine receptor by SKF-81297 also reduced FADD (25%) and increased p-FADD (32%). Disruption of MEK-ERK activation with SL327 did not modify clonidine (α2A-adrenoceptor)-induced FADD inhibition, indicating that agonist effect was not dependent on ERK signaling. The various monoamine receptor agonists and antagonists did not alter FLIP-L content, or the activation of executioner caspase-3 and PARP-1 cleavage, indicating that the agonists attenuated apoptotic signals and promoted neuroplasticity through FADD regulation. These novel results indicate that inhibition of pro-apoptotic FADD adaptor could function as a common signaling step in the initial activation of monoamine receptors in the brain. PMID:25286119

  6. Evaluation of the pharmacological similarities between phenylpropanolamine and amphetamine: effects on schedule-controlled behavior.

    PubMed

    Wagner, G C; Jarvis, M F

    1990-01-01

    In an effort to determine the degree to which the repeated administration of phenylpropanolamine (PPA) results in the development of tolerance to its disruptive effects on operant responding as well as cross-tolerance to the effects of acutely administered amphetamine, water-deprived rats were first trained on a fixed-ratio 5 (FR-5) schedule for water presentation. Dose-response curves for the effects of PPA and amphetamine (administered IP, 15 min presession) were then determined (ED50 = 35.0 and 2.6 mg/kg, respectively) followed by the chronic administration of 40.0 mg/kg PPA (administered IP, 15 min prior to each session). When responding returned to prechronic rates, the dose-response curves were redetermined for both PPA (ED50 = 220 mg/kg) and amphetamine (ED50 = 4.8 mg/kg). In a second set of rats, trained under similar conditions, it was observed that pretreatment with alpha-methyltyrosine (AMT, 100 mg/kg IP, 2 h presession) antagonized the disruptive effects of both PPA and amphetamine, whereas pretreatment with reserpine (0.31 mg/kg, IP, 12 h presession) antagonized the disruptive effects of PPA, but exacerbated the disruptive effects of amphetamine. In a separate experiment, the repeated administration of PPA 100 mg/kg or 200 mg/kg IP resulted in no long-lasting depletions of rat striatal dopamine, serotonin, or 3,4-dihydroxyphenylacetic acid (DOPAC) concentrations. These observations indicate that PPA and amphetamine share a similar mechanism of action to the degree that cross-tolerance develops, but which is nonetheless dissociable with respect to their differential sensitivity to antagonists and their neurotoxic efficacy.

  7. Homology modeling, molecular dynamics, and virtual screening of NorA efflux pump inhibitors of Staphylococcus aureus

    PubMed Central

    Bhaskar, Baki Vijaya; Babu, Tirumalasetty Muni Chandra; Reddy, Netala Vasudeva; Rajendra, Wudayagiri

    2016-01-01

    Emerging drug resistance in clinical isolates of Staphylococcus aureus might be implicated to the overexpression of NorA efflux pump which is capable of extruding numerous structurally diverse compounds. However, NorA efflux pump is considered as a potential drug target for the development of efflux pump inhibitors. In the present study, NorA model was constructed based on the crystal structure of glycerol-3-phosphate transporter (PDBID: 1PW4). Molecular dynamics (MD) simulation was performed using NAMD2.7 for NorA which is embedded in the hydrated lipid bilayer. Structural design of NorA unveils amino (N)- and carboxyl (C)-terminal domains which are connected by long cytoplasmic loop. N and C domains are composed of six transmembrane α-helices (TM) which exhibits pseudo-twofold symmetry and possess voluminous substrate binding cavity between TM helices. Molecular docking of reserpine, totarol, ferruginol, salvin, thioxanthene, phenothiazine, omeprazole, verapamil, nalidixic acid, ciprofloxacin, levofloxacin, and acridine to NorA found that all the molecules were bound at the large hydrophobic cleft and indicated significant interactions with the key residues. In addition, structure-based virtual screening was employed which indicates that 14 potent novel lead molecules such as CID58685302, CID58685367, CID5799283, CID5578487, CID60028372, ZINC12196383, ZINC72140751, ZINC72137843, ZINC39227983, ZINC43742707, ZINC12196375, ZINC66166948, ZINC39228014, and ZINC14616160 have highest binding affinity for NorA. These lead molecules displayed considerable pharmacological properties as evidenced by Lipinski rule of five and prophecy of toxicity risk assessment. Thus, the present study will be helpful in designing and synthesis of a novel class of NorA efflux pump inhibitors that restore the susceptibilities of drug compounds. PMID:27757014

  8. The evaluation of the novel pressor activity of gamma-piperidinobutyramide (WY 20051, DF480).

    PubMed Central

    Alps, B J; Devoy, P W; Waterfall, J F

    1976-01-01

    1 gamma-Piperidinobutyramide (Wy 20051, DF480) injected intravenously evoked pressor responses in the anaesthetized ganglion blocked rat preparation over the dose range 2.4 x 10(-6)-3.0 x 10(-4) mol/kg. 2 High doses (greater than 3.8 x 10(-5) mol/kg) or even repeated submaximal doses (1.9 x 10(-5) mol/kg) of Wy 20051 caused tachyphylaxis of this pressor response. 3 The noradrenaline pressor-response curve was shifted significantly to the right of the control curve following a dose of Wy 20051 (1.5 x 10(-4) mol/kg cumulative). 4 The dose-response curve for the pressor action of Wy 20051 was potentiated in reserpine-treated anaesthetized rats. In contrast, tyramine-induced pressor responses were abolished. 5 Wy 20051 contracted the guinea-pig isolated aortic spiral preparation (3.8 x 10(-5)-6.0 x 10(-4) mol) and evoked constrictor responses in the perfused mesenteric vasculature preparation of the rat (5.9 x 10(-7)-1.2 x 10(-5) mol). At higher doses the responses were reduced. 6 Wy 20051-induced constrictor responses of the perfused mesentery were unaffected by blockade of alpha-adrenoceptors or by tachyphylaxis of 5-hydroxytryptamine receptors. 7 The time for abolition of Wy 20051-induced constrictor responses of the mesentery in a calcium-free medium was not significantly different from that required for noradrenaline, but was significantly greater than that for KCl (P less than 0.001). 8 Wy 20051 and noradrenaline, but not KCl, evoked constrictor responses in the depolarized rat mesenteric vasculature. 9 The results indicate that Wy 20051 evokes pressor responses which have some of the characteristics of those of noradrenaline. However, the responses are not elicited by an alpha-adrenoceptor mechanism. PMID:3247

  9. Lung epinephrine synthesis

    SciTech Connect

    Kennedy, B.; Elayan, H.; Ziegler, M.G. )

    1990-04-01

    We studied in vitro and in vivo epinephrine (E) synthesis by rat lung. Nine days after removal of the adrenal medullas, circulating E was reduced to 7% of levels found in sham-operated rats but 30% of lung E remained. Treatment of demedullated rats with 6 hydroxydopamine plus reserpine did not further reduce lung E. In the presence of S-(3H)adenosylmethionine lung homogenates readily N-methylated norepinephrine (NE) to form (3H)E. The rate of E synthesis by lung homogenates was progressively more rapid with increasing NE up to a concentration of 3 mM, above which it declined. The rate of E formation was optimal at an incubation pH of 8 and at temperatures of approximately 55 degrees C. We compared the E-forming enzyme(s) of lung homogenates with those of adrenal and cardiac ventricle. The adrenal contains mainly phenylethanolamine N-methyltransferase (PNMT), which is readily inhibited by SKF 29661 and methylates dopamine (DA) very poorly. Cardiac ventricles contain mainly nonspecific N-methyltransferase (NMT), which is poorly inhibited by SKF 29661 and readily methylates both DA and NE. Lung homogenates were inhibited by SKF 29661 about half as well as adrenal but more than ventricle. We used the rate of E formation from NE as an index of PNMT-like activity and deoxyepinephrine synthesis from DA as an index of NMT-like activity. PNMT and NMT activity in rat lung homogenates were not correlated with each other, displayed different responses to change in temperature, and were affected differently by glucocorticoids.

