VMAT2/vesicular monoamine transporter 2

Vesicular monoamine transporter 2 is inhibited by serpine hydrochloride (VMAT2). The density of dopamine D1 receptors in the rat striatum is significantly impacted by serpine hydrochloride (F2,12=8.81, p<0.01). Both acute and chronic reserpine withdrawal do not alter affinity (Kd) for dopamine D1 and D2 receptors [1]. Reserpine hydrochloride treatment for one day resulted in IC50 values of 43.9 and 54.9 μM for JB6 P+ and HepG2-C8 cells, respectively. In the concentration range of 5 to 50 μM, reserpine hydrochloride induced luciferase activity in a dose-dependent manner; no discernible induction was seen at concentrations lower than 5 μM. The outcomes demonstrated that reserpine hydrochloride (2.5 to 10 μM) also boosted Nrf2, HO-1, and NQO1 protein expression. After 7 days of treatment, mRNA expression of DNMT1, DNMT3a, and DNMT3b in JB6 P+ cells was decreased by serpine hydrochloride at concentrations ranging from 2.5 to 10 μM in a concentration-dependent manner. A noteworthy variation in DNMT3a expression was observed at 10 μM reserpine hydrochloride (p<0.05)[2].

Reserpine hydrochloride injections given over a long period of 14 days, without an acute phase, at a dose of 0.2 mg/kg, followed by a 48-hour drug withdrawal period will significantly shorten immobility time (F2,18=3.68, p<0.05), but not increase it. Rats' forced swim test (FST) climbing time was (F2,18=4.48, p<0.02) while their swimming time remained unchanged (F2,18=1.78; NS) [1]. In contrast to control animals, vanillylmandelic acid (VMA) was significantly excreted in the urine at a dose of 5 mg/kg body weight of serpine hydrochloride. 5-hydroxyindoleacetic acid (5-HIAA) was found to be excreted at higher rates in reserpine-treated animals than in control animals. Reserpine hydrochloride was found to cause dose-dependent hypotension. At doses of 0.5, 1, 5, 10, and 15 μg/kg, resperpine hydrochloride significantly (p<0.01) lowered blood pressure in comparison to the control group [3].

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The effects of graded doses of zinc sulfate pretreatment on reserpine-induced gastric ulceration and on lysosomal fragility both in vivo and in vitro, were studied in rats. Reserpine treatment (5 mg/kg, i.p., 18 h before sacrifice) induced marked gastric glandular ulceration and elicited the release of free beta-glucuronidase from lysosomes in the gastric mucosa. A similar effect on release of this enzyme from isolated rat hepatic lysosomes was observed after in vitro incubation with reserpine. Zinc sulfate (22, 44 or 88 mg/kg, i.p., 30 h before reserpinization, or 10(-3) M in vitro) inhibited the reserpine-induced response, and zinc sulfate alone (10(-11)--10(-3) M) also stabilized lysosomal membrane permeability to beta-glucuronidase. No direct effect of zinc or reserpine on purified beta-glucuronidase activity was observed. In conclusion, it is postulated that the stabilizing effect of zinc on lysosomal membranes, as manifest by reduced release of beta-glucuronidase from isolated lysosomes, is one of the protective mechanisms of zinc against reserpine-induced ulceration [4].

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This project's aim was to determine the reserpine-induced gastric ulcer preventive effect of polysaccharide of Larimichthys crocea swim bladder (PLCSB) in ICR mice. The anti-gastric ulcer effects of polysaccharide of Larimichthys crocea swim bladder was evaluated in mice model using morphological test, serum levels assay, cytokine levels assay, tissue contents analysis, reverse transcription-polymerase chain reaction (RT-PCR) analysis and western bolt assay. High concentration (50 mg/kg dose) of PLCSB reduced IFN-γ as compared to low concentration (25 mg/kg dose) and control mice. SS and VIP serum levels of PLCSB treated mice were higher than those of control mice, and MOT and SP serum levels were lower than control mice. Gastric ulcer inhibitory index of PLCSB treatment groups mice were much lower than control mice, and the high concentration treated mice were similar to the ranitidine treated mice. The SOD and GSH-Px activities of PLCSB treated mice were higher than control mice, close to normal mice and ranitidine treated mice. PLCSB treated mice also showed the similar contents of NO and MDA to normal group. By RT-PCR and western blot assay, PLCSB significantly induced inflammation in tissues of mice by downregulating NF-κB, iNOS, and COX-2, and upregulating IκB-α. These results suggest that PLCSB showed a good gastric ulcer preventive effect as the gastric ulcer drug of ranitidine. Polysaccharide of Larimichthys crocea swim bladder may be used as a drug material from marine products. [5]

After incubation for 24 h, JB6 P+ cells (1×10~5 cells/10-cm dish) are treated with various concentrations of Reserpine hydrochloride. Whole cell lysates are prepared from the treated cells using radioimmunoprecipitation assay buffer supplemented with a protease inhibitor cocktail, and a BCA kit is used to determine protein concentrations [2].

