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Cell Reports Dec 2018Highly glycolytic cancer cells prevent intracellular acidification by excreting the glycolytic end-products lactate and H via the monocarboxylate transporters 1 (MCT1)...
Highly glycolytic cancer cells prevent intracellular acidification by excreting the glycolytic end-products lactate and H via the monocarboxylate transporters 1 (MCT1) and 4 (MCT4). We report that syrosingopine, an anti-hypertensive drug, is a dual MCT1 and MCT4 inhibitor (with 60-fold higher potency on MCT4) that prevents lactate and H efflux. Syrosingopine elicits synthetic lethality with metformin, an inhibitor of mitochondrial NADH dehydrogenase. NAD+, required for the ATP-generating steps of glycolysis, is regenerated from NADH by mitochondrial NADH dehydrogenase or lactate dehydrogenase. Syrosingopine treatment leads to high intracellular lactate levels and thereby end-product inhibition of lactate dehydrogenase. The loss of NAD+ regeneration capacity due to combined metformin and syrosingopine treatment results in glycolytic blockade, leading to ATP depletion and cell death. Accordingly, ATP levels can be partly restored by exogenously provided NAD+, the NAD precursor nicotinamide mononucleotide (NMN), or vitamin K2. Thus, pharmacological inhibition of MCT1 and MCT4 combined with metformin treatment is a potential cancer therapy.
Topics: Acids; Animals; Cell Line, Tumor; Energy Metabolism; Humans; Intracellular Space; Lactic Acid; Male; Metformin; Mice, Inbred C57BL; Monocarboxylic Acid Transporters; Muscle Proteins; NAD; Neoplasms; Reserpine; Symporters; Synthetic Lethal Mutations
PubMed: 30540938
DOI: 10.1016/j.celrep.2018.11.043 -
Journal of Psychopharmacology (Oxford,... Mar 2023Reserpine is an effective antihypertensive drug, but its role in routine practice has declined such that it is rarely used. This is largely based on the assumption that... (Review)
Review
BACKGROUND
Reserpine is an effective antihypertensive drug, but its role in routine practice has declined such that it is rarely used. This is largely based on the assumption that reserpine causes depression. This assumption was a foundation for the original monoamine hypothesis of depression. However, there remains conflicting evidence as to whether reserpine causes depression, and no systematic review of available evidence.
AIMS
We systematically reviewed evidence on effects of reserpine on depressive and related symptoms (e.g. anxiety, suicidal ideation).
METHOD
Electronic searches of MEDLINE, Embase and PsycINFO were conducted to identify studies up to 14 February 2021. Studies of any methodological design involving reserpine-treated and reserpine-untreated conditions, in any adult human population, were included and a narrative synthesis of findings was undertaken. Risk of bias (RoB) was examined using ROBINS-I.
RESULTS
Of the 35 studies meeting inclusion criteria, 9 were randomised controlled trials. Eleven studies reported some depressogenic effects, 13 reported no effect and 11 reported putative antidepressant effects. Studies identifying depressive effects were more likely to examine people without psychiatric disorders at baseline, while studies identifying a potential antidepressant effect tended to treat fewer participants for shorter durations, at higher doses. Around one-third of studies conducted in people with psychiatric disorders showed beneficial effects on depression symptoms. 30/35 studies were at high RoB.
CONCLUSIONS
Associations between reserpine and depression are inconsistent and limited by a lack of high-quality evidence. Due to reserpine's apparently complex effects, we urge nuance rather than simplicity surrounding the monoamine hypothesis of depression.
Topics: Adult; Humans; Depression; Reserpine; Antidepressive Agents; Anxiety; Anxiety Disorders
PubMed: 36000248
DOI: 10.1177/02698811221115762 -
The Cochrane Database of Systematic... Apr 2016In the 1940s reserpine, refined from a plant extract that had been used for centuries, began to be used as a treatment for people with mental disorders and was one of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
In the 1940s reserpine, refined from a plant extract that had been used for centuries, began to be used as a treatment for people with mental disorders and was one of the very first antipsychotic drugs. Its irreversible pharmacological potency and adverse effects meant that it has been withdrawn in the UK and its role has been superceded by 'newer' compounds. The effects of reserpine are of historical interest although there are some reports of it still being used in highly specialist situations in psychiatry. Chlorpromazine is also an old drug but it is still used for treatment of people with schizophrenia.
OBJECTIVES
To investigate the effects of two old medications (reserpine and chlorpromazine) for people with schizophrenia. Reserpine is now rarely used while chlorpromazine remains on the essential list of drugs of the World Health Organization (WHO).