  10. An Antioxidant Extract of the Insectivorous Plant Drosera burmannii Vahl. Alleviates Iron-Induced Oxidative Stress and Hepatic Injury in Mice

    PubMed Central

    Das, Abhishek; Panja, Sourav; Mandal, Nripendranath

    2015-01-01

    Free iron typically leads to the formation of excess free radicals, and additional iron deposition in the liver contributes to the oxidative pathologic processes of liver disease. Many pharmacological properties of the insectivorous plant Drosera burmannii Vahl. have been reported in previous studies; however, there is no evidence of its antioxidant or hepatoprotective potential against iron overload. The antioxidant activity of 70% methanolic extract of D. burmannii (DBME) was evaluated. DBME showed excellent DPPH, hydroxyl, hypochlorous, superoxide, singlet oxygen, nitric oxide, peroxynitrite radical and hydrogen peroxide scavenging activity. A substantial iron chelation (IC50 = 40.90 ± 0.31 μg/ml) and supercoiled DNA protection ([P]50 = 50.41 ± 0.55 μg) were observed. DBME also displayed excellent in vivo hepatoprotective activity in iron-overloaded Swiss albino mice compared to the standard desirox treatment. Administration of DBME significantly normalized serum enzyme levels and restored liver antioxidant enzymes levels. DBME lowered the raised levels of liver damage parameters, also reflected from the morphological analysis of the liver sections. DBME also reduced liver iron content by 115.90% which is also seen by Perls’ staining. A phytochemical analysis of DBME confirms the presence of various phytoconstituents, including phenols, flavonoids, carbohydrates, tannins, alkaloids and ascorbic acid. Alkaloids, phenols and flavonoids were abundantly found in DBME. An HPLC analysis of DBME revealed the presence of purpurin, catechin, tannic acid, reserpine, methyl gallate and rutin. Purpurin, tannic acid, methyl gallate and rutin displayed excellent iron chelation but exhibited cytotoxicity toward normal (WI-38) cells; while DBME found to be non-toxic to the normal cells. These findings suggest that the constituents present in DBME contributed to its iron chelation activity. Additional studies are needed to determine if DBME can be used as a treatment for

  11. Mechanisms of L-NG-nitro arginine methyl ester-induced antinociception in mice: a role for serotonergic and adrenergic neurons.

    PubMed

    Mustafa, A A

    1992-11-01

    1. The mechanisms involved in the antinociceptive action of L-NG-nitro arginine methyl ester (L-NAME) were investigated in mice. 2. Intraperitoneal administration of L-NAME produced a dose-dependent antinociception in the tail-flick, hot-plate and phenyl-p-quinone-induced writhing tests. 3. Pretreatment with the catecholamine depletors 6-hydroxydopamine (5 micrograms i.c.v.) or reserpine (5 mg/kg i.p.) or the serotonin synthesis inhibitor, p-chlorophenylalanine methyl ester (200 mg/kg i.p. on 2 consecutive days) resulted in a significant decrease in the antinociceptive effect of L-NAME. 4. Similarly, pretreatment with the selective alpha 1-adrenoceptor antagonist prazonin (2.5 mg/kg, i.p.), or the non-selective alpha-adrenoceptor blocker, phentolamine (5 mg/kg, i.p.) antagonized the antinociceptive effect of L-NAME. 5. However, the administration of the selective alpha 2-adrenoceptor antagonist, idazoxan (2.5 mg/kg i.p.) was without effect. 6. Likewise, pretreatment with the serotonin 5-HT2 receptor blocker, ketanserin (1 mg/kg, i.p.), the D2 dopamine receptor antagonist (+/-) sulpiride (30 mg/kg, i.p.) or the opioid antagonist naloxone (5 mg/kg, i.p.) did not inhibit the antinociceptive effect of L-NAME. 7. These results suggest that L-NAME produces antinociception in the mouse probably by an action on adrenergic and serotonergic synapses. PMID:1362551

  12. Total Sleep Deprivation Alters Endothelial Function in Rats: A Nonsympathetic Mechanism

    PubMed Central

    Sauvet, Fabien; Florence, Geneviève; Van Beers, Pascal; Drogou, Catherine; Lagrume, Christophe; Chaumes, Cyrielle; Ciret, Sylvain; Leftheriotis, Georges; Chennaoui, Mounir

    2014-01-01

    Study Objectives: Sleep loss is suspected to induce endothelial dysfunction, a key factor in cardiovascular risk. We examined whether sympathetic activity is involved in the endothelial dysfunction caused by total sleep deprivation (TSD). Design: Two groups: TSD (24-h wakefulness), using slowly rotating wheels, and wheel control (WC). Participants: Seven-month-old male Wistar rats. Interventions: Pharmacological sympathectomy (reserpine, 5 mg/kg, intraperitoneal), nitric oxide synthase (NOS) inhibition (NG-nitro-L-arginine, 20 mg/kg, intraperitoneally 30 min before experiment) and cyclooxygenase (COX) inhibition (indomethacin, 5 mg/kg, intraperitoneally 30 min before experiment). Measurements and Results: In protocol 1, changes in heart rate (HR) and blood pressure were continuously recorded in the sympathectomized and non-sympathectomized rats. Blood pressure and HR increased during TSD in non-sympathectomized rats. In protocol 2, changes in skin blood flow (vasodilation) were assessed in the sympathectomized and non-sympathectomized rats using laser-Doppler flowmetry coupled with iontophoretic delivery of acetylcholine (ACh), sodium nitroprusside (SNP), and anodal and cathodal currents. ACh- and cathodal current-induced vasodilations were significantly attenuated after TSD in non-sympathectomized and sympathectomized rats (51% and 60%, respectively). In protocol 3, ACh-induced vasodilation was attenuated after NOS and COX inhibition (66% and 49%, respectively). Cathodal current-induced vasodilation decreased by 40% after COX inhibition. In TSD compared to WC a decrease in ACh-induced vasodilation was still observed after COX inhibition. No changes in SNP- and anodal current-induced vasodilation were detected. Conclusion: These results demonstrate that total sleep deprivation induces a reduction in endothelial-dependent vasodilation. This endothelial dysfunction is independent of blood pressure and sympathetic activity but associated with nitric oxide synthase and

  13. PDE10A inhibitors stimulate or suppress motor behavior dependent on the relative activation state of the direct and indirect striatal output pathways

    PubMed Central

    Megens, Anton A H P; Hendrickx, Herman M R; Mahieu, Michel M A; Wellens, Annemie L Y; de Boer, Peter; Vanhoof, Greet

    2014-01-01

    The enzyme phosphodiesterase 10A (PDE10A) regulates the activity of striatal, medium spiny neurons (MSNs), which are divided into a behaviorally stimulating, Gs-coupled D1 receptor-expressing “direct” pathway and a behaviorally suppressant, Gi-coupled D2 receptor-expressing “indirect” pathway. Activating both pathways, PDE10A inhibitors (PDE10AIs) combine functional characteristics of D2 antagonists and D1 agonists. While the effects of PDE10AIs on spontaneous and stimulated behavior have been extensively reported, the present study investigates their effects on suppressed behavior under various conditions of reduced dopaminergic neurotransmission: blockade of D1 receptors with SCH-23390, blockade of D2 receptors with haloperidol, or depletion of dopamine with RO-4-1284 or reserpine. In rats, PDE10AIs displayed relatively low cataleptic activity per se. After blocking D1 receptors, however, they induced pronounced catalepsy at low doses close to those required for inhibition of apomorphine-induced behavior; slightly higher doses resulted in behavioral stimulant effects, counteracting the catalepsy. PDE10AIs also counteracted catalepsy and related behaviors induced by D2 receptor blockade or dopamine depletion; catalepsy was replaced by behavioral stimulant effects under the latter but not the former condition. Similar interactions were observed at the level of locomotion in mice. At doses close to those inhibiting d-amphetamine-induced hyperlocomotion, PDE10AIs reversed hypolocomotion induced by D1 receptor blockade or dopamine depletion but not hypolocomotion induced by D2 receptor blockade. It is concluded that PDE10AIs stimulate or inhibit motor behavior dependent on the relative activation state of the direct and indirect striatal output pathways. PMID:25505601

  14. Internephron heterogeneity of growth factors and sclerosis--modulation of platelet-derived growth factor by angiotensin II.

    PubMed

    Tanaka, R; Sugihara, K; Tatematsu, A; Fogo, A

    1995-01-01

    We studied the early phase after 5/6 nephrectomy in Munich-Wistar rats to determine whether treatment with angiotensin II receptor antagonist (AIIRA) modulates the expression of platelet-derived growth factor (PDGF) mRNA and its protein among the glomeruli which are undergoing progressive hypertrophy and sclerosis. Average PDGF-B immunohistochemistry staining score (IHS, 0 to 3 scale) in glomeruli and PDGF-B chain mRNA from kidneys were both increased in 5/6 nephrectomy rats (N = 6) versus age-matched normal (N = 5) at week 4, when glomeruli were at early stages of sclerosis (IHS, 0.81 +/- 0.12 vs. 0.19 +/- 0.05; sclerosis index, S.I., 0 to 4 scale: 0.41 +/- 0.04 vs. 0.05 +/- 0.01, both P < 0.05). AIIRA (80 mg/liter drinking water, N = 6) started at time of 5/6 nephrectomy prevented the development of sclerosis (S.I. 0.08 +/- 0.03) and decreased PDGF-B protein (IHS 0.22 +/- 0.08, both P = NS vs. normal), and PDGF-B chain mRNA. In contrast, triple therapy (TRX; hydralazine, reserpine and hydrochlorothiazide, N = 5) in doses which controlled systemic blood pressure resulted in intermediate level of glomerulosclerosis at this early time point of progressive injury. Concurrently, TRX failed to affect the expression of PDGF-B protein (IHS 0.86 +/- 0.19) or its mRNA expression. The PDGF-B distribution was not uniform amongst the glomeruli with varying stages of sclerosis. There was a strong correlation in individual glomeruli of increased PDGF-B staining with early sclerotic changes (P < 0.01), with the disappearance of this correlation in glomeruli with advanced sclerosis.(ABSTRACT TRUNCATED AT 250 WORDS)

  15. Calcium and magnesium in exocrine secretion--an X-ray microanalytical study

    SciTech Connect

    Roomans, G.M.; Barnard, T.

