Action Of Reserpine Research Articles

Lipid-dependent regulation of neurotransmitter release from sympathetic nerve endings in mice atria

Neurotransmitter release from sympathetic terminals is a key avenue for heart regulation. Herein, presynaptic exocytotic activity was monitored in mice atrial tissue using a false fluorescent neurotransmitter FFN511, a substrate for monoamine transporters. FFN511 labeling had similarity with tyrosine hydroxylase immunostaining. High [K+]o depolarization caused FFN511 release, which was augmented by reserpine, an inhibitor of neurotransmitter uptake. However, reserpine lost the ability to increase depolarization-induced FFN511 unloading after depletion of ready releasable pool with hyperosmotic sucrose. Cholesterol oxidase and sphingomyelinase modified atrial membranes, changing in opposite manner fluorescence of lipid ordering-sensitive probe. Plasmalemmal cholesterol oxidation increased FFN511 release upon K+-depolarization and more markedly potentiated FFN511 unloading in the presence of reserpine. Hydrolysis of plasmalemmal sphingomyelin profoundly enhanced the rate of FFN511 loss due to K+-depolarization, but completely prevented potentiating action of reserpine on FFN511 unloading. If cholesterol oxidase or sphingomyelinase got access to membranes of recycling synaptic vesicles, then the enzyme effects were suppressed. Hence, a fast neurotransmitter reuptake dependent on exocytosis of vesicles from ready releasable pool occurs during presynaptic activity. This reuptake can be enhanced or inhibited by plasmalemmal cholesterol oxidation or sphingomyelin hydrolysis, respectively. These modifications of plasmalemmal (but not vesicular) lipids increase the evoked neurotransmitter release.

Importance of dopaminergic neurotransmission for the RU 24969-induced locomotor activity of male and female rats during the preweanling period.

There is disagreement about whether the locomotor activity produced by serotonin (5-HT) 1A/1B receptor agonists is ultimately mediated through a dopaminergic mechanism or is independent of dopamine (DA) system functioning. Using a developing rat model, we examined whether DA neurotransmission is necessary for the locomotor activity produced by 5-HT1A/1B receptor stimulation. Depending on experiment, male and female preweanling rats were pretreated with vehicle, the monoamine-depleting agent reserpine, the 5-HT synthesis inhibitor 4-chloro-DL-phenylalanine methyl ester hydrochloride (PCPA), the DA synthesis inhibitor ∝-methyl-DL-p-tyrosine (AMPT), or the D1 and D2 receptor antagonists SCH 23390 and raclopride, respectively. After completing the pretreatment regimen, the behavioral effects of saline and the 5-HT1A/1B receptor agonist RU 24969 were assessed during a 2-h test session. Locomotor activity in the center and margin of the testing chamber was recorded. RU 24969's locomotor activating effects were sensitive to blockade of the D2 receptor, but not the D1 receptor. The DA synthesis inhibitor (AMPT) significantly attenuated the RU 24969-induced locomotor activity of preweanling rats, as did the 5-HT synthesis inhibitor PCPA. The latter result suggests that presynaptic 5-HT1A/1B receptors may have a role in mediating RU 24969-induced locomotion during the preweanling period. DA neurotransmission, especially involving D2 receptors, is necessary for the 5-HT1A/1B-mediated locomotor activity of preweanling rats. The actions of PCPA, reserpine, and SCH 23390 differ substantially between preweanling and adult rats, suggesting that the neural mechanisms underlying these DA/5-HT interactions vary across ontogeny.

Rb1, the Primary Active Ingredient in Panax ginseng C.A. Meyer, Exerts Antidepressant-Like Effects via the BDNF-Trkb-CREB Pathway.