SEARCH METHODS
We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (24 March 2016).
SELECTION CRITERIA
We included randomised clinical trials focusing on chlorpromazine versus reserpine for schizophrenia that presented useable data.
DATA COLLECTION AND ANALYSIS
We extracted data independently. For binary outcomes, we calculated risk ratio (RR) and its 95% confidence interval (CI), on an intention-to-treat basis. We employed a fixed-effect model for analyses. We assessed risk of bias for included studies and created a 'Summary of findings' table using GRADE.
MAIN RESULTS
The review currently includes nine studies with an average 60 participants per study. All of these studies are now over 60 years old, conducted between 1955 and 1962. When chlorpromazine was compared with reserpine for people with schizophrenia, improvement in global state was better at short term for those receiving chlorpromazine (n = 781, 6 RCTs, RR 'not improved' 0.75 95% CI 0.62 to 0.92, low-quality evidence). Short-term improvement in paranoid distortion was measured using the Multidimensional Scale for Rating Psychiatric Patients (MSRPP). Data showed no clear difference between treatment groups (n = 19, 1 RCT, RR 1.33 95% CI 0.62 to 2.89, very low-quality evidence). There was no difference in functioning: occupational adjustment, medium term (n = 40, 1 RCT, RR 0.83 95% CI 0.47 to 1.47, moderate-quality evidence) and general behaviour (n = 98, 1 RCT, RR 0.79 CI 0.41 to 1.53, moderate-quality evidence). Adverse events were poorly reported. For 'toxic reaction' there was, again, no obvious difference between the two compounds (n = 210, 3 RCTs, RR 1.68 95% CI 0.43 to 6.54, moderate-quality evidence), and this also applied to leaving the study early (n = 229, 4 RCTs, RR 1.16 95% CI 0.94 to 1.42, moderate-quality evidence).
AUTHORS' CONCLUSIONS
Judged by standards of today, the evidence is largely of limited quality. However, some of these 1950s studies are remarkable in their foresight and clarity. Reserpine did have some effect on global state - but chlorpromazine did seem to perform better. Important issues regarding adverse effects were not really addressed by these trials. Chlorpromazine remains on the WHO list of essential drugs. Reserpine is now almost obsolete, although, probably as a result of evidence other than that reported in the pioneering trials used in this review.
Topics: Antipsychotic Agents; Chlorpromazine; Humans; Randomized Controlled Trials as Topic; Reserpine; Schizophrenia
PubMed: 27124109
DOI: 10.1002/14651858.CD012122.pub2 -
American Journal of Hypertension Aug 2020Refractory hypertension (RfHTN), a phenotype of antihypertensive treatment failure, is defined as uncontrolled automated office blood pressure (AOBP) ≥130/80 mm Hg and...
BACKGROUND
Refractory hypertension (RfHTN), a phenotype of antihypertensive treatment failure, is defined as uncontrolled automated office blood pressure (AOBP) ≥130/80 mm Hg and awake ambulatory blood pressure (ABP) ≥130/80 mm Hg on ≥5 antihypertensive medications, including chlorthalidone and a mineralocorticoid receptor antagonist. Previous studies suggest that RfHTN is attributable to heightened sympathetic tone. The current study tested whether reserpine, a potent sympatholytic agent, lowers blood pressure (BP) in patients with RfHTN.
METHODS
Twenty-one out of 45 consecutive patients with suspected RfHTN were determined to be fully adherent with their antihypertensive regimen. Seven patients agreed to participate in the current clinical trial with reserpine and 6 patients completed the study. Other sympatholytic medications, such as clonidine or guanfacine, were tapered and discontinued before starting reserpine. Reserpine 0.1 mg daily was administered in an open-label fashion for 4 weeks. All patients were evaluated by AOBP and 24-hour ABP at baseline and after 4 weeks of treatment.
RESULTS
Reserpine lowered mean systolic and diastolic AOBP by 29.3 ± 22.2 and 22.0 ± 15.8 mm Hg, respectively. Mean 24-hour systolic and diastolic ABPs were reduced by 21.8 ± 13.4 and 15.3 ± 9.6 mm Hg, mean awake systolic and diastolic ABPs by 23.8 ± 11.8 and 17.8 ± 9.2 mm Hg, and mean asleep systolic and diastolic ABPs by 21.5 ± 11.4 and 13.7 ± 6.4 mm Hg, respectively.
CONCLUSIONS
Reserpine, a potent sympatholytic agent, lowers BP in patients whose BP remained uncontrolled on maximal antihypertensive therapy, lending support to the hypothesis that excess sympathetic output contributes importantly to the development of RfHTN.