    1982-01-01

    Calcium and magnesium distribution in mammalian exocrine glands under resting, stimulated and pathological conditions was investigated by X-ray microanalysis of thick and ultrathin cryosections. Ultrathin sections were cut from tissue frozen in the presence of a polymer cryoprotectant, dextran. The effect of this treatment on isolated rabbit pancreas. Dextran caused a disturbance in water and ion transport, partly due to an osmotic effect and the impermeability of the pancreatic epithelium to dextran; this does, however, not necessarily invalidate intracellular measurements on frozen-dried sections. Cholinergic stimulation of the rat pancreas caused a change of Ca distribution from the basal to the apical part of the cell; this may be a component of the secretory Ca flux. Kinetic considerations make a significant Ca movement via the ER-Golgi endomembrane space less likely. The mitochondrial Ca concentration is low, and not significantly changed by cholinergic stimulation. X-ray microanalysis was carried out on submandibular glands of rats after chronic treatment with reserpin and/or isoproterenol (an animal model for cystic fibrosis, CF). The acinar cells had elevated Mg and Ca and lowered K concentrations. Analysis of ultrathin cryosections showed high levels of Ca and Mg in secretory granules, mucus globules and the ER. Ca and Mg in the ER may be transported intracellularly with secretory proteins to secretion granules or mucus globules. The decrease in cell K may be due to efflux of K caused by elevated cytoplasmic Ca levels. A similar decrease in cell K was caused by incubation of rat salivary glands with diluted serum from CF patients, a treatment which has been reported to mimic the effect of a rise in cytoplasmic Ca.

  16. Ambient Mass Spectrometry Imaging with Picosecond Infrared Laser Ablation Electrospray Ionization (PIR-LAESI).

    PubMed

    Zou, Jing; Talbot, Francis; Tata, Alessandra; Ermini, Leonardo; Franjic, Kresimir; Ventura, Manuela; Zheng, Jinzi; Ginsberg, Howard; Post, Martin; Ifa, Demian R; Jaffray, David; Miller, R J Dwayne; Zarrine-Afsar, Arash

    2015-12-15

    A picosecond infrared laser (PIRL) is capable of cutting through biological tissues in the absence of significant thermal damage. As such, PIRL is a standalone surgical scalpel with the added bonus of minimal postoperative scar tissue formation. In this work, a tandem of PIRL ablation with electrospray ionization (PIR-LAESI) mass spectrometry is demonstrated and characterized for tissue molecular imaging, with a limit of detection in the range of 100 nM for reserpine or better than 5 nM for verapamil in aqueous solution. We characterized PIRL crater size using agar films containing Rhodamine. PIR-LAESI offers a 20-30 μm vertical resolution (∼3 μm removal per pulse) and a lateral resolution of ∼100 μm. We were able to detect 25 fmol of Rhodamine in agar ablation experiments. PIR-LAESI was used to map the distribution of endogenous methoxykaempferol glucoronide in zebra plant (Aphelandra squarrosa) leaves producing a localization map that is corroborated by the literature. PIR-LAESI was further used to image the distribution inside mouse kidneys of gadoteridol, an exogenous magnetic resonance contrast agent intravenously injected. Parallel mass spectrometry imaging (MSI) using desorption electrospray ionization (DESI) and matrix assisted laser desorption ionization (MALDI) were performed to corroborate PIR-LAESI images of the exogenous agent. We further show that PIR-LAESI is capable of desorption ionization of proteins as well as phospholipids. This comparative study illustrates that PIR-LAESI is an ion source for ambient mass spectrometry applications. As such, a future PIRL scalpel combined with secondary ionization such as ESI and mass spectrometry has the potential to provide molecular feedback to guide PIRL surgery.

  17. From Supercomputer Modeling to Highest Mass Resolution in FT-ICR.

    PubMed

    N Nikolaev, Evgene; N Vladimirov, Gleb; Jertz, Roland; Baykut, Gökhan

    2013-01-01

    Understanding of behavior of ion ensembles inside FT-ICR cell based on the computer simulation of ion motion gives rise to the new ideas of cell designs. The recently introduced novel FT-ICR cell based on a Penning ion trap with specially shaped excitation and detection electrodes prevents distortion of ion cyclotron motion phases (normally caused by non-ideal electric trapping fields) by averaging the trapping DC electric field during the ion motion in the ICR cell. Detection times of 5 min resulting in resolving power close to 40,000,000 have been reached for reserpine at m/z 609 at a magnetic field of only 7 Tesla. Fine structures of resolved 13Cn isotopic cluster groups could be measured for molecular masses up to 5.7 kDa (insulin) with resolving power of 4,000,000 at 7 Tesla. Based on resolved fine structure patterns atomic compositions can be directly determined using a new developed algorithm for fine structure processing. Mass spectra of proteins and multimers of proteins reaching masses up to 186 kDa (enolase tetramer) could be measured with isotopic resolution. For instance, at 7 Tesla resolving power of 800,000 was achieved for enolase dimer (96 kDa) and 500,000 for molecular masses above 100 kDa. Experimental data indicate that there is practically no limit for the resolving power of this ICR cell except by collisional damping in the ultrahigh vacuum chamber.

  18. The effect of cold storage on the adrenergic mechanisms of intestinal smooth muscle

    PubMed Central

    Hattori, K.; Kurahashi, K.; Mori, J.; Shibata, S.

    1972-01-01

    1. In the guinea-pig taenia caecum, fluorescent adrenergic fibres terminate in both muscle layers. The density of these fibres is greater in the taenia than in the underlying circular muscle layer. The myenteric plexus and individual ganglion cells are also densely innervated by intensely fluorescent adrenergic nerve fibres. 2. After three days of cold storage, the specific fluorescence disappeared from all tissue layers of the taenia caecum and smooth muscle fibres. In contrast, cholinesterase active substances were still demonstrable in all tissue layers even after seven days of cold storage but the density of these substances was decreased. 3. Cold storage (3-7 days) decreased the tissue noradrenaline content and did not modify the cholinesterase enzyme activity (4 days). 4. In cold stored strips, the inhibitory response to nicotine, 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) or electrical transmural stimulation was abolished and enhancement of the contractile response occurred. Cold storage also inhibited the inhibitory action of tyramine. Similar results were observed after reserpine treatment. 5. In fresh taenia, the relaxation produced by nicotine, DMPP and electrical transmural stimulation was inhibited by adrenoceptor blocking agents and bretylium. In cold storage preparations, contraction produced by these stimuli was blocked by parasympathetic blocking agents and potentiated by anti-cholinesterase. These results indicate that the inhibitory response to these stimulants is mediated by stimulation of the adrenergic nerve system more than by non-adrenergic nerves; the excitatory effect is probably due to stimulation of cholinergic nerves. 6. These results suggest that the adrenergic mechanisms of the taenia caecum are more labile in cold storage than the cholinergic mechanisms. Thus, the inhibitory action of cold storage on the relaxation produced by nicotine, DMPP, and transmural stimulation is probably explained by selective physical degeneration of

  19. Cannabinoid agonists stimulate [3H]GABA release in the globus pallidus of the rat when G(i) protein-receptor coupling is restricted: role of dopamine D2 receptors.

    PubMed

    Gonzalez, Brenda; Paz, Francisco; Florán, Leonor; Aceves, Jorge; Erlij, David; Florán, Benjamín

    2009-03-01

    The motor effects of cannabinoids in the globus pallidus appear to be caused by increases in interstitial GABA. To elucidate the mechanism of this response, we investigated the effect of the selective cannabinoid type 1 receptor (CB1) cannabinoid agonist arachidonyl-2-chloroethylamide (ACEA) on [(3)H]GABA release in slices of the rat globus pallidus. ACEA had two effects: concentrations between 10(-8) and 10(-6) M stimulated release, whereas higher concentrations (IC(50) approximately 10(-6) M) inhibited it. Another cannabinoid agonist, WIN-55,212-2, also had bimodal effects on release. Studies of cAMP production indicate that under conditions of low G(i/o), availability the coupling of CB1 receptors with G(i/o) proteins can be changed into CB1:G(s/olf) coupling; therefore, we determined the effects of conditions that limit G(i/o) availability on [(3)H]GABA release. Blockers of G(i/o) protein interactions, pertussis toxin and N-ethylmaleimide, transformed the inhibitory effects of ACEA on GABA release into stimulation. It also has been suggested that stimulation of D2 receptors can reduce G(i/o) availability. Blocking D2 receptors with sulpiride [(S)-5-aminosulfonyl-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2-methoxybenzamidersqb] or depleting dopamine with reserpine inhibited the ACEA-induced stimulation of release. Thus, the D2 dependence of stimulation is consistent with the proposal that D2 receptors reduce G(i/o) proteins available for binding to the CB1 receptor. In summary, CB1 receptor activation has dual effects on GABA release in the globus pallidus. Low concentrations stimulate release through a process that depends on activation of dopamine D2 receptors that may limit G(i/o) protein availability. Higher concentrations of cannabinoid inhibit GABA release through mechanisms that are independent of D2 receptor activation.