Panax ginseng C.A. Meyer (Araliaceae), a popular tonic and dietetic herbal medicine, has been traditionally prescribed in China and other countries to treat affective disorders. The medicinal parts of ginseng, the roots and flower buds, have become increasingly popular as dietary supplements due to the current holistic healthcare trend. We have investigated for the first time the antidepressive actions of the different medicinal parts, namely, the main roots, fibrous roots, and flower buds (in water extract and powder), of garden-cultivated ginseng through behavioral and drug-induced tests in mice. The water extracts, but not the powders of ginseng fibrous roots, flower buds, and main roots (1.5 g of crude drug per kilogram, p.o.), significantly reduced the immobility time in the forced swim test (FST) and tail suspension test (TST); moreover, the water extracts enhanced the 5-hydroxytryptophan (5-HTP)-induced head-twitch response and antagonized the action of reserpine in the mouse. We then explored the antidepressive mechanism of action of the ginsenoside Rb1 (Rb1) related to the brain-derived neurotrophic factor (BDNF) and its downstream proteins in mice exposed to chronic unpredictable mild stress (CUMS). Treatment with Rb1 (20 mg/kg, p.o.) for 21 days significantly attenuated the CUMS-induced decrease in the activities of BDNF, tropomyosin-related kinase B (TrkB), protein kinase B (AKT), extracellular regulatory protein kinase (ERK), and cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) in the mouse hippocampal CA3 region and prefrontal cortex (PFC). Interestingly, treatment with the novel TrkB antagonist ANA-12 (0.5 mg/kg, i.p.) did not alter the level of BDNF but significantly blocked the antidepressive effects of Rb1 on proteins downstream of BDNF in CUMS-treated mice. These results suggest that BDNF–TrkB–CREB signaling may be involved in the antidepressive mechanism of the action of Rb1.

An in silico approach towards identification of virulence factors in red complex pathogens targeted by reserpine

Oral cavity hosts an exhaustive collection of microorganisms which are known to be associated with disease such as dental caries, periodontal and deep-seated infections. Elimination of these pathogens from the site of infection remains a perplexing task, which demands the use of antibiotics. The emergence of drug resistant forms has spurred interest into identifying novel therapeutic targets against these pathogens. In this context, the present study has been designed to analyse and identify potential drug targets of the phytocompound reserpine in red complex pathogens. Computational tools were used to identify the targets, assess its functional role and virulence property. Further, the peptide epitopes present in the virulence factors were identified using BepiPred tool. The subcellular location of the virulence proteins were also elucidated using PSORTb. Reserpine was found to target vital protein transporters such as ABC transporter and efflux pumps which are known to play a crucial role in the survival of bacterial cells. Hence the present in silico study provides substantial evidence on the anti-bacterial activity of reserpine against red complex pathogens. However, in vitro studies using the compound is warranted to further confirm the efficacy of the compound.

Effect of reserpine on Pseudomonas aeruginosa quorum sensing mediated virulence factors and biofilm formation

This study aimed to evaluate the effect of reserpine, a plant-derived indole-alkaloid, against Pseudomonas aeruginosa PAO1 biofilms. The anti-biofilm activity of reserpine was evaluated by crystal violet staining, MTT assay, confocal laser scanning microscopy and scanning electron microscopy. Reserpine effects were also assessed by qRT-PCR of quorum sensing (QS)-regulated genes and biochemical quantification of the QS-mediated virulence factors pyocyanin, rhamnolipids, proteases and elastases. Reserpine reduced biofilm formation, cell motility, virulence factor production, and QS-controlled gene expression. Additionally, molecular docking analysis for AHL synthase LasI and QS transcriptional regulators LasR/MvfR revealed a plausible molecular mechanisms of reserpine QS inhibition. These findings provide insights into the underlying mode of action of reserpine, which may be useful in the development of new drugs against biofilm-related infections.

Comparative standardization study for determination of reserpine in Rauwolfia serpentina homoeopathic mother tinctures manufactured by different pharmaceutical industries using HPTLC as a check for quality control