Topics: Adult; Antihypertensive Agents; Blood Pressure Determination; Blood Pressure Monitoring, Ambulatory; Chromatography, Liquid; Drug Therapy, Combination; Female; Humans; Hypertension; Male; Medication Adherence; Middle Aged; Proof of Concept Study; Reserpine; Tandem Mass Spectrometry; Treatment Failure
PubMed: 32179903
DOI: 10.1093/ajh/hpaa042 -
ELife Mar 2023Ciliopathies manifest from sensory abnormalities to syndromic disorders with multi-organ pathologies, with retinal degeneration a highly penetrant phenotype....
Ciliopathies manifest from sensory abnormalities to syndromic disorders with multi-organ pathologies, with retinal degeneration a highly penetrant phenotype. Photoreceptor cell death is a major cause of incurable blindness in retinal ciliopathies. To identify drug candidates to maintain photoreceptor survival, we performed an unbiased, high-throughput screening of over 6000 bioactive small molecules using retinal organoids differentiated from induced pluripotent stem cells (iPSC) of mouse, which is a model of Leber congenital amaurosis (LCA) type 10 caused by mutations in the cilia-centrosomal gene . We identified five non-toxic positive hits, including the lead molecule reserpine, which maintained photoreceptor development and survival in organoids. Reserpine also improved photoreceptors in retinal organoids derived from induced pluripotent stem cells of patients and in mouse retina in vivo. Reserpine-treated patient organoids revealed modulation of signaling pathways related to cell survival/death, metabolism, and proteostasis. Further investigation uncovered dysregulation of autophagy associated with compromised primary cilium biogenesis in patient organoids and mouse retina. Reserpine partially restored the balance between autophagy and the ubiquitin-proteasome system at least in part by increasing the cargo adaptor p62, resulting in improved primary cilium assembly. Our study identifies effective drug candidates in preclinical studies of retinal ciliopathies through cross-species drug discovery using iPSC-derived organoids, highlights the impact of proteostasis in the pathogenesis of ciliopathies, and provides new insights for treatments of retinal neurodegeneration.
Topics: Mice; Animals; Reserpine; Proteostasis; Antigens, Neoplasm; Cytoskeletal Proteins; Retina; Photoreceptor Cells; Ciliopathies
PubMed: 36975211
DOI: 10.7554/eLife.83205 -
The Cochrane Database of Systematic... Dec 2016Many antihypertensive agents exist today for the treatment of primary hypertension (systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg, or... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Many antihypertensive agents exist today for the treatment of primary hypertension (systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg, or both). Randomised controlled trials (RCTs) have been carried out to investigate the evidence for these agents. There is, for example, strong RCT evidence that thiazides reduce mortality and morbidity. Some of those trials used reserpine as a second-line therapy. However, the dose-related blood pressure reduction with this agent is not known.
OBJECTIVES
The primary objective of this review was to quantify the dose-related efficacy of reserpine versus placebo or no treatment in reducing systolic blood pressure (SBP) or diastolic blood pressure (DBP), or both.We also aimed to evaluate the dose-related effects of reserpine on mean arterial blood pressure (MAP) and heart rate (HR), as well as the dose-related effects on withdrawals due to adverse events.
SEARCH METHODS
We searched the Cochrane Hypertension Group Specialised Register (January 1946 to October 2016), CENTRAL (2016, Issue 10), MEDLINE (January 1946 to October 2016), Embase (January 1974 to October 2016), and ClinicalTrials.gov (all dates to October 2016). We also traced citations in the reference sections of the retrieved studies.
SELECTION CRITERIA
Included studies were truly randomised controlled trials (RCTs) comparing reserpine monotherapy to placebo or no treatment in participants with primary hypertension.
DATA COLLECTION AND ANALYSIS
We assessed methods of randomisation and concealment. We extracted and analysed data on blood pressure reduction, heart rate, and withdrawal due to adverse effects.
MAIN RESULTS
We found four RCTs (with a total of 237 participants) that met the inclusion criteria, none of which we found through the 2016 update search. The overall pooled effect demonstrates a statistically significant systolic blood pressure (SBP) reduction in participants taking reserpine compared with placebo (weighted mean difference (WMD) -7.92, 95% confidence interval (CI) -14.05 to -1.78). Because of significant heterogeneity across the trials, a significant effect in diastolic blood pressure (DBP), mean arterial pressure (MAP), and heart rate (HR) could not be found. A dose of reserpine 0.5 mg/day or greater achieved the SBP effects. However, we could not determine the dose-response pattern because of the small number of trials. We did not combine data from the trial that investigated Rauwiloid against placebo with reserpine data from the remaining three trials. This is because Rauwiloid is a different alkaloid extract of the plant Rauwolfia serpentina, and the dose used is not comparable to reserpine. None of the included trials reported withdrawals due to adverse effects.