  20. Development of transcriptomic resources for interrogating the biosynthesis of monoterpene indole alkaloids in medicinal plant species.

    PubMed

    Góngora-Castillo, Elsa; Childs, Kevin L; Fedewa, Greg; Hamilton, John P; Liscombe, David K; Magallanes-Lundback, Maria; Mandadi, Kranthi K; Nims, Ezekiel; Runguphan, Weerawat; Vaillancourt, Brieanne; Varbanova-Herde, Marina; Dellapenna, Dean; McKnight, Thomas D; O'Connor, Sarah; Buell, C Robin

    2012-01-01

    The natural diversity of plant metabolism has long been a source for human medicines. One group of plant-derived compounds, the monoterpene indole alkaloids (MIAs), includes well-documented therapeutic agents used in the treatment of cancer (vinblastine, vincristine, camptothecin), hypertension (reserpine, ajmalicine), malaria (quinine), and as analgesics (7-hydroxymitragynine). Our understanding of the biochemical pathways that synthesize these commercially relevant compounds is incomplete due in part to a lack of molecular, genetic, and genomic resources for the identification of the genes involved in these specialized metabolic pathways. To address these limitations, we generated large-scale transcriptome sequence and expression profiles for three species of Asterids that produce medicinally important MIAs: Camptotheca acuminata, Catharanthus roseus, and Rauvolfia serpentina. Using next generation sequencing technology, we sampled the transcriptomes of these species across a diverse set of developmental tissues, and in the case of C. roseus, in cultured cells and roots following elicitor treatment. Through an iterative assembly process, we generated robust transcriptome assemblies for all three species with a substantial number of the assembled transcripts being full or near-full length. The majority of transcripts had a related sequence in either UniRef100, the Arabidopsis thaliana predicted proteome, or the Pfam protein domain database; however, we also identified transcripts that lacked similarity with entries in either database and thereby lack a known function. Representation of known genes within the MIA biosynthetic pathway was robust. As a diverse set of tissues and treatments were surveyed, expression abundances of transcripts in the three species could be estimated to reveal transcripts associated with development and response to elicitor treatment. Together, these transcriptomes and expression abundance matrices provide a rich resource for

  1. A pharmacological, crystallographic, and quantum chemical study of new inotropic agents.

    PubMed

    Dorigo, P; Gaion, R M; Belluco, P; Fraccarollo, D; Maragno, I; Bombieri, G; Benetollo, F; Mosti, L; Orsini, F

    1993-08-20

    The cardiac activity of a series of milrinone analogues, 2-substituted 3-acyl-1,6-dihydro-6-oxo-5-pyridinecarbonitriles, 1,6,3,2,11,12-hexahydro-6,3-dioxo-5-quinolinecarbonitriles, the correlated carboxylic acids, 2-substituted 3-acyl-6(1H)-pyridones, and 7,8-dihydro-2,5(1H,6H)-quinolinediones, was evaluated in spontaneously beating and in electrically driven atria from reserpine-treated guinea pigs. Their effects were compared with those induced by amrinone and milrinone in both the atria preparations. Compounds SF28 (3-acetyl-1,6-dihydro-2-methyl-6-oxo-5-pyridinecarbonitrile) and SF40 (7,8-dihydro-7-methyl-2,5(1H,6H)-quinolinedione) were the most effective positive inotropic agents. An inhibition of the negative influence exerted by endogenous adenosine on heart preparations seems to be involved in their contractile activity. SF38 (3-benzoyl-2-phenyl-6(1H)-pyridinone), on the contrary, reduced the contractile force and the frequency rate of guinea pig atria with a mechanism not related to an activation of cholinergic or purinergic inhibitory receptors on the heart. X-ray analysis carried out on the three model compounds, SF28, SF40 (positive inotropic agents), and SF38 (negative inotropic agent), and molecular modeling evidenced that the change from phenyl (SF38) to methyl (SF28) or the introduction of a side cyclic aliphatic chain (SF40) results in a variation of conformational preference and topography which may address the different molecules toward distinct receptor pockets according to the resulting inotropic effect.

  2. Carrier-mediated transport of enkephalins and N-Tyr-MIF-1 across blood-brain barrier

    SciTech Connect

    Banks, W.A.; Kastin, A.J.; Fischman, A.J.; Coy, D.H.; Strauss, S.L.

    1986-10-01

    The saturable, carrier-mediated system capable of the brain-to-blood transport of small peptides with an N-terminal tyrosine was characterized. The rate of disappearance of intraventricularly injected iodinated peptide in the presence or absence of the inhibitor being tested was determined from formulas based on the residual radioactivity in the brains of mice after decapitation. The injection of 100 nmol/mouse of unlabeled N-Tyr-MIF-1 (TMIF) increased the half-time disappearance of 125I-TMIF (ITMIF) in the central nervous system (CNS) from 14.1 to 88.7 min (P less than 0.00005). Technetium, a substance transported out of the brain by the same system that transports iodine, was used as a control; the half-time disappearance of technetium pertechnetate was unaffected by unlabeled TMIF. With two related but distinct techniques, the maximum transport rate out of the CNS (Vmax) for TMIF was 0.266 nmol X g of brain per min (method 1) and 0.297 nmol X g-1 X min-1 (method 2), while the amount of unlabeled material needed to achieve 50% of Vmax (Km) was 15.2 nmol/g (method 1) and 15.1 nmol/g (method 2). The lack of effect of the tyrosinated fragments of TMIF as inhibitors indicates that TMIF is being transported in intact form. The Vmax for methionine enkephalin determined with labeled and unlabeled methionine enkephalin was 0.630 nmol X g-1 X min-1 and the Km was 24.95 nmol/g. Studies with the metabolic modulators furosemide, acetozolamide, reserpine, ouabain, and theophylline suggest that the system is sodium dependent and probably independent of ATPase.

  3. Antidepressant-like activity of liposomal formulation containing nimodipine treatment in the tail suspension test, forced swim test and MAOB activity in mice.

    PubMed

    Moreno, Lina Clara Gayoso E Almendra Ibiapina; Rolim, Hercília Maria Lins; Freitas, Rivelilson Mendes; Santos-Magalhães, Nereide Stela

    2016-09-01

    Previous studies have shown that intracellular calcium ion dysfunction may be an etiological factor in affective illness. Nimodipine (NMD) is a Ca(2+) channel blocker that has been extensively investigated for therapy of central nervous system (CNS) disorders. In this work, we have evaluated the antidepressant-like activity of nimodipine encapsulated into liposomes (NMD-Lipo) in mice through tail suspension and forced swim assays, as well as MAOB activity. During the tail suspension test, the administration of NMD-Lipo at 0.1, 1 and 10mg/kg was able to promote a reduction in the immobility time of animals greater than the positive control (imipramine). In the forced swim test, the immobility time of mice treated with NMD-Lipo was reduced. This reduction was significantly greater than that found in the animals treated with imipramine and paroxetine. This may suggest that NMD-Lipo provides more antidepressant-like activity than in positive controls. The groups that received a combination of liposomal NMD and antidepressant drugs showed lower immobility time than the groups, which were treated only with imipramine or paroxetine. The mice treated with the combination of NMD-Lipo and reserpine presented an increase in the time of immobility compared with animals treated only with NMD-Lipo. There was a significant decrease in MAOB activity in animals treated with NMD-Lipo compared with untreated animals. The results of the tail suspension test, forced swim test and MAOB activity suggested that the antidepressant activity of NMD-Lipo may be related to an increase in the cerebral monoamine concentrations.

  4. The Role of De Novo Catecholamine Synthesis in Mediating Methylmercury-Induced Vesicular Dopamine Release From Rat Pheochromocytoma (PC12) Cells

    PubMed Central

    Atchison, William D.

    2013-01-01

    The purpose of this study was to characterize methylmercury (MeHg)–induced dopamine (DA) release from undifferentiated pheochromocytoma (PC12) cells and to examine the potential role for DA synthesis in this process. MeHg caused a significant increase in DA release that was both concentration- and time-dependent. DA release was significantly increased by 2µM MeHg at 60min and by 5µM MeHg at 30min; 1µM MeHg was without effect. Because DA release induced by 5µM MeHg was associated with a significant percentage of cell death at 60 and 120min, 2µM MeHg was chosen for further characterization of release mechanisms. MeHg-induced DA release was attenuated but not abolished in the absence of extracellular calcium, whereas the vesicular content depleting drug reserpine (50nM) abolished release. Thus, MeHg-induced DA release requires vesicular exocytosis but not extracellular calcium. MeHg also increased intracellular DA and the rate of DA storage utilization, suggesting a role for DA synthesis in MeHg-induced DA release. The tyrosine hydroxylase inhibitor α-methyltyrosine (300µM, 24h) completely abolished MeHg-induced DA release. MeHg significantly increased DA precursor accumulation in cells treated with 3-hydroxybenzylhydrazine (10µM), revealing that MeHg increases tyrosine hydroxylase activity. Overall, these data demonstrate that MeHg facilitates DA synthesis, increases intracellular DA, and augments vesicular exocytosis. PMID:23425605

  5. Comparison of bretylium and guanethidine: tolerance, and effects on adrenergic nerve function and responses to sympathomimetic amines

    PubMed Central

    Boura, A. L. A.; Green, A. F.