Nuclear factor erythroid-2 related factor 2 (Nrf2) is a crucial transcription factor that regulates the expression of defensive antioxidants and detoxification enzymes in cells. In a previous study, we showed that expression of the Nrf2 gene is regulated by an epigenetic modification. Rauvolfia verticillata, a traditional Chinese herbal medicine widely used in China, possesses anticancer and antioxidant effects. In this study, we investigated how Nrf2 is epigenetically regulated by reserpine, the main active component in R. verticillata, in mouse skin epidermal JB6 P+ cells. Reserpine induced ARE (antioxidant response element)-luciferase activity in HepG2-C8 cells. Accordingly, in JB6 P+ cells, it upregulated the mRNA and protein levels of Nrf2 and its downstream target genes heme oxygenase-1 (HO-1) and [2]
Nad(p)h: quinone oxidoreductase 1 (NQO1), while it only increased the protein level of UDP-glucuronosyltransferase 1A1 (UGT1A1). Furthermore, reserpine decreased the TPA (12-O-tetradecanoylphorbol-13-acetate)-induced colony formation of JB6 cells in a dose-dependent manner. DNA sequencing and methylated DNA immunoprecipitation further demonstrated the demethylation effect of reserpine on the first 15 CpGs of the Nrf2 promoter in JB6 P+ cells. Reserpine also reduced the mRNA and protein expression of DNMT1 (DNA methyltransferase 1), DNMT3a (DNA methyltransferases 3a), and DNMT3b (DNA methyltransferases 3b). Moreover, reserpine induced Nrf2 expression via an epigenetic pathway in skin epidermal JB6 P+ cells, enhancing the protective antioxidant activity and decreasing TPA-induced cell transformation. These results suggest that reserpine exhibits a cancer preventive effect by reactivating Nrf2 and inducing the expression of target genes involved in cellular protection, potentially providing new insight into the chemoprevention of skin cancer using reserpine. [2]

Reserpine treatment (5 mg/kg) produced a significant increase in the urinary excretion of VMA, 5-HIAA and HVA while RMN at doses of equal to and double the equimolar doses of reserpine (5 and 10 mg/kg) produced significant increase in VMA and 5-HIAA excretion without producing any effect on HVA excretion compared to control animals. Reserpine in the dose range of 0.5 to 15 microg/kg produced significant reduction in blood pressure compared to control. RMN was also found to produce significant decrease in blood pressure at doses of 10, 25 and 50 microg/kg body weight in comparison to control. The results indicated peripheral depletion of biogenic amines by RMN without affecting the central stores of the amines. [3]

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\n\nReserpine can be used for establishing pharmacological model of Gastrointestinal ulcer
\nRats: Wistar rats • Male • 200-290 g
\nAdministration route: 5 mg/kg • intraperitoneal injection • euthanized rats after 18 hours of injection
\nMice: ICR mice • Male • 7 weeks old
\nAdministration route: 10 mg/kg • intraperitoneal injection • once a day, for a total of 3 days\n\n

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\n\nReserpine can be used for establishing pharmacological model of depression
\nRats: Wistar rats • Male • 120-150 g
\nAdministration route: 0.5 mg/kg • intraperitoneal injection • once a day, for a total of 14 days
\nMouse: C57BL/6 mice • Male • 7 weeks old
\nAdministration route: 0.5 mg/kg • intraperitoneal injection • once a day, for a total of 10 days\n

\nReserpine is an inhibitor of the vesicular monoamine transporter 2 (VMAT2) and monoamine releaser, so it can be used as a pharmacological model of depression. In the present paper, we investigated the behavioral and neurochemical effects of withdrawal from acute and repeated administration of a low dose of reserpine (0.2 mg/kg) in Wistar Han rats. We demonstrated the behavioral and receptor oversensitivity (postsynaptic dopamine D1) during withdrawal from chronic reserpine. It was accompanied by a significant increase in motility in the locomotor activity test and climbing behavior in the forced swim test (FST). Neurochemical studies revealed that repeated but not acute administration the a low dose of reserpine triggered opposing adaptive changes in the noradrenergic and serotonin system function analyzed during reserpine withdrawal, i.e. 48 h after the last injection. The tissue concentration of noradrenaline was significantly decreased in the hypothalamus and nucleus accumbens only after repeated drug administration (by about 20% and 35% vs. control; p<0.05, respectively). On the other hand, the concentration of its extraneuronal metabolite, normetanephrine (NM) increased significantly in the VTA during withdrawal both from acute and chronic reserpine. The serotonin concentration was significantly reduced in the VTA after chronic reserpine (by about 40% vs. the control group, p<0.05) as well as its main metabolite, 5-HIAA (by about 30% vs. control; p<0.05) in the VTA and hypothalamus. Dopamine and its metabolites were not changed after acute or chronic reserpine administration. In vivo microdialysis studies clearly evidenced the lack of the effect of a single dose of reserpine, and its distinct effects after chronic treatment on the release of noradrenaline and serotonin in the rat striatum. In fact, the withdrawal from repeated administration of reserpine significantly increased an extraneuronal concentration of noradrenaline in the rat striatum but at the same time produced a distinct fall in the extraneuronal serotonin in this brain structure. On the basis of the presented behavioral and neurochemical experiments, we suggest that chronic administration of reserpine even in such low dose which not yet acted on the release of monoamines but produced an inhibition of VMAT2 caused a long-lasting disadvantageous effect of plasticity in the brain resembling depressive disorders. [1]\n