AUTHORS' CONCLUSIONS
Reserpine is effective in reducing SBP roughly to the same degree as other first-line antihypertensive drugs. However, we could not make definite conclusions regarding the dose-response pattern because of the small number of included trials. More RCTs are needed to assess the effects of reserpine on blood pressure and to determine the dose-related safety profile before the role of this drug in the treatment of primary hypertension can be established.
Topics: Antihypertensive Agents; Blood Pressure; Heart Rate; Humans; Hypertension; Randomized Controlled Trials as Topic; Rauwolfia; Reserpine
PubMed: 27997978
DOI: 10.1002/14651858.CD007655.pub3 -
Molecules (Basel, Switzerland) Apr 2020Alzheimer's disease (AD) is a multifactorial disorder characterized by exponential loss of memory and cognitive deficit involving several disease modifying targets...
Alzheimer's disease (AD) is a multifactorial disorder characterized by exponential loss of memory and cognitive deficit involving several disease modifying targets (amyloid beta, beta-secretase, monoaminoxidase-B, and cholinesterase). The present study explores multi-target directed ligand approach using secondary metabolite reserpine (RES) and ajmalicine (AJM) obtained from roots. Novel LCMS and HPLC methods were developed for identification and quantification of reserpine and ajmalicine. In vitro enzyme inhibition assays were performed to evaluate anti-cholinesterase, β-site amyloid cleaving enzyme (BACE-1) inhibition and monoamine oxidase-B (MAO-B) inhibition, further analyzed with in silico analysis. Anti-amyloidogenic potential was studied using anti-aggregation studies along with TEM and circular dichroism (CD) analysis. In vitro neuroprotective potential against Aβ toxicity and anti-oxidative stress was demonstrated using PC12 cell cultures. Reserpine is a more potent dual cholinesterase inhibitor than ajmalicine (IC values of 1.7 μM (AChE) and 2.8 μM (BuChE)). The anti-aggregation activity of reserpine (68%) was more than ajmalicine (56%). Both compounds demonstrated neuroprotective activity against Aβ42 (92%) and HO (93%) induced toxicity in PC12 cells against controls. Phytocompounds also inhibited MAO-B and BACE-1 enzymes in concentration dependent manner. Molecular docking studies indicated the strong binding of compounds to the catalytic site of targets. This novel study demonstrated that reserpine and ajmalicine as a multi-target directed ligand that have disease modifying potential for amelioration of AD.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Survival; Cholinesterase Inhibitors; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Humans; Indole Alkaloids; Ligands; PC12 Cells; Phytochemicals; Plant Extracts; Protein Aggregates; Protein Aggregation, Pathological; Rats; Reproducibility of Results; Reserpine; Secologanin Tryptamine Alkaloids; Spectrometry, Mass, Electrospray Ionization; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Structure-Activity Relationship
PubMed: 32244635
DOI: 10.3390/molecules25071609 -
International Journal of Molecular... Sep 2021Depression is the most frequent affective disorder and is the leading cause of disability worldwide. In order to screen antidepressants and explore molecular mechanisms,...
Depression is the most frequent affective disorder and is the leading cause of disability worldwide. In order to screen antidepressants and explore molecular mechanisms, a variety of animal models were used in experiments, but there is no reliable high-throughput screening method. Zebrafish is a common model organism for mental illness such as depression. In our research, we established chronic unpredictable mild stress (CUMS) models in C57BL/6 mice and zebrafish; the similarities in behavior and pathology suggest that zebrafish can replace rodents as high-throughput screening organisms. Stress mice (ip., 1 mg/kg/d, 3 days) and zebrafish (10 mg/L, 20 min) were treated with reserpine. As a result, reserpine caused depression-like behavior in mice, which was consistent with the results of the CUMS mice model. Additionally, reserpine reduced the locomotor ability and exploratory behavior of zebrafish, which was consistent with the results of the CUMS zebrafish model. Further analysis of the metabolic differences showed that the reserpine-induced zebrafish depression model was similar to the reserpine mice model and the CUMS mice model in the tyrosine metabolism pathway. The above results showed that the reserpine-induced depression zebrafish model was similar to the CUMS model from phenotype to internal metabolic changes and can replace the CUMS model for antidepressants screening. Moreover, the results from this model were obtained in a short time, which can shorten the cycle of drug screening and achieve high-throughput screening. Therefore, we believe it is a reliable high-throughput screening model.