    1962-01-01

    Bretylium depresses the slope of regression lines relating frequency of sympathetic nerve stimulation to magnitude of contractions of the cat nictitating membrane. In contrast, guanethidine and reserpine preferentially abolish responses to low rates of nerve stimulation and cause a roughly parallel shift of the regression lines. The hypersensitivity of the nictitating membranes of cats to intravenous adrenaline or noradrenaline is far greater after a series of small daily doses of bretylium or guanethidine than after single large doses. The maximal sensitivity produced was similar to that after postganglionic sympathetic nerve section and exceeded that produced by ganglion blockade. The development of hypersensitivity to catechol amines is accompanied by some return of responses of the nictitating membranes to sympathetic nerve stimulation despite continued daily administration of bretylium or guanethidine. In cats given bretylium daily, responses to low rates of nerve stimulation become greater than in controls unless the dose of bretylium given subcutaneously is 50 mg/kg or more. When marked hypersensitivity to catechol amines has been produced by giving bretylium or guanethidine daily for 7 or 14 days, the sympathomimetic effects of these compounds are greater. Responses to intravenous dimethylphenylpiperazinium are also increased and the results suggest that even large daily doses of adrenergic neurone blocking agents do not appreciably impair the functioning of the adrenal medulla. The pressor effects of intravenous adrenaline, noradrenaline and dimethylphenylpiperazinium iodide increase less than the corresponding nictitating membrane responses. These results are discussed in relation to tolerance to adrenergic neurone blockade, and differences between the effects of bretylium and guanethidine found in man. Bretylium and guanethidine depress the slopes of the dose-response curves for the pressor and nictitating membrane contracting effects of tyramine. When

  6. Role of P27 -P55 operon from Mycobacterium tuberculosis in the resistance to toxic compounds

    PubMed Central

    2011-01-01

    Background The P27-P55 (lprG-Rv1410c) operon is crucial for the survival of Mycobacterium tuberculosis, the causative agent of human tuberculosis, during infection in mice. P55 encodes an efflux pump that has been shown to provide Mycobacterium smegmatis and Mycobacterium bovis BCG with resistance to several drugs, while P27 encodes a mannosylated glycoprotein previously described as an antigen that modulates the immune response against mycobacteria. The objective of this study was to determine the individual contribution of the proteins encoded in the P27-P55 operon to the resistance to toxic compounds and to the cell wall integrity of M. tuberculosis. Method In order to test the susceptibility of a mutant of M. tuberculosis H37Rv in the P27-P55 operon to malachite green, sodium dodecyl sulfate, ethidium bromide, and first-line antituberculosis drugs, this strain together with the wild type strain and a set of complemented strains were cultivated in the presence and in the absence of these drugs. In addition, the malachite green decolorization rate of each strain was obtained from decolorization curves of malachite green in PBS containing bacterial suspensions. Results The mutant strain decolorized malachite green faster than the wild type strain and was hypersensitive to both malachite green and ethidium bromide, and more susceptible to the first-line antituberculosis drugs: isoniazid and ethambutol. The pump inhibitor reserpine reversed M. tuberculosis resistance to ethidium bromide. These results suggest that P27-P55 functions through an efflux-pump like mechanism. In addition, deletion of the P27-P55 operon made M. tuberculosis susceptible to sodium dodecyl sulfate, suggesting that the lack of both proteins causes alterations in the cell wall permeability of the bacterium. Importantly, both P27 and P55 are required to restore the wild type phenotypes in the mutant. Conclusions The results clearly indicate that P27 and P55 are functionally connected in

  7. Characteristics, specificity, and efferent control of frog cutaneous cold receptors.

    PubMed

    Spray, D C

    1974-02-01

    norepinephrine in doses of 10(-6)-10(-7) g/ml. Ephedrine, another adrenergic agonist, also mimics the enhancement of cold receptors by sympathetic stimulation.9. Larger fibres are recruited to account for the increased sensitivity of thermoreceptors following sympathetic stimulation and epinephrine application.10. Propranolol and phentolamine both block the enhancement of the response by sympathetic stimulation, but propranolol blocks the response of the receptor to thermal stimulation as well. Reserpine pre-treatment blocks the effect of sympathetic stimulation on the cold response. PMID:4545023

  8. Histamine H(3) receptor-mediated inhibition of depolarization-induced, dopamine D(1) receptor-dependent release of [(3)H]-gamma-aminobutryic acid from rat striatal slices.

    PubMed

    Arias-Montaño, J A; Floran, B; Garcia, M; Aceves, J; Young, J M

    2001-05-01

    1. A study was made of the regulation of [(3)H]-gamma-aminobutyric acid ([(3)H]-GABA) release from slices of rat striatum by endogenous dopamine and exogenous histamine and a histamine H(3)-agonist. Depolarization-induced release of [(3)H]-GABA was Ca(2+)-dependent and was increased in the presence of the dopamine D(2) receptor family antagonist, sulpiride (10 microM). The sulpiride-potentiated release of [(3)H]-GABA was strongly inhibited by the dopamine D(1) receptor family antagonist, SCH 23390 (1 microM). Neither antagonist altered basal release. 2. The 15 mM K(+)-induced release of [(3)H]-GABA in the presence of sulpiride was inhibited by 100 microM histamine (mean inhibition 78+/-3%) and by the histamine H(3) receptor-selective agonist, immepip, 1 microM (mean inhibition 81+/-5%). The IC(50) values for histamine and immepip were 1.3+/-0.2 microM and 16+/-2 nM, respectively. The inhibitory effects of histamine and immepip were reversed by the H(3) receptor antagonist, thioperamide, 1 microM. 3. The inhibition of 15 mM K(+)-induced [(3)H]-GABA release by immepip was reversed by the H(3) receptor antagonist, clobenpropit, K(d) 0.11+/-0.04 nM. Clobenpropit alone had no effect on basal or stimulated release of [(3)H]-GABA. 4. Elevated K(+) caused little release of [(3)H]-GABA from striatal slices from reserpinized rats, unless the D(1) partial agonist, R(+)-SKF 38393, 1 microM, was also present. The stimulated release in the presence of SKF 38393 was reduced by 1 microM immepip to the level obtained in the absence of SKF 38393. 5. These observations demonstrate that histamine H(3) receptor activation strongly inhibits the dopamine D(1) receptor-dependent release of [(3)H]-GABA from rat striatum; primarily through an interaction at the terminals of GABA neurones.

  9. Tolerance of Listeria monocytogenes to Quaternary Ammonium Sanitizers Is Mediated by a Novel Efflux Pump Encoded by emrE

    PubMed Central

    Ziegler, Jennifer; Wałecka-Zacharska, Ewa; Reimer, Aleisha; Kitts, David D.; Gilmour, Matthew W.

    2015-01-01

    A novel genomic island (LGI1) was discovered in Listeria monocytogenes isolates responsible for the deadliest listeriosis outbreak in Canada, in 2008. To investigate the functional role of LGI1, the outbreak strain 08-5578 was exposed to food chain-relevant stresses, and the expression of 16 LGI1 genes was measured. LGI1 genes with putative efflux (L. monocytogenes emrE [emrELm]), regulatory (lmo1851), and adhesion (sel1) functions were deleted, and the mutants were exposed to acid (HCl), cold (4°C), salt (10 to 20% NaCl), and quaternary ammonium-based sanitizers (QACs). Deletion of lmo1851 had no effect on the L. monocytogenes stress response, and deletion of sel1 did not influence Caco-2 and HeLa cell adherence/invasion, whereas deletion of emrE resulted in increased susceptibility to QACs (P < 0.05) but had no effect on the MICs of gentamicin, chloramphenicol, ciprofloxacin, erythromycin, tetracycline, acriflavine, and triclosan. In the presence of the QAC benzalkonium chloride (BAC; 5 μg/ml), 14/16 LGI1 genes were induced, and lmo1861 (putative repressor gene) was constitutively expressed at 4°C, 37°C, and 52°C and in the presence of UV exposure (0 to 30 min). Following 1 h of exposure to BAC (10 μg/ml), upregulation of emrE (49.6-fold), lmo1851 (2.3-fold), lmo1861 (82.4-fold), and sigB (4.1-fold) occurred. Reserpine visibly suppressed the growth of the ΔemrELm strain, indicating that QAC tolerance is due at least partially to efflux activity. These data suggest that a minimal function of LGI1 is to increase the tolerance of L. monocytogenes to QACs via emrELm. Since QACs are commonly used in the food industry, there is a concern that L. monocytogenes strains possessing emrE will have an increased ability to survive this stress and thus to persist in food processing environments. PMID:26590290

  10. The inhibitory action of noradrenaline and adrenaline on acetylcholine output by guinea-pig ileum longitudinal muscle strip.