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\nTreatment with the antihypertensive agent reserpine depletes monoamine levels, resulting in depression. In the present study, we evaluated the antidepressant effects of Gyejibokryeong-hwan (GBH), a traditional Korean medicine, in a mouse model of reserpine-induced depression. Mice were treated with reserpine (0.5 mg·kg-1, i.p.) or phosphate-buffered saline (PBS, i.p., normal) once daily for 10 days. GBH (50, 100, 300, and 500 mg·kg-1), PBS (normal, control), fluoxetine (FXT, 20 mg·kg-1), or amitriptyline (AMT, 30 mg·kg-1) was administered orally 1 h prior to reserpine treatment. Mouse behavior was examined in the forced swim test (FST), tail suspension test (TST), and open-field test (OFT) following completion of the treatment protocol. Administration of GBH reduced immobility time in the FST and TST and significantly increased the total distance traveled in the OFT. Plasma serotonin levels were significantly lower in control mice than in normal mice, although these decreases were significantly attenuated to a similar extent by treatment with GBH, FXT, or AMT. Reserpine-induced increases in plasma corticosterone were also attenuated by GBH treatment. Moreover, GBH attenuated reserpine-induced increases in interleukin- (IL-) 1β, IL-6, and tumor necrosis factor- (TNF-) α mRNA expression in the hippocampus. In addition, GBH mice exhibited increased levels of brain-derived neurotrophic factor (BDNF) and a higher ratio of phosphorylated cAMP response element-binding protein (p-CREB) to CREB (p-CREB/CREB) in the hippocampus. Our results indicated that GBH can ameliorate depressive-like behaviors, affect the concentration of mood-related hormones, and help to regulate immune/endocrine dysfunction in mice with reserpine-induced depression, likely via activation of the BDNF-CREB pathway. Taken together, these findings indicate that GBH may be effective in treating patients with depression. [7]\n

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\n\nDepression is a major psychological disorder that contributes to global health problem. This study aimed to evaluate the anti-depressant effect of Cerebrolysin (CBL) in Reserpine-induced depressed rats, its effect on oxidative stress, inflammation, regulatory cyclic AMP-dependent response element binding protein (CREB)/brain derived neurotropic factor (BDNF) signaling pathways, brain monoamines and histopathological changes was assessed. Rats received either the vehicle or Reserpine (0.5 mg/kg, i.p.) for 14 days. The other three groups were pretreated with CBL (2.5, 5 ml/kg; i.p.) or fluoxetine (FLU) (5 mg/kg, p.o.), respectively for 14 days, 30 min before reserpine injection. Then analyses were conducted. CBL reversed Reserpine-induced reduction in latency to immobility and prolongation of immobility time in the forced swimming test (FST), reduced malondialdehyde (MDA), elevated reduced glutathione (GSH), reduced tumor necrosis factor-alpha (TNF-ɑ), and elevated BDNF cortical and hippocampal brain contents. CBL elevated protein kinase A (PKA) and nuclear factor kappa-B (NF-κB) cortical and hippocampal protein expressions. CBL also ameliorated alterations in mRNA expressions of protein kinase B (AKT), CREB and BDNF in the cortical and hippocampal tissues. CBL elevated nor-epinephrine (NE), serotonin (5-HT), and dopamine (DA) and reduced 5-Hydroxyindoleacetic acid (5-HTAA), 3,4-Dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) cortical and hippocampal contents. CBL effects were in parallel to those observed with the standard anti-depressant drug, FLU. This study shows that CBL exerted anti-depressant effect evidenced by attenuation of oxidative stress and inflammation as well as enhancement of neurogenesis, amelioration of monoaminergic system and histopathological changes. [8]