Background: Rauwolfia serpentina (L.) Benth. ex Kurz (Apocynaceae) (Indian snakeroot), popularly known as Sarpagandha (Sanskrit), is used for the treatment of insanity, fever, snake bites, anxiety and in neuropsychiatric conditions. The antihypertensive actions of Reserpine are a result of its ability to deplete catecholamines (amongst other monoamine neurotransmitters) from peripheral sympathetic nerve endings which are normally involved in controlling heart rate, force of cardiac contraction and peripheral vascular resistance. Objective: Comparative study of Reserpine content in R. serpentina homoeopathic mother tinctures manufactured by different pharmaceutical industries and in-house mother tinctures applying high-performance thin-layer chromatography investigative techniques to facilitate the use of correct species. Materials and Methods: The authentic samples of roots of R. serpentina were supplied by Centre of Medicinal Plants Research in Homoeopathy, Emerald, Tamil Nadu, India. Authentic plant material was used to prepare the mother tincture (as per Homoeopathic Pharmacopoeia of India). Reserpine (C33H40N2O9,M.P. 360°C, purity >99% w/w by high-performance liquid chromatography [HPLC]) was purchased from Sigma-Aldrich as a standard reference. The solvents for the study, namely, ethanol, HPLC water, toluene, ethyl acetate, diethylamine and chloroform were of analytical grade purity (MERCK Ltd.,), used throughout. Results: Five samples of mother tinctures were used for the study, in-house mother tinctures (labelled: D and E) of R. serpentina shows a higher amount of Reserpine content than the marketed samples (labelled: A, B and C). Conclusion: It may be concluded that mother tinctures prepared by authentic plants showed the excess amount of Reserpine rather than that of mother tinctures procured from the market.

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

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 [<citeref rid="ref1">1</citeref>,<citeref rid="ref2">2</citeref>]. 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; P_flp-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 P_flp-11::GFP. This protection had 2 components. The promoter of FLP-11 with the reporter GFP, P_flp-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 P_flp-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.

Using tests and models to assess antidepressant-like activity in rodents

Abstract In today's world, depression is one of the more prevalent forms of mental illness. According to WHO, about 10%-30% of all women and 7%-15% of all men are afflicted by depression at least once in their life-times. Today, depression is assessed to be affecting 350 million people. Regarding this issue, an important challenge for current psychopharmacology is to develop new, more effective pharmacotherapy and to understand the mechanism of action of known antidepressants. Furthermore, there is the necessity to improve the effectiveness of anti-depression treatment by way of bringing about an understanding of the neurobiology of this illness. In achieving these objectives, animal models of depression can be useful. Yet, presently, all available animal models of depression rely on two principles: the actions of known antidepressants or the responses to stress. In this paper, we present an overview of the most widely used animal tests and models that are employed in assessing antidepressant-like activity in rodents. These include amphetamine potentiation, reversal of reserpine action, the forced swimming test, the tail suspension test, learned helplessness, chronic mild stress and social defeat stress. Moreover, the advantages and major drawbacks of each model are also discussed.

The Chlorpromazine Enigma

Two revolutionary drugs were introduced into psychiatry in the early 1950s for the treatment of agitated mental patients — reserpine and chlorpromazine. These drugs initiated the modern era of drug treatment for schizophrenia and other psychoses. Early research revealed that, although the pharmacological profiles of the two drugs overlapped considerably, they had different mechanisms of action. The mechanism of action of reserpine was determined first: it depletes monoamines from the brain and other tissues. By contrast, chlorpromazine has little or no effect on brain monoamine concentrations. The mystery created by two drugs that have similar pharmacological profiles but different mechanisms of action is the chlorpromazine enigma. For about eight years after the mechanism of action of reserpine was determined, researchers followed several false leads about the mechanism of action of chlorpromazine. Then, in 1963, Arvid Carlsson and Margit Lindqvist proposed that chlorpromazine (and haloperidol) work by blocking “monoaminergic” receptors. It was quickly determined that dopamine receptor blockade was the most important action. Although the idea of chemical communication between central neurons had yet to gain wide acceptance, this idea was central to resolving the chlorpromazine enigma.

Reserpine modulates neurotransmitter release to extend lifespan and alleviate age-dependent Aβ proteotoxicity in Caenorhabditis elegans