    PubMed

    Paton, W D; Vizi, E S

    1969-01-01

    stimulation.8. In strips obtained from animals treated with reserpine and guanethidine, a rise in resting acetylcholine output and in stimulation output at low frequencies was found. In these conditions, noradrenaline was still effective.9. Reducing the hydroxytryptamine content of the strips by treatment with p-chloro-(+/-)-phenylalanine did not significantly affect acetylcholine output.10. It is concluded that acetylcholine output by the nervous networks of the longitudinal strip is under the normal control of the sympathetic by a species of presynaptic inhibition mediated by alpha receptors. This implies that for a tissue under dual autonomic control, withdrawal of sympathetic control will lead to a parasympathetic response which is not only unopposed but also itself enhanced.

  11. From Bench to Bedside and Back Again: A Personal Journey with Dexmedetomidine.

    PubMed

    Maze, Mervyn

    2016-09-01

    Dexmedetomidine Diminishes Halothane Anesthetic Requirements in Rats Through a Postsynaptic Alpha 2 Adrenergic Receptor. By Segal IS, Vickery RG, Walton JK, Doze VA, and Maze M. ANESTHESIOLOGY 1988; 125:590-4. Abstract reprinted with permission.The effect of 4(5)-[1-(2,3-dimethylphenyl)ethyl]imidazole (medetomidine), the α2 adrenergic agonist, on anesthetic requirements was investigated in rats anesthetized with halothane. Halothane MAC was determined before and after either dexmedetomidine (D-enantiomer) or levomedetomidine (L-enantiomer) 10, 30, and 100 μg/kg, or vehicle intraperitoneally. There was a dose-dependent increase in MAC with the D-, but not the L-, stereoisomer. At the highest dose of dexmedetomidine (100 μg/kg), halothane could be discontinued for up to 30 min with no response to tail clamping. To determine whether α2 adrenoreceptors mediated this effect of dexmedetomidine on MAC, cohorts of rats were pretreated with idazoxan, 10 mg/kg intraperitoneally, a highly selective α2 antagonist. This completely prevented the reduction of MAC caused by dexmedetomidine. To determine whether the reduction of MAC caused by dexmedetomidine was mediated in part through either opiate or adenosine receptors, groups of rats were pretreated with either naltrexone, 5 mg/kg intraperitoneally, an opiate antagonist, or 8-phenyltheophylline, 2.5 mg/kg intraperitoneally, an A1 adenosine antagonist. These two pretreatments did not alter the reduction of MAC by dexmedetomidine. To determine whether postsynaptic mechanisms mediate the anesthetic effect of dexmedetomidine, rats were depleted of central catecholamine stores with either n-(2-chloroethyl)-n-ethyl-2-bromobenzylamine or reserpine and α-methyl-para-tyrosine, and MAC was determined before and after each dose of dexmedetomidine. While the catecholamine-depleted rats had a lower basal MAC than the vehicle controls, there was still a profound reduction in halothane MAC after administration of

  12. Electrophysiological and pharmacological evaluation of the nicotinic cholinergic system in chagasic rats

    PubMed Central

    2013-01-01

    Background Two theories attempt to explain the changes observed in the nicotinic acetylcholine receptors (nAChRs) in chagasic cardiomyopathy. The neurogenic theory proposes that receptor changes are due to loss of intracardiac ganglia parasympathetic neurons. The immunogenic theory proposes that the nAChRs changes are the result of autoantibodies against these receptors. Both theories agreed that nAChRs functional expression could be impaired in Chagas disease. Methods We evaluated nAChRs functional integrity in 54 Sprague Dawley rats, divided in two groups: healthy and chronic chagasic rats. Rats were subjected to electrocardiographic studies in the whole animal under pentobarbital anesthesia, by isolation and stimulation of vagus nerves and in isolated beating hearts (Langendorff’s preparation). Results Nicotine, 10 μM, induced a significant bradycardia in both groups. However, rats that had previously received reserpine did not respond to nicotine stimulation. β-adrenergic stimulation, followed by nicotine treatment, induced tachycardia in chagasic rats; while inducing bradycardia in healthy rats. Bilateral vagus nerve stimulation induced a significantly higher level of bradycardia in healthy rats, compared to chagasic rats; physostigmine potentiated the bradycardic response to vagal stimulation in both experimental groups. Electric stimulation (e.g., ≥ 2 Hz), in the presence of physostigmine, produced a comparable vagal response in both groups. In isolated beating-heart preparations 1 μM nicotine induced sustained bradycardia in healthy hearts while inducing tachycardia in chagasic hearts. Higher nicotine doses (e.g.,10 – 100 uM) promoted the characteristic biphasic response (i.e., bradycardia followed by tachycardia) in both groups. 10 nM DHβE antagonized the effect of 10 μM nicotine, unmasking the cholinergic bradycardic effect in healthy rats only. 1 nM α-BGT alone induced bradycardia in healthy hearts but antagonized the 10 μM nicotine

  13. Discovery of a marine-derived bis-indole alkaloid fascaplysin, as a new class of potent P-glycoprotein inducer and establishment of its structure-activity relationship.

    PubMed

    Manda, Sudhakar; Sharma, Sadhana; Wani, Abubakar; Joshi, Prashant; Kumar, Vikas; Guru, Santosh K; Bharate, Sonali S; Bhushan, Shashi; Vishwakarma, Ram A; Kumar, Ajay; Bharate, Sandip B

    2016-01-01

    The screening of IIIM natural products repository for P-gp modulatory activity in P-gp over-expressing human adenocarcinoma LS-180 cells led to the identification of 7 natural products viz. withaferin, podophyllotoxin, 3-demethylcolchicine, agnuside, reserpine, seseberecine and fascaplysin as P-gp inducers. Fascaplysin (6a), a marine-derived bis-indole alkaloid, was the most potent among all of them, showing induction of P-gp with EC50 value of 25 nM. P-gp induction is one of the recently targeted strategy to increase amyloid-β clearance from Alzheimer brains. Thus, we pursued a medicinal chemistry of fascaplysin to establish its structure-activity relationship for P-gp induction activity. Four series of analogs viz. substituted quaternary fascaplysin analogs, D-ring opened quaternary analogs, D-ring opened non-quaternary analogs, and β-carbolinium analogs were synthesized and screened for P-gp induction activity. Among the total of 48 analogs screened, only quaternary nitrogen containing analogs 6a-g and 10a, 10h-l displayed promising P-gp induction activity; whereas non-planar non-quaternary analogs 9a-m, 13a-n, 15a-h were devoid of this activity. The P-gp induction activity of best compounds was then confirmed by western-blot analysis, which indicated that fascaplysin (6a) along with 4,5-difluoro analog of fascaplysin 6f and D-ring opened analog 10j displayed 4-8 fold increase in P-gp expression in LS-180 cells at 1 μM. Additionally, compounds 6a and 6f also showed inhibition of acetylcholinestease (AChE), an enzyme responsible for neuronal loss in Alzheimer's disease. Thus, fascaplysin and its analogs showing promising P-gp induction along with AChE inhibition at 1 μM, with good safety window (LS-180: IC50 > 10 μM, hGF: 4 μM), clearly indicates their promise for development as an anti-Alzheimer agent.

  14. Piperine potentiates the antidepressant-like effect of trans-resveratrol: involvement of monoaminergic system.

    PubMed

    Huang, Wu; Chen, Zhuoyou; Wang, Qiandong; Lin, Mengmeng; Wu, Shujuan; Yan, Qizhi; Wu, Fan; Yu, Xuefeng; Xie, Xupei; Li, Gaowen; Xu, Ying; Pan, Jianchun

    2013-12-01

    Major depression is characterized by dysfunction of neuroendocrine and immune networks. Trans-resveratrol, a phenolic compound presented in polygonum cuspidatum, was demonstrated previously to exert antidepressant-like effects through regulating monoaminergic system, oxidative/antioxidant defense and inflammatory response. The present study investigated the synergistic antidepressant-like effect of trans-resveratrol and piperine, a bioavailability enhancer, in mice and explored the possible mechanism. Trans-resveratrol was shown to reduce the immobility time both in the tail suspension and forced swimming tests (TST and FST). But the maximal inhibition was nearly 60% even if the doses were increased by 160 mg/kg; while piperine produced weak antidepressant-like effects in these two models. The interaction between trans-resveratrol and piperine was shown a clear-cut synergistic effect as evidenced by an isobolographic analysis. The further study suggested that the anti-immobility response from the subthreshold dose of piperine (2.5 mg/kg) and low doses of trans-resveratrol (10 and 20 mg/kg) was abolished by pretreatment with para-chlorophenylalanine (PCPA, 300 mg/kg, i.p.) in TST and FST, indicating the involvement of serotonergic system. Moreover, treatment with the subthreshold dose of piperine and low doses of trans-resveratrol attenuated reserpine-induced hypothermia and ptosis arguing for the relevance of noradrenaline. Additional evidence from neurochemical (monoamines in the frontal cortex, hippocampus, and hypothalamus) and biochemical (monoamine oxidase, MAO activity) assays corroborated the synergistically elevated monoaminergic system after co-treatment with trans-resveratrol and piperine. The present results indicate the effect of trans-resveratrol combined with piperine on depressive-like behaviors may be partly due to the potentiated activation of monoaminergic system in the brain. Further studies are necessary to elucidate the involvement of the

  15. The extraneuronal uptake and localization of noradrenaline in the cat spleen and the effect on this of some drugs, of cold and of denervation

    PubMed Central

    Gillespie, J. S.; Hamilton, D. N. H.; Hosie, R. Jeanette A.