Topics: Animals; Antidepressive Agents; Behavior, Animal; Depression; Disease Models, Animal; Drug Evaluation, Preclinical; Exploratory Behavior; Locomotion; Male; Mice; Reserpine; Stress, Psychological; Zebrafish
PubMed: 34502414
DOI: 10.3390/ijms22179505 -
Planta Medica May 2024Plants are an incredible source of metabolites showing a wide range of biological activities. Among these, there are the alkaloids, which have been exploited for medical... (Review)
Review
Plants are an incredible source of metabolites showing a wide range of biological activities. Among these, there are the alkaloids, which have been exploited for medical purposes since ancient times. Nowadays, many plant-derived alkaloids are the main components of drugs used as therapy for different human diseases. This review deals with providing an overview of the alkaloids used to treat eye diseases, describing the historical outline, the plants from which they are extracted, and the clinical and molecular data supporting their therapeutic activity. Among the different alkaloids that have found application in medicine so far, atropine and pilocarpine are the most characterized ones. Conversely, caffeine and berberine have been proposed for the treatment of different eye disorders, but further studies are still necessary to fully understand their clinical value. Lastly, the alkaloid used for managing hypertension, reserpine, has been recently identified as a potential drug for ameliorating retinal disorders. Other important aspects discussed in this review are different solutions for alkaloid production. Given that the industrial production of many of the plant-derived alkaloids still relies on extraction from plants, and the chemical synthesis can be highly expensive and poorly efficient, alternative methods need to be found. Biotechnologies offer a multitude of possibilities to overcome these issues, spanning from genetic engineering to synthetic biology for microorganisms and bioreactors for plant cell cultures. However, further efforts are needed to completely satisfy the pharmaceutical demand.
Topics: Humans; Alkaloids; Eye Diseases; Atropine; Pilocarpine; Plants, Medicinal; Caffeine; Plant Extracts; Reserpine
PubMed: 38452806
DOI: 10.1055/a-2283-2350 -
Acta Pharmacologica Sinica Jul 2023Depression is one of the common non-motor symptoms of Parkinson's disease (PD). In the clinic, botulinum neurotoxin A (BoNT/A) has been used to treat depression. In this...
Botulinum neurotoxin A ameliorates depressive-like behavior in a reserpine-induced Parkinson's disease mouse model via suppressing hippocampal microglial engulfment and neuroinflammation.
Depression is one of the common non-motor symptoms of Parkinson's disease (PD). In the clinic, botulinum neurotoxin A (BoNT/A) has been used to treat depression. In this study, we investigated the mechanisms underlying the anti-depressive effect of BoNT/A in a PD mouse model. Mice were administered reserpine (3 μg/mL in the drinking water) for 10 weeks. From the 10 week, BoNT/A (10 U·kg·d) was injected into the cheek for 3 consecutive days. We showed that chronic administration of reserpine produced the behavioral phenotypes of depression and neurochemical changes in the substantia nigra pars compacta (SNpc) and striatum. BoNT/A treatment significantly ameliorated the depressive-like behaviors, but did not improve TH activity in SNpc of reserpine-treated mice. We demonstrated that BoNT/A treatment reversed reserpine-induced complement and microglia activation in the hippocampal CA1 region. Furthermore, BoNT/A treatment significantly attenuated the microglial engulfment of presynaptic synapses, thus ameliorating the apparent synapse and spine loss in the hippocampus in the reserpine-treated mice. Moreover, BoNT/A treatment suppressed microglia-mediated expression of pro-inflammatory cytokines TNF-α and IL-1β in reserpine-treated mice. In addition, we showed that BoNT/A (0.1 U/mL) ameliorated reserpine-induced complement and microglia activation in mouse BV2 microglial cells in vitro. We conclude that BoNT/A ameliorates depressive-like behavior in a reserpine-induced PD mouse model through reversing the synapse loss mediated by classical complement induced-microglial engulfment as well as alleviating microglia-mediated proinflammatory responses. BoNT/A ameliorates depressive-like behavior, and reverses synapse loss mediated by classical complement pathway-initiated microglia engulfment as well as alleviates microglia-mediated proinflammatory response in the reserpine-induced Parkinson's disease mouse model.
Topics: Mice; Animals; Parkinson Disease; Microglia; Botulinum Toxins, Type A; Reserpine; Neuroinflammatory Diseases; Disease Models, Animal; Hippocampus; Mice, Inbred C57BL
PubMed: 36765267
DOI: 10.1038/s41401-023-01058-x