Absorption, Distribution and Excretion
Reserpine is extensively metabolized into inactive compounds and is primarily excreted slowly via urine and feces. In humans, after oral administration of 0.25 mg (3)H-reserpine, tritium is rapidly absorbed into the bloodstream, reaching peak concentration within 1-2 hours. The radioactive component binds tightly to erythrocytes and remains stable for 96 hours. …Within 24 hours, 6% of the dose is excreted in the urine, primarily as trimethoxybenzoic acid; however, radioactivity can still be detected in plasma, urine, and feces 11-12 days after administration. Following parenteral administration of reserpine, the concentration in the brains of newborn rats is higher than in adult rats… Simultaneously, the consumption of norepinephrine in the brains of infants is also higher than in adult rats. This may be due to the weaker ability of newborn rats to metabolize reserpine… This may also explain the higher concentrations of reserpine in adult plasma and tissues. Reserpine leaves the bloodstream within minutes after intravenous injection and accumulates in adipose tissue… reaching maximum concentration in 4-6 hours. Reserpine also accumulates in the liver. Most of the drug from a single dose is excreted from fat and liver within 48 hours. Five days after a single dose, the brain still retains…risperidone and…metabolites…
…It is claimed to be adequately absorbed from the gastrointestinal tract, but the difference in efficacy between oral and intravenous doses casts doubt on its adequacy. It has a slow onset of action and a long duration of action.
For more complete data on the absorption, distribution, and excretion of reserpine (a total of 8 metabolites), please visit the HSDB record page.

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Metabolites/Metabolites
In rats, cats, and mice, 3,4,5-trimethoxybenzoic acid is produced;
In rats and cats, reserpine methyl ester is produced;
Identified metabolites are reserpine acid, syringic acid, and syringoyl reserpine methyl ester.
In rats, oral reserpine is rapidly hydrolyzed to reserpine methyl ester; in mice, oral or intravenous reserpine is metabolized to trimethoxybenzoic acid. In rats, reserpine methyl ester appears to form in the intestinal mucosa. Trimethoxybenzoic acid is rapidly excreted in mouse urine. Elimination pathway: Reserpine is extensively metabolized into inactive compounds, primarily excreted slowly via urine and feces. Biological half-life: In humans, after oral administration of 0.25 mg (3)H-reserpine, the disappearance of plasma radioactivity exhibits a biphasic pattern: the first phase half-life is 4.5 hours, and the second phase half-life is 271 hours.