    1970-01-01

    /ml. prevented both uptake and loss of NA in arterial smooth muscle but had no effect on collagen. 5. Chronic post-ganglionic denervation or reserpine had no effect on the development of fluorescence in any extraneuronal tissue. ImagesFig. 1Fig. 4Fig. 6Fig. 7Fig. 8Fig. 9 PMID:5498506

  16. Pentosan polysulfate preserves renal microvascular P2X1 receptor reactivity and autoregulatory behavior in DOCA-salt hypertensive rats.

    PubMed

    Guan, Zhengrong; Singletary, Sean T; Cha, Haword; Van Beusecum, Justin P; Cook, Anthony K; Pollock, Jennifer S; Pollock, David M; Inscho, Edward W

    2016-03-15

    Inflammation contributes to ANG II-associated impairment of renal autoregulation and microvascular P2X1 receptor signaling, but its role in renal autoregulation in mineralocorticoid-induced hypertension is unknown. Autoregulatory behavior was assessed using the blood-perfused juxtamedullary nephron preparation. Hypertension was induced in uninephrectomized control rats (UNx) by subcutaneous implantation of a DOCA pellet plus administration of 1% NaCl in the drinking water (DOCA-salt) for 3 wk. DOCA-salt rats developed hypertension that was unaltered by anti-inflammatory treatment with pentosan polysulfate (DOCA-salt+PPS) but was suppressed with "triple therapy" (hydrochlorothiazide, hydralazine, and reserpine; DOCA-salt+TTx). Baseline arteriolar diameters were similar across all groups. UNx rats exhibited pressure-dependent vasoconstriction with diameters declining to 69 ± 2% of control at 170 mmHg, indicating intact autoregulation. DOCA-salt treatment significantly blunted this pressure-mediated vasoconstriction. Diameters remained between 91 ± 4 and 98 ± 3% of control over 65-170 mmHg, indicating impaired autoregulation. In contrast, pressure-mediated vasoconstriction was preserved in DOCA-salt+PPS and DOCA-salt+TTx rats, reaching 77 ± 7 and 75 ± 3% of control at 170 mmHg, respectively. ATP is required for autoregulation via P2X1 receptor activation. ATP- and β,γ-methylene ATP (P2X1 receptor agonist)-mediated vasoconstriction were markedly attenuated in DOCA-salt rats compared with UNx (P < 0.05), but significantly improved by PPS or TTx (P < 0.05 vs. DOCA-salt) treatment. Arteriolar responses to adenosine and UTP (P2Y2 receptor agonist) were unaffected by DOCA-salt treatment. PPS and TTx significantly reduced MCP-1 and protein excretion in DOCA-salt rats. These results support the hypothesis that hypertension triggers inflammatory cascades but anti-inflammatory treatment preserves renal autoregulation in DOCA-salt rats, most likely by normalizing renal

  17. Evaluation of drug treatment in mild hypertension: VA-NHLBI feasibility trial. Plan and preliminary results of a two-year feasibility trial for a multicenter intervention study to evaluate the benefits versus the disadvantages of treating mild hypertension. Prepared for the Veterans Administration-National Heart, Lung, and Blood Institute Study Group for Evaluating Treatment in Mild Hypertension.

    PubMed

    1978-03-30

    A feasibility trial to investigate the practicality of determining the advantages and disadvantages of prompt pharmacologic treatment for mild hypertension was jointly funded by the Veterans Administration and the National Heart, Lung and Blood Institute. Its clinical phase has been completed, and it demonstrated 1. that the required relatively young asymptomatic population could be enrolled in the study and 2. that it could be persuaded to adhere to the protocol for 2 years; however, it was evident that intensive efforts would be required in both areas. The feasibility trial screened almost 120,000 potential subjects over a period of 16 months to randomize about 1,000 subjects at four clinical centers. These men and women were 21 to 50 years old, had diastolic pressures from 85 to 105 mm Hg as outpatients, and had no evidence of cardiovascular renal abnormalities. They were randomized in double-blind fashion into active drug therapy and placebo groups. Stepped care therapy involved 50 mg chlorthalidone (Step 1), 100 mg chlorthalidone (Step 2) and 100 chlorthalidone plus 0.25 mg reserpine (Step 3). Death, myocardial infarction, stroke, angina pectoris, and congestive heart failure were the "major" morbid events that were looked for; also recorded were "minor" morbid events consisting primarily of electrocardiographic arrhythmias. The development of significant hypertension was considered a treatment failure. Side effects were carefully tabulated in both active drug and placebo groups. The study revealed an average drop in diastolic pressure of almost 12 mm Hg for active drug group and less than half of that for the placebo group; once established 6 months after randomization, the new pressure levels persisted almost without change throughout the study. Although the feasibility trial was not designed to answer the primary question regarding the benefits of treatment, the events were tabulated for each group. A total of 12 placebo-treated subjects developed

  18. Dopamine and T cells: dopamine receptors and potent effects on T cells, dopamine production in T cells, and abnormalities in the dopaminergic system in T cells in autoimmune, neurological and psychiatric diseases.

    PubMed

    Levite, M

    2016-01-01

    expression and/or responses to dopamine or production of dopamine, (xiii) drugs that affect the dopaminergic system have potent effects on T cells (e.g. dopamine=Intropin, L-dopa, bromocriptine, haloperidol, quinpirole, reserpine, pergolide, ecopipam, pimozide, amantadine, tetrabenazine, nomifensine, butaclamol). Dopamine-induced activation of resting Teffs and suppression of Tregs seem beneficial for health and may also be used for immunotherapy of cancer and infectious diseases. Independently, suppression of DRs in autoimmune and pro-inflammatory T cells, and also in cancerous T cells, may be advantageous. The review is relevant to Immunologists, Neurologists, Neuroimmunologists, Hematologists, Psychiatrists, Psychologists and Pharmacologists.

  19. Topoisomerase II and IV quinolone resistance-determining regions in Stenotrophomonas maltophilia clinical isolates with different levels of quinolone susceptibility.

    PubMed

    Valdezate, Sylvia; Vindel, Ana; Echeita, Aurora; Baquero, Fernando; Cantó, Rafael

    2002-03-01

    The quinolone resistance-determining regions (QRDRs) of topoisomerase II and IV genes from Stenotrophomonas maltophilia ATCC 13637 were sequenced and compared with the corresponding regions of 32 unrelated S. maltophilia clinical strains for which ciprofloxacin MICs ranged from 0.1 to 64 microg/ml. GyrA (Leu-55 to Gln-155, Escherichia coli numbering), GyrB (Met-391 to Phe-513), ParC (Ile-34 to Arg-124), and ParE (Leu-396 to Leu-567) fragments from strain ATCC 13637 showed high degrees of identity to the corresponding regions from the phytopathogen Xylella fastidiosa, with the degrees of identity ranging from 85.0 to 93.5%. Lower degrees of identity to the corresponding regions from Pseudomonas aeruginosa (70.9 to 88.6%) and E. coli (73.0 to 88.6%) were observed. Amino acid changes were present in GyrA fragments from 9 of the 32 strains at positions 70, 85, 90, 103, 112, 113, 119, and 124; but there was no consistent relation to higher ciprofloxacin MICs. The absence of changes at positions 83 and 87, commonly involved in quinolone resistance in gram-negative bacteria, was unexpected. The GyrB sequences were identical in all strains, and only one strain (ciprofloxacin MIC, 16 microg/ml) showed a ParC amino acid change (Ser-80-->Arg). In contrast, a high frequency (16 of 32 strains) of amino acid replacements was present in ParE. The frequencies of alterations at positions 437, 465, 477, and 485 were higher (P < 0.05) in strains from cystic fibrosis patients, but these changes were not linked with high ciprofloxacin MICs. An efflux phenotype, screened by the detection of decreases of at least twofold doubling dilutions of the ciprofloxacin MIC in the presence of carbonyl cyanide m-chlorophenylhydrazone (0.5 microg/ml) or reserpine (10 microg/ml), was suspected in seven strains. These results suggest that topoisomerases II and IV may not be the primary targets involved in quinolone resistance in S. maltophilia.