Aging is a debilitating process often associated with chronic diseases such as diabetes, cardiovascular and neurodegenerative diseases like Alzheimer's disease (AD). AD occurs at a very high incidence posing a huge burden to the society. Model organisms such as C. elegans become essential to understand aging or lifespan extension – the etiology, molecular mechanism and identification of new drugs against age associated diseases. The AD model, manifesting Aβ proteotoxicity, in C. elegans is well established and has provided valuable insights. Earlier, we have reported that Reserpine, an FDA-approved antihypertensive drug, increases C. elegans lifespan with a high quality of life and ameliorates Aβ toxicity in C. elegans. But reserpine does not seem to act through the known lifespan extension pathways or inhibition of its known target, vesicular monoamine transporter, VMAT. Reserpine's mode of action and the pathways it activates are not known. Here, we have evaluated the presynaptic neurotransmitter(s) release pathway and identified acetylcholine (ACh) as the crucial player for reserpine's action. The corroborating evidences are: i) lack of lifespan extension in the ACh loss of function (hypomorphic) – synthesis (cha-1) and transport (unc-17) mutants; ii) mitigation of chronic aldicarb effect; iii) lifespan extension in dopamine (cat-2) and dopamine and serotonin (bas-1) biosynthetic mutants; iv) no rescue from exogenous serotonin induced paralysis in the AD model worms; upon reserpine treatment. Thus, modulation of acetylcholine is essential for reserpine's action.

THE ACTION OF RESERPINE AND ALPHA-METHYL-M-TYROSINE ON THE ANALGESIC EFFECT OF MORPHINE IN RATS AND MICE.

Abstract The actions of α-methyl-m-tyrosine (mmt) and reserpine upon the analgesic effect of morphine has been studied in rats and mice. In rats, reserpine antagonised the effect of morphine, while mmt did not cause any appreciable change of the effect of morphine, injected either 2 or 24 hr after mmt. Reserpine also produced its antagonistic action to morphine in rats which were previously (24 hr) treated with mmt. Both mmt and reserpine potentiated the effect of morphine in rats pretreated (24 hr previously) with iproniazid. In mice, both mmt and reserpine antagonised the effect of morphine. Reserpine failed to do so in mmt pretreated animals. The effect of morphine was restored 24 hr after the injection of mmt. It is suggested that the inhibitory action of reserpine upon the analgesic effect of morphine is due to the antagonistic action of brain 5-ht, which is activated after being released from its stores by reserpine. The pattern of reserpine—mmt—morphine interactions in rats probably differs from that in mice.

Selective protection of 5-hydroxytryptamine stores against the action of reserpine by treatment with 5-hydroxytryptophan

Selective protection of 5-hydroxytryptamine stores against the action of reserpine by treatment with 5-hydroxytryptophan

The effect of reserpine and alpha-methyldopa on the analgesic action of morphine in the mouse.

Abstract In the tail clip test, reserpine inhibited the analgesic action of morphine, and this action of reserpine was prevented by pretreatment with α-methyldopa. In the hot plate test reserpine potentiated the action of morphine, and α-methyldopa pre- treatment had no inhibitory action on reserpine. α-Methyldopa alone, and in combination with reserpine, showed an analgesic action in the hot plate test.

Analgesic Action of Chlorpromazine and Reserpine in Relation to that of Morphine

Abstract An analgesic action of reserpine is reported in mice. This effect, detected by the hot-plate method, is of little, or only of moderate intensity, in the first 2 hr. after injection; maximal intensity is obtained 48–72 hr. after the injection of the drug, and then decreases gradually; after 144 hr. injected animals behave again like controls. The analgesic effect of reserpine seems to differ from that shown by morphine or that shown by chlorpromazine which is quicker in onset and disappears in a few hours. Reserpine potentiates the analgesic action of morphine. This potentiation can be observed 2 hr. after the injection of reserpine. The early potentiating period is followed by a later period of summation of effects. Since a short interval after the injection, reserpine does not exert any analgesic effect, but is able to potentiate morphine analgesia, this action has been regarded as a direct one; the later period of analgesia and summation of effects with morphine has been interpreted as an indirect action of the drug

The hypothermic and sedative action of reserpine in the mouse.

AbstractThe sedative action of reserpine has been studied by its effects upon the body temperature of the mouse, in comparison with chlorpromazine and 5-hydroxytryptamine (5-HT). Reserpine and chlorpromazine produce hypothermia and sedation in the mouse by interference with the mechanism of temperature regulation, but 5-HT acts in a different manner. The central stimulants, lysergic acid diethylamide, amphetamine and tetrahydro-β-naphthylamine, antagonised the hypothermic effects of reserpine, chlorpromazine and 5-HT. Iproniazid antagonised the hypothermic effects of reserpine, while potentiating those of chlorpromazine and 5-HT. This evidence does not seem to support the hypothesis that the sedative action of reserpine is mediated by 5-HT.