Toxicity Summary
Identification: Reserpine is an antihypertensive drug. Source: An alkaloid extracted from the roots of certain Rauwolfia species, typically Rauwolfia serpintina or R. vomitoria. Reserpine can also be synthesized artificially. Color: White or pale yellow to slightly yellow. Insoluble in water, readily soluble in chloroform and acetic acid, slightly soluble in ethanol and ether. Bioavailability: The bioavailability after oral administration is approximately 50%. Indications: Description: Hypertension; Raynaud's phenomenon; possibly for the prevention of familial Mediterranean fever attacks. Possibly for the treatment of thyroid storm unresponsive to standard therapy. Human Exposure: Major Risks and Target Organs: The major risks of reserpine poisoning include central nervous system depression, psychogenic depression, cardiovascular toxicity, and gastrointestinal irritation. The major target organs are the central nervous system, cardiovascular system, and gastrointestinal tract. Clinical Manifestations Overview: Clinical manifestations include sedation and somnolence (rarely progressing to coma) and gastrointestinal irritation (including nausea, vomiting, and abdominal cramps). Gastrointestinal irritation can be severe, leading to ulcers, perforation, and bleeding. Mental depression can be severe, causing suicidal thoughts and potentially nightmares and dizziness. Cardiovascular effects include hypotension and bradycardia. Nasal congestion and flushing are also common. Hypothermia has also been reported. These effects are generally more common in cases of poisoning. The most common adverse reactions include facial flushing, drowsiness (rarely progressing to coma), hypotension, and bradycardia. Two cases of death due to hypotension have been reported. Contraindications: Absolute contraindications: pregnancy, depression, active peptic ulcer, ulcerative colitis, Parkinson's disease, pheochromocytoma, and hypersensitivity to any Rauvolfia alkaloids. Relative contraindications (reserpine should be used with caution and started at a lower dose): elderly patients, arrhythmias, myocardial infarction, renal insufficiency, and asthma. Route of administration: Oral: the most common route of administration and route of poisoning. Injection: Intramuscular injection has been used for the emergency treatment of hypertension. Intra-arterial injection has been used to treat Raynaud's syndrome, but appears to be ineffective. Absorption pathway: The reported bioavailability after oral administration is approximately 50% to 70%. Absorption is relatively rapid, with peak concentrations reached approximately 1 to 2 hours after oral administration. Slower absorption has also been reported, with peak concentrations reached in 2 to 4 hours. Distribution pathway: Volume of distribution has not been reported. Reserpine is widely distributed in the brain, liver, spleen, kidneys, and adipose tissue. Reserpine binds to erythrocytes and peripheral neurons at its site of action. It has been reported that it does not bind to plasma proteins. Reserpine can cross the placental barrier and is present in breast milk. The initial distribution half-life after oral administration is approximately 4 to 5 hours. Biological half-life: The pharmacokinetics of reserpine can be described using a two-compartment model. The elimination half-life in plasma is 45 to 168 hours. Due to the binding of reserpine to erythrocytes, the terminal elimination half-life is longer in whole blood concentrations, reported to be up to 386 hours. The half-life is even longer in patients with renal impairment. Patients with creatinine clearance below 10 mL/min have a significantly prolonged elimination half-life. Metabolism: Less than 50% of reserpine is eliminated by hepatic metabolism, with the remainder excreted in feces. Some unmetabolized reserpine and its metabolites are excreted in urine. In the human body, the metabolites are reserpine methyl ester and trimethoxybenzoic acid. Metabolism may be more pronounced with intramuscular injection. Elimination via route of administration: After intramuscular injection, approximately 30% of reserpine and its metabolites are eliminated in feces; after oral administration, approximately 60% is eliminated within 4 days, primarily as unmetabolized reserpine. During the same period, approximately 8% of the administered dose is recovered in urine, mainly as a trimethoxybenzoic acid metabolite. Pharmacology and toxicology: Mechanism of action: Toxicology: The toxic mechanism of reserpine is similar to its pharmacological mechanism of action. Reserpine inhibits normal sympathetic activity in the central and peripheral nervous systems by binding to catecholamine storage vesicles. This prevents the normal storage of catecholamines and serotonin in nerve cells, leading to catecholamine depletion. Reserpine is also described as inhibiting catecholamine synthesis by blocking dopamine from entering storage vesicles. Pharmacodynamics: Reserpine inhibits normal sympathetic activity by reducing the storage of catecholamines in presynaptic, central, and peripheral neurons. Reserpine binds to storage vesicles, causing catecholamines to leak into the synaptic cleft, preventing their release when presynaptic neurons are stimulated. This process appears to affect serotonin storage in a similar manner. Long-term use of reserpine leads to a decrease in cardiac output and peripheral vascular resistance, which appears approximately 3 weeks after the start of treatment. Heart rate and renin concentration decrease, accompanied by sodium and water retention. Human Data: Adults: Cases of reserpine toxicity in adults are rare. Of the 151 cases reported in the United States between 1959 and 1960, only 4% were adults. These patients presented with symptoms such as nausea, vomiting, hypotension, sedation, and coma. Depression has historically been the most significant side effect of long-term reserpine use for hypertension. Depression is most common with high doses of reserpine, and its frequency decreases significantly with decreasing doses. Depression is usually severe, can occur in patients without a prior history of depression, and can persist for months after discontinuation of reserpine. Children: Most reported cases of reserpine poisoning occur in children. Of the 151 cases of Rauvolfia poisoning, 142 were children under 13 years of age. Approximately 40% of cases presented with some symptoms, the most common being mild central nervous system depression, such as drowsiness or sedation, followed by facial flushing. Of the 142 pediatric cases, 24 required hospitalization due to poisoning. Other reported symptoms include nausea, vomiting, hypotension, and dizziness. Each case includes information on the reserpine dose and the course of the poisoning. A 20-month-old boy developed drowsiness, facial flushing, tachycardia, and bradyventricular contractions after ingesting reserpine. Within 21 hours, the symptoms subsided without further treatment except for the administration of a laxative. Mild leukocytosis resolved within two weeks. Three other cases of children aged 30 months to 4 years accidentally ingested reserpine were reported. Two of these cases involved high doses of reserpine, and one involved an unknown dose. All children exhibited varying degrees of toxicity. All cases presented with drowsiness and central nervous system depression, eventually progressing to coma. Bradycardia and hypothermia were recorded in all cases; the youngest child developed hypertension and tachycardia approximately 10 hours after administration. Carcinogenicity: No apparent association exists between reserpine administration and cancer. Teratogenicity: Among 48 mothers who took reserpine in early pregnancy, the incidence of birth defects was 8%, higher than expected, but no major malformations were observed. Women who took reserpine at any time during pregnancy did not have an increased risk of birth defects in their fetuses. Drug Interactions: The