  20. Topoisomerase II and IV Quinolone Resistance-Determining Regions in Stenotrophomonas maltophilia Clinical Isolates with Different Levels of Quinolone Susceptibility

    PubMed Central

    Valdezate, Sylvia; Vindel, Ana; Echeita, Aurora; Baquero, Fernando; Cantó, Rafael

    2002-01-01

    The quinolone resistance-determining regions (QRDRs) of topoisomerase II and IV genes from Stenotrophomonas maltophilia ATCC 13637 were sequenced and compared with the corresponding regions of 32 unrelated S. maltophilia clinical strains for which ciprofloxacin MICs ranged from 0.1 to 64 μg/ml. GyrA (Leu-55 to Gln-155, Escherichia coli numbering), GyrB (Met-391 to Phe-513), ParC (Ile-34 to Arg-124), and ParE (Leu-396 to Leu-567) fragments from strain ATCC 13637 showed high degrees of identity to the corresponding regions from the phytopathogen Xylella fastidiosa, with the degrees of identity ranging from 85.0 to 93.5%. Lower degrees of identity to the corresponding regions from Pseudomonas aeruginosa (70.9 to 88.6%) and E. coli (73.0 to 88.6%) were observed. Amino acid changes were present in GyrA fragments from 9 of the 32 strains at positions 70, 85, 90, 103, 112, 113, 119, and 124; but there was no consistent relation to higher ciprofloxacin MICs. The absence of changes at positions 83 and 87, commonly involved in quinolone resistance in gram-negative bacteria, was unexpected. The GyrB sequences were identical in all strains, and only one strain (ciprofloxacin MIC, 16 μg/ml) showed a ParC amino acid change (Ser-80→Arg). In contrast, a high frequency (16 of 32 strains) of amino acid replacements was present in ParE. The frequencies of alterations at positions 437, 465, 477, and 485 were higher (P < 0.05) in strains from cystic fibrosis patients, but these changes were not linked with high ciprofloxacin MICs. An efflux phenotype, screened by the detection of decreases of at least twofold doubling dilutions of the ciprofloxacin MIC in the presence of carbonyl cyanide m-chlorophenylhydrazone (0.5 μg/ml) or reserpine (10 μg/ml), was suspected in seven strains. These results suggest that topoisomerases II and IV may not be the primary targets involved in quinolone resistance in S. maltophilia. PMID:11850246

  1. [Methoxyflurane and ethanol do not inhibit the neuronal uptake of noradrenaline (uptake 1) at the desipramine binding site].

    PubMed

    Kress, H G; Schömig, E

    1990-07-01

    We recently demonstrated that the net accumulation of 3H-norepinephrine in the rat pheochromocytoma cell line PC12 was reduced by anesthetic concentrations of n-alkanols and the volatile anesthetics halothane, enflurane, isoflurane, and methoxyflurane. In PC12 cells, as in adrenergic neurons, norepinephrine is transported across the plasma membrane by a saturable, high-affinity, carrier-mediated mechanism (uptake1), which follows Michaelis-Menten kinetics, is energy- and sodium-dependent, and is inhibited by low concentrations of cocaine and the tricyclic antidepressant desipramine. Although uptake1 is the most important process for the removal of norepinephrine from the synaptic cleft, the net accumulation of norepinephrine within the neuron also depends on other factors including its vesicular uptake and storage within the granules, its metabolism by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT), and the efflux of its more lipophilic metabolites. In our previous report we could not exclude the contribution of any of these factors to the observed inhibitory effects of volatile substances. Therefore, the aim of the present study with ethanol and methoxyflurane was: (1) to elucidate further the exact mechanism responsible for the reduction of the norepinephrine accumulation; and (2) to investigate the anesthetics' interaction with the substrate recognition site, which is identical with the desipramine binding site on the norepinephrine carrier. METHODS. For 3H-norepinephrine uptake experiments, PC12 cells were cultured on dishes (60 mm, Nunc) coated with polyornithine. Reserpine (10 microM) was added to the culture 24 h before the experiment to deplete endogenous norepinephrine. The initial carrier-mediated transport rate (60 s) was measured as previously described. 3H-desipramine equilibrium binding was determined with isolated plasma membranes prepared from PC12 cells grown in suspension culture. The carrier-mediated uptake of 3H

  2. Ovariectomized mouse uterotrophic assay of 36 chemicals.

    PubMed

    Ohta, Ryo; Takagi, Atsuya; Ohmukai, Hideo; Marumo, Hideki; Ono, Atsushi; Matsushima, Yuko; Inoue, Tohru; Ono, Hiroshi; Kanno, Jun

    2012-01-01

    The concern over endocrine disruptors prompted international establishment of a strategic framework for the identification of the estrogenic compounds. OECD has launched the Conceptual Framework tool box containing various screening and testing methods including the uterotrophic assay. The (anti)estrogenicity of 36 chemicals suspected to be estrogen-receptor interactive by in silico and/or in vitro screening in the Extended Scheme for Endocrine Disruptor Screening and Testing of the Ministry of Health, Labour and Welfare, Japan, were monitored by the uterotrophic assay using C57BL/6J ovariectomized adult female mice after a 7-day exposure by oral gavage (po) and subcutaneous injection (sc). Ethynyl estradiol was used as reference for agonist and antagonist detection. In addition, Bisphenol A (sc) and Genistein (po) were tested for the comparison to rat assays. Among the 36, 2-[Bis(4-hydroxy-phenyl)methyl]benzylalcohol, 2,2',4,4'-Tetrahydroxybenzophenone, 2,4-Dihydroxybenzophenone, 3,3',5-Triiodothyroacetic acid, New fuchsin and alpha-Naphtholbenzein, showed both estrogenic agonistic and antagonistic activities; first two showed U-shaped dose-response in antagonistic studies. N,N-Diphenyl-p-phenylenediamine, 2,2'-Dihydroxy-4,4'-dimethoxybenzophenone, n-Butyl 4-hydroxybenzoate, and Reserpine were agonistic by sc. Benzo [a] pyrene, Benz [a] anthracene, Dibenz [a,h] anthracene, 2-(2H-Benzotriazol-2-yl)-4,6-di(t-pentyl)phenol, Rosemarinic acid, meta-Thymol, 6-Gingerol, Colchicine, Malachite green base, Fenbuconazole, and Lead acetate were antagonistic. The rest, i.e. n-Heptyl 4-hydroxybenzoate, Tetrazolium violet, Pravastatin sodium salt, Physostigmine, salicylate (1:1), Nordihydroguaiaretic acid, o-Cresolphthalein, 1,3-Dinitrobenzene, C.I. Pigment orange, Tetrabromobis-phenol-A, 2-Hydroxy-4-methoxybenzophenone, Ethylparaben, Propyl p-hydroxybenzoate, Kaempferol, 2-(2-Benzotriazolyl)-p-cresol and Phenolphthalein were negative for both effects. Taking together with in

  3. Mobilization of iron from neoplastic cells by some iron chelators is an energy-dependent process.

    PubMed

    Richardson, D R

    1997-05-16

    Iron (Fe) chelators of the pyridoxal isonicotinoyl hydrazone (PIH) class may be useful agents to treat Fe overload disease and also cancer. These ligands possess high activity at mobilizing 59Fe from neoplastic cells, and the present study has been designed to examine whether their marked activity may be related to an energy-dependent transport process across the cell membrane. Initial experiments examined the release of 59Fe from SK-N-MC neuroblastoma (NB) cells prelabelled for 3 h at 37 degrees C with 59Fe-transferrin (1.25 microM) and then reincubated in the presence and absence of the chelators for 3 h at 4 degrees C or 37 degrees C. Prelabelled cells released 4-5% of total cellular 59Fe when reincubated in minimum essential medium at 4 degrees C or 37 degrees C. When the chelators desferrioxamine (DFO; 0.1 mM) or PIH (0.1 mM) were reincubated with labelled cells at 4 degrees C, they mobilized only 4-5% of cellular 59Fe, whereas as 37 degrees C, these ligands mobilized 21% and 48% of cell 59Fe, respectively. The lipophilic PIH analogue, 311 (2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone; 0.1 mM), which exhibits high anti-proliferative activity, released 10% and 53% of cellular 59Fe when reincubated with prelabelled cells at 4 degrees C and 37 degrees C, respectively. Almost identical results were obtained using the SK-Mel-28 melanoma cell line. These data suggest that perhaps temperature-dependent mechanisms are essential for 59Fe mobilization from these cells. Interestingly, the metabolic inhibitors, 2,4-dinitrophenol, oligomycin, rotenone, and sodium azide, markedly decreased 59Fe mobilization mediated by PIH, but had either no effect or much less effect on 59Fe release by 311. Considering that an ATP-dependent process was involved in 59Fe release by PIH, further studies examined 4 widely used inhibitors of the multi-drug efflux pump P-glycoprotein (P-gp). All of these inhibitors, namely, verapamil (Ver), cyclosporin A (CsA), reserpine (Res) and

  4. The influence of hormonal and neuronal factors on rat heart adrenoceptors

    PubMed Central

    Kunos, George; Mucci, Lucia; O'Regan, Seana

    1980-01-01

    potency of phenylephrine and the blocking effect of phenoxybenzamine to or beyond values observed in euthyroid controls. The density of [3H]-DHA binding sites was higher and that of [3H]-WB-4101 binding sites was lower in the denervated than in the innervated hypothyroid myocardium. Depletion of endogenous noradrenaline stores by reserpine did not significantly alter the adrenoceptor response pattern of the hypothyroid preparations and did not influence the density or affinity of [3H]-DHA and [3H]-WB-4101 binding sites. 6 These results indicate that thyrotropin or steroids do not contribute to the reciprocal changes in the sensitivity of cardiac α1- and β-adrenoceptors in altered thyroid states. These thyroid hormone-dependent changes are probably due to a parallel, reciprocal change in the numbers but not the affinities of α1- and β-adrenoceptors. Reciprocal regulation of cardiac α1- and β-adrenoceptors by thyroid hormones requires intact sympathetic innervation but not the presence of normal stores of the neurotransmitter. PMID:7470752