VALIDITY OF PTOSIS AS A MEASURE OF THE CENTRAL DEPRESSANT ACTION OF RESERPINE.

VALIDITY OF PTOSIS AS A MEASURE OF THE CENTRAL DEPRESSANT ACTION OF RESERPINE.

The influence of beta-tetrahydronaphthylamine and a derivative on the central effects of 5-hydroxytryptamine, reserpine and iproniazid.

Abstract N-Methyl-N-propyl-β-tetrahydromphthylamine, a specific antagonist of 5-hydroxytryptamine on the isolated rat uterus preparation, fails to inhibit 5-hydroxytryptamine potentiation of the hypnotic action of hexobarbitone in mice. The potentiating actions of reserpine and iproniazid are likewise unaffected. The action of β-tetrahydronaphthylamine as an antagonist of the potentiating action of 5-hydroxytryptamine on hexobarbitone sleeping time in mice has been confirmed, and it has also been shown to be an effective antagonist of the sleep prolonging effects of reserpine. β-Tetrahydronaphthylamine also shows a partial antagonism to iproniazid potentiation of hexobarbitone hypnosis. These results provide an example of the lack of parallelism between the central and smooth muscle actions of 5-hydroxytryptamine antagonists.

Biochemical Properties of Bretylium

Abstract The effect of bretylium (10−3 m) on the respiration of brain slices and certain enzyme systems has been investigated. This concentration of drug is similar to that present in cat sympathetic ganglia after doses of bretylium sufficient to impair adrenergic nerve function. It was a weak inhibitor of monoamine oxidase, but had no effect on the other enzymes investigated. Prolonged treatment with bretylium (10 mg./kg.) did not affect the catecholamine levels of cat adrenals and sympathetic ganglia; larger doses depleted the amine from the ganglia. The noradrenaline content of rabbit spleen tended to rise after chronic dosage with the drug and this treatment appeared to render the amine refractory to the depleting action of reserpine.

Effect upon the analgesic action of reserpine of central nervous system stimulants and drugs affecting the metabolism of catechol- and indole-amines.

Abstract The effect upon the analgesic action of reserpine of central nervous system stimulants and of drugs affecting the metabolism of catechol-and indole-amines as measured in mice by a hot-plate method has been analysed. The analgesic effect, which has a maximal intensity 48 hr. after injection of the alkaloid, is partially or totally counteracted by MAO inhibitors, LSD-25 and 5-hydroxytryptophan. Central nervous system stimulants given to reserpinised mice before each test were effective in reducing the reaction time to the heat stimulation only 24 and 48 hr. after reserpine. DOPA showed no significant ability to reduce the analgesic effect of reserpine. In the light of these findings a suggestion has been made that 5-hydroxytryptamine rather than catecholamines would be involved in the mechanism of the analgesic effect due to reserpine and since central nervous system stimulants are able to reduce this action initially but are ineffective later, part of the effect is thought to be due to sedation of the animals, the participation of the stimulants being confined to a direct antagonism against the sedation. The lasting analgesic effect is supposed to correspond to a lack of 5-hydroxytryptamine in the cerebral structures.

The depletion and recovery of noradrenaline in the brain and some sympathetically innervated mammalian tissues after tetrabenazine.

Abstract The depleting effect of tetrabenazine on the monoamine levels appears generally to be less in peripheral tissues than in the central nervous system. The noradrenaline levels in brain and some sympathetically innervated tissues such as heart, submandibular glands, and skeletal muscle were examined in the rat after administration of the drug. The levels of 5-hydroxytryptamine, dopamine and noradrenaline were also estimated in the rabbit brain after tetrabenazine and compared with the levels in the rabbit heart. In both the brain and peripheral tissues the monoamine levels were strongly reduced 4 hr after tetrabenazine and increased thereafter, reaching normal levels after about 36 to 48 hr. The site of action of tetrabenazine is briefly discussed and compared to the site of action of reserpine.