following drugs have been reported to interact with reserpine: alcohol and central nervous system depressants: increase sedation; nonsteroidal anti-inflammatory drugs (NSAIDs): increase the risk of gastric irritation; anticholinergic drugs: increase gastric acid secretion; β-adrenergic blockers: superimpose β-adrenergic blocking effects; bromocriptine: increase serum prolactin levels and decrease bromocriptine activity; digitalis glycosides: may increase bradycardia and arrhythmias; quinidine: may increase arrhythmias; estrogens: reduce the hypotensive effect of reserpine; drugs that cause extrapyramidal adverse reactions: enhance extrapyramidal activity; antihypertensive drugs: cause hypotension; levodopa: reduce the efficacy of levodopa; monoamine oxidase inhibitors: increase central nervous system depression or increase blood pressure and central nervous system excitation; sympathomimetic drugs: reduce the effect of reserpine. Major adverse reactions: The main adverse reactions to reserpine treatment include drowsiness and common adverse reactions to reserpine include sedation, depression, hypotension, nausea, vomiting, abdominal cramps, gastric ulcers, nightmares or vivid dreams, bradycardia, and bronchospasm (in asthmatic patients). Symptoms such as rash or itching, Parkinson's syndrome, and thrombocytopenia are less common. Adverse reactions are more common when taking 0.5 mg or higher doses of reserpine daily. Drowsiness and sedation are more common when used in combination with other central nervous system depressants. Adverse reactions were reported in 26 of 231 hospitalized patients treated with reserpine. Three reactions were considered life-threatening after intramuscular injection of 0.5 mg or higher doses of reserpine (two cases of hypotension and one case of cerebral edema), but no deaths were attributed to reserpine. Bronchospasm has been reported in asthmatic patients taking reserpine, and this may be relatively common. Cases of withdrawal psychosis have been reported. Clinical Manifestations: Acute Poisoning: Ingestion: The most common outcome of reserpine poisoning is drowsiness and sedation, and in rare cases, coma. Other manifestations include depression, hypothermia, facial flushing, nausea, vomiting, abdominal cramps, and cardiovascular toxicity, including hypotension and bradycardia. Parenteral Exposure: Intramuscular administration of therapeutic doses of reserpine can cause hypotension, bronchospasm, drowsiness, and sedation. These reactions are usually secondary to larger doses and are expected to be similar to the adverse reactions of oral reserpine. Chronic Poisoning: Ingestion: The most serious adverse reactions of long-term reserpine use are depression (which can be severe), gastric ulcers, and bleeding. Adverse reactions such as nasal congestion, dry mouth, diarrhea, abdominal pain, drowsiness, Parkinson's-like symptoms, breast enlargement, galactorrhea, impotence, sodium retention, peripheral edema, and weight gain are less frequently reported. Parenteral Exposure: Intramuscular reserpine can produce adverse reactions similar to those of oral administration. Due to the larger intramuscular dose and higher bioavailability, adverse reactions following intramuscular administration are more commonly reported. Course of illness, prognosis, and cause of death: Symptoms of poisoning appear within 4 hours of ingestion and usually subside within 18 to 24 hours. The prognosis is generally good, with patients recovering without sequelae. Mental depression may take several months to resolve. Two cases of reserpine poisoning-related death have been reported in Russian literature. Both were adults who died within days of ingestion from cardiovascular failure and multiple organ failure. Systemic description of clinical manifestations: Cardiovascular system: Cardiovascular effects associated with reserpine poisoning are relatively rare; only 2 cases of hypotension were reported out of a total of 151 patients. Bradycardia has also been reported, and another patient developed tachycardia and hypertension approximately 10 hours after ingestion. Angina-like symptoms and arrhythmias may occur when reserpine is taken concurrently with patients taking digitoxin, quinidine, or procainamide. Respiratory system: Upper airway bronchospasm and nasal congestion may occur. Nervous System: Central Nervous System: The most common symptoms of poisoning are drowsiness and sedation, presenting in 44% of 151 cases of Rauvolfia poisoning. Coma is much less common. Fever may occur. Poisoning can lead to depression, but this is more common in patients taking reserpine long-term. Other central nervous system effects include nightmares and vivid dreams, dizziness, headache, lightheadedness, tension, anxiety, and, rarely, hearing loss. Reserpine has also been reported to cause extrapyramidal symptoms, including dystonia and Parkinson's symptoms, but it is unclear whether these symptoms occur after poisoning or only after long-term use. There has been one case of a 66-year-old woman who developed reserpine withdrawal psychosis one week after stopping her daily 3 mg reserpine. Reserpine lowers the seizure threshold, but only one case of clonic seizures has been reported. Peripheral Nervous System: The effect of reserpine on peripheral nervous system catecholamine storage is expected to reduce the responsiveness of patients with reserpine poisoning to indirect-acting vasoconstrictors such as dopamine. For hypotension unresponsive to intravenous infusion, direct-acting drugs such as phenylephrine, metaraminol, and norepinephrine are recommended as vasoconstrictors. Autonomic nervous system: No direct effects observed. Gastrointestinal ulceration has been described as due to increased gastric acid secretion, which may be due to alterations in autonomic nervous system function. Skeletal and smooth muscle: Gastric cramps have been reported. Muscle weakness may also occur. Gastrointestinal tract: Abdominal cramps, nausea, vomiting. Gastric ulcers and bleeding are less common. Urinary system: Other: Painful or difficult urination has been described as a rare adverse reaction to long-term treatment. Endocrine and reproductive system: Long-term treatment is associated with breast tenderness and galactorrhea. Gynecomastia, increased prolactin levels, decreased libido, and impotence are also potential adverse reactions to long-term treatment. It is unclear whether these effects occur in acute poisoning. Dermatology: Facial flushing, rash, and pruritus. Eyes, ears, nose, and throat: Local effects: Nasal congestion, salivation, mild color blindness, conjunctival congestion, lacrimation, and miosis. Hematology: Thrombocytopenic purpura. Immunology: Angioimmunoblastic lymphadenopathy. Metabolism: Fluid and electrolyte disturbances: Sodium and water retention, leading to edema. Allergic reactions: Cross-sensitivity reactions exist between different Rauvolfia components and reserpine. No reports of allergic reactions have been found. Special risks: Reserpine use in late pregnancy may cause nasal congestion, breathing difficulties, cyanosis, feeding difficulties, and lethargy in newborns. Reserpine is an acceptable treatment during lactation. Animal/plant studies: Carcinogenicity: Rat and mouse studies at doses at least 100 times higher than the usual human dose have shown an increased incidence of mammary fibroadenoma, seminal vesicle malignancy, and adrenal medullary malignancy. Teratogenicity: High doses of reserpine have been shown to be teratogenic in rats and guinea pigs. Mutagenicity: Recent studies have shown that reserpine lacks mutagenicity, genotoxicity, and recombinant toxicity.
Reserpine's mechanism of action is through inhibition of the ATP/Mg2+ pump, which is responsible for isolating neurotransmitters into storage vesicles located in presynaptic neurons. Neurotransmitters not isolated into storage vesicles are readily metabolized by monoamine oxidase (MAO), leading to a reduction in catecholamines.
Hepatotoxicity

Elevated serum transaminases during reserpine treatment are uncommon, but specific elevation rates compared to placebo have not been reported. Although reserpine has been used for decades, only a few clinically significant cases of acute liver injury have been associated with it, and these cases lack conclusive evidence. Published cases have all presented with jaundice and abdominal pain one year after reserpine use, but this is usually in combination with other known hepatotoxic drugs such as dihydrazine, phenobarbital, and quinidine. The few reported cases are self-limiting, resolving within months of discontinuation. The last reported case of suspected reserpine-related liver injury was more than 50 years ago.
Probability Score: E (Unlikely to be a clinically obvious cause of liver damage).

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Effects during pregnancy and lactation
◉ Overview of medication use during lactation
Since there is currently no information on the use of reserpine during lactation, and reserpine may have adverse effects on breastfed infants, alternative medications are recommended, especially for breastfed newborns or premature infants.
◉ Effects on breastfed infants
Although there is a lack of sufficient literature, reserpine has been reported to cause nasal congestion and increased tracheobronchial secretions in breastfed infants.
◉ Effects on lactation and breast milk
Reserpine has been reported to cause galactorrhea and was once used to increase breast milk production, but this use is no longer permitted.

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Protein binding
62%Toxicity data
LD50: 420 mg/kg (oral, rat) (A308)
LD50: 44 mg/kg (intraperitoneal (parenteral), rat) (A308)
LD50: 15 mg/kg (intravenous (parenteral), rat) (A308)
LD50: 200 mg/kg (oral, mouse) (A308)
LD50: 52 mg/kg (subcutaneous (parenteral), mouse) (A308)
LD50: 7 mg/kg (intraperitoneal (parenteral), rabbit) (A308)Interactions
Nine male Wistar rats were protected from the carcinogenic effects of nitrosodiethylamine (50 mg/L in drinking water) after being fed a diet of 16 mg/kg.
Starting at 50 days of age, rats received subcutaneous injections of reserpine for 15 consecutive days, followed by a single intravenous injection of dimethylbenzo[a]anthracene at 55 days of age. Results showed that reserpine inhibited the formation of dimethylbenzo[a]anthracene in breast tumors (81% vs 100%). Reserpine enhanced the toxicity of parathion and carbaryl in rats. Reserpine may sensitize anesthetics and interfere with cardiovascular regulation during surgery. The antihypertensive effect of rauwort alkaloids may be enhanced when used in combination with diuretics or other antihypertensive drugs. For more interaction (complete) data and non-human toxicity values for RESERPINE (13 in total), please visit the HSDB record page.

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Non-human toxicity values
Oral LD50 in rats: 420 mg/kg
Intraperitoneal LD50 in rats: 44 mg/kg
Subcutaneous LD50 in rats: 25 mg/kg
Intravenous LD50 in rats: 15 mg/kg
For more complete data on non-human toxicity values of RESERPINE (11 in total), please visit the HSDB records page.

[1]. Withdrawal from repeated administration of a low dose of reserpine induced opposing adaptive changes in the noradrenaline and serotonin system function: a behavioral and neurochemical ex vivo and in vivo studies in the rat. Prog Neuropsychopharmacol Biol Psychiatry. 2015 Mar 3;57:146-54.

[2]. Reserpine Inhibit the JB6 P+ Cell Transformation Through Epigenetic Reactivation of Nrf2-Mediated Anti-oxidative Stress Pathway. AAPS J. 2016 May;18(3):659-69.

[3]. Reserpine methonitrate, a novel quaternary analogue of reserpine augments urinary excretion of VMA and 5-HIAA without affecting HVA in rats. BMC Pharmacol. 2004 Nov 16;4:30.

[4]. Reserpine-induced gastric ulcers: protection by lysosomal stabilization due to zinc. Eur J Pharmacol. 1980 Feb;61(4):347-53.

[5]. Preventive Effect of Polysaccharide of Larimichthys crocea Swim Bladder on Reserpine Induced Gastric Ulcer in ICR Mice. Korean J Physiol Pharmacol. 2014 Apr;18(2):183-90.

[6]. Mechanism of ulcerogenic activity of reserpine in albino rats. Eur J Pharmacol. 1974 Jul;27(2):269-71.

[7]. Antidepressant-Like Effects of Gyejibokryeong-hwan in a Mouse Model of Reserpine-Induced Depression. Biomed Res Int. 2018 Jun 26;2018:5845491.

[8]. Anti-depressant effect of cerebrolysin in reserpine-induced depression in rats: Behavioral, biochemical, molecular and immunohistochemical evidence. Chem Biol Interact. 2021 Jan 25;334:109329.

Reserpine is an alkaloid extracted from Rauwolfia serpentina and was once widely used to treat hypertension. In recent years, its use has decreased due to its central effects inducing depression and extrapyramidal symptoms. In this study, a novel reserpine quaternary ammonium analog, reserpine metronidazole (RMN), was synthesized and its central and peripheral amine depletion effects in rats were biochemically evaluated. At the same time, the effect of RMN on blood pressure in anesthetized rats was determined and compared with reserpine [3].

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Therapeutic Uses
Adrenergic reuptake inhibitor; antihypertensive drug; antipsychotic drug; sympathomimetic blocker
Rixaprine… can reduce heart rate, tremor and gaze in patients with hyperthyroidism and relieve palpitations, anxiety and tension.
The only important application of the cardiovascular effects of rixaprine is the treatment of hypertension… It is also occasionally used to treat Raynaud's syndrome.
Intravenous injection… is indicated for… severe hypertension and hypertensive emergencies.
For more complete data on the therapeutic uses of reserpine (18 in total), please visit the HSDB record page.

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Drug Warnings
…It should not be given to patients with a history of depression. If depressive symptoms occur, the drug should be discontinued. Reserpine may increase gastric acid secretion; patients with a history of peptic ulcer disease should use it with caution. If symptoms suggest an ulcer recurrence, the drug should be discontinued.
When reserpine is used to treat eclampsia, it enters the placental circulation via the parenteral route, which may cause neonatal lethargy, nasal congestion, cyanosis, and anorexia. Sodium and water retention may occur if a diuretic is not taken concurrently.
Due to serious side effects, reserpine is no longer commonly used as a sedative.
…Reserpine is contraindicated in patients with ulcerative colitis because it increases intestinal motility.
For more complete data on the drug warnings of reserpine (23 in total), please visit the HSDB record page.

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Pharmacodynamics
Reserpine is an adrenergic blocker that treats mild to moderate hypertension by interfering with norepinephrine vesicle storage. Reserpine's antihypertensive effect stems from its ability to deplete catecholamines in peripheral sympathetic nerve endings. These substances are typically involved in controlling heart rate, myocardial contractility, and peripheral resistance.

C33H40N2O9.HCL

645.13964

644.25

16994-56-2

Reserpine;50-55-5; 1263-94-1 (phosphate); 16994-56-2 (HCL)

21155894

Off-white to yellow solid powder

700.1ºC at 760mmHg

377.2ºC

1.91E-19mmHg at 25°C

4.911

2

10

10

45

1000

6

CO[C@H]1[C@@H](C[C@@H]2CN3CCC4=C([C@H]3C[C@@H]2[C@@H]1C(=O)OC)NC5=C4C=CC(=C5)OC)OC(=O)C6=CC(=C(C(=C6)OC)OC)OC.Cl

ZYWIWGUMKCZKOO-BQTSRIDJSA-N

InChI=1S/C33H40N2O9.ClH/c1-38-19-7-8-20-21-9-10-35-16-18-13-27(44-32(36)17-11-25(39-2)30(41-4)26(12-17)40-3)31(42-5)28(33(37)43-6)22(18)15-24(35)29(21)34-23(20)14-19;/h7-8,11-12,14,18,22,24,27-28,31,34H,9-10,13,15-16H2,1-6H3;1H/t18-,22+,24-,27-,28+,31+;/m1./s1

methyl (1R,15S,17R,18R,19S,20S)-6,18-dimethoxy-17-(3,4,5-trimethoxybenzoyl)oxy-1,3,11,12,14,15,16,17,18,19,20,21-dodecahydroyohimban-19-carboxylate;hydrochloride

Reserpine hydrochloride; 16994-56-2; Reserpine (hydrochloride); Reserpine HCl; UNII-GWN3C4FTI8; GWN3C4FTI8; EINECS 241-074-6; methyl (1R,15S,17R,18R,19S,20S)-6,18-dimethoxy-17-(3,4,5-trimethoxybenzoyl)oxy-1,3,11,12,14,15,16,17,18,19,20,21-dodecahydroyohimban-19-carboxylate;hydrochloride;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~50 mg/mL (~77.50 mM)
H2O : ~1 mg/mL (~1.55 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (3.88 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (3.88 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (3.22 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)