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Journal of Ethnopharmacology May 2024Olea europaea L. and Hyphaene thebaica L. are commonly employed by traditional healers in Africa for treating and preventing hypertension, either individually or in a... (Observational Study)
Observational Study
Ifanosine: Olea europaea L. and Hyphaene thebaica L. combination, from traditional utilization to rational formulation: Preclinical and clinical efficacy on hypertensives patients.
ETHNOPHARMACOLOGICAL RELEVANCE
Olea europaea L. and Hyphaene thebaica L. are commonly employed by traditional healers in Africa for treating and preventing hypertension, either individually or in a polyherbal preparation (Ifanosine).
AIM OF THE STUDY
The primary aim was to assess the antihypertensive effects of Olea europaea L. leaves aqueous extract (OEL), Hyphaene thebaica L. mesocarp extract (HT), and the Ifanosine on isolated rat aorta rings. The secondary objective was to evaluate the clinical benefits of a new oral formulation of Ifanosine.
MATERIALS AND METHODS
In vitro studies using an isometric transducer examined the antihypertensive effects of HT, OEL, and Ifanosine on rat aorta. Ussing chambers technic were employed to measure mucosal to serosal fluxes and total transepithelial electrical conductance (Gt) to assess the intestinal bioavailability of HT, OEL, and Ifanosine. HPLC was utilized to determine the phytochemical composition of OEL and HT extracts. Subchronic toxicity investigations involved two groups of rats, treated with either water (control) or Ifanosine at 5 g/kg for 28 days. Clinical benefits of the new Ifanosine formulation were evaluated in an observational study with 32 hypertensive patients receiving a fixed oral dose of 3.5 mg three times a day for 30 days.
RESULTS
Aqueous extracts induced dose-dependent relaxation of rat aorta rings, with HT and OEL having higher IC50 values than Ifanosine (IC50 = 44.76 ± 1.35 ng/mL, 58.67 ± 1.02 ng/mL, and 29.46 ± 0.26 ng/mL, respectively). The pA2 values of OEL and HT were 1 and 0.6, respectively, while Ifanosine was 0.06. Intestinal bioavailability studies revealed better Prazosin bioavailability than plant extracts. Toxicological studies demonstrated the safety of Ifanosine, supported by histological examinations and biochemical parameters in rat blood. Biochemical analyses indicated flavonoids and phenolic acids as dominant active constituents. Clinical benefits in humans included reduced SBP, DBP, LDL-c, VLDL-c, and TAG, and increased HDL-c without overt adverse effects.
CONCLUSION
This study validates the traditional use of OEL and HT for hypertension and advocates for alternative and combinatorial polyphytotherapy (ACP) to enhance traditional remedies.
Topics: Humans; Rats; Animals; Antihypertensive Agents; Olea; Hypertension; Plant Extracts; Plant Leaves; Treatment Outcome
PubMed: 38309486
DOI: 10.1016/j.jep.2024.117834 -
Urologia Aug 2023Different strategies have been proposed to treat cytokine storm syndrome (CSS), the final deadly complication of COVID-19. One approach is to target CSS by blocking the...
Different strategies have been proposed to treat cytokine storm syndrome (CSS), the final deadly complication of COVID-19. One approach is to target CSS by blocking the interleukin-6 (IL-6) pathway. A promising group of medications blocking the IL-6 pathway is α-blockers, such as prazosin. First, we hypothesized that Panax ginseng, commonly known as ginseng, can be an effective therapeutic agent in preventing CSS due to its blocking activity on alpha-1 adrenergic receptors (α1-AR). Furthermore, we suggested that herbs with 5α-reductase inhibitory effects, such as Saw palmetto, Nettle root, soya, black pepper, and green tea, can have debilitating impacts on pulmonary function since they can lead to impairment of the lung's ability to regenerate. Thus, we encourage the prospective studies to explore the potential effect of herbal medications, with possible beneficial effects for benign prostatic hyperplasia, during the COVID-19 pandemic since they are commonly consumed.
Topics: Male; Humans; Prostatic Hyperplasia; Interleukin-6; Pandemics; Prospective Studies; COVID-19; Adrenergic alpha-Antagonists
PubMed: 37067043
DOI: 10.1177/03915603231162387 -
Canadian Journal of Physiology and... Mar 2024Hypotensive influences of benzodiazepines and other GABA receptor ligands, recognized in clinical practice, seem to stem from the existence of "vascular" GABA receptors...
Hypotensive influences of benzodiazepines and other GABA receptor ligands, recognized in clinical practice, seem to stem from the existence of "vascular" GABA receptors in peripheral blood vessels, besides any mechanisms in the central and peripheral nervous systems. We aimed to further elucidate the vasodilatatory effects of ligands acting through GABA receptors. Using immunohistochemistry, the rat aortic smooth muscle layer was found to express GABA γ2 and α1-5 subunit proteins. To confirm the role of "vascular" GABA receptors, we investigated the vascular effects of standard benzodiazepines, midazolam, and flumazenil, as well as the novel compound MP-III-058. Using two-electrode voltage clamp electrophysiology and radioligand binding assays, MP-III-058 was found to have modest binding but substantial functional selectivity for α5β3γ2 over other αβ3γ2 GABA receptors. Tissue bath assays revealed comparable vasodilatory effects of MP-III-058 and midazolam, both of which at 100 µmol/L concentrations had efficacy similar to prazosin. Flumazenil exhibited weak vasoactivity per se, but significantly prevented the relaxant effects of midazolam and MP-III-058. These studies indicate the existence of functional GABA receptors in the rat aorta, where ligands exert vasodilatory effects by positive modulation of the benzodiazepine binding site, suggesting the potential for further quest for leads with optimized pharmacokinetic properties as prospective adjuvant vasodilators.
Topics: Animals; Rats; Midazolam; Flumazenil; Benzodiazepines; Aorta; Receptors, GABA-A; gamma-Aminobutyric Acid
PubMed: 37909404
DOI: 10.1139/cjpp-2023-0285 -
Behavioural Brain Research Mar 2024The dorsal raphe nucleus (DRN) is essential for the control of food intake. Efferent projections from the DRN extend to several forebrain regions that are involved in...
The dorsal raphe nucleus (DRN) is essential for the control of food intake. Efferent projections from the DRN extend to several forebrain regions that are involved in the control of food intake. However, the neurotransmitters released in the DRN related to the control of food intake are not known. We have previously demonstrated that a tonic α1 action on DRN neurons contributes to satiety in the fed rats. In this study we investigated the participation of norepinephrine (NE) signaling in the DRN in the satiety response. Intra-DRN administration of NE causes an increase in the 2-hour food intake of sated mice, an effect that was blocked by previous administration of yohimbine, an α2 antagonist. Similarly, Intra-DRN administration of clonidine, an α2 agonist, increases food intake in sated mice. This result indicates that in the satiated mice exogenous NE acts on α2 receptors to increase food intake. Furthermore, administration of phenylephrine, an α1 agonist, decreases food intake in fasted mice and prazosin, an α1 antagonist, increases food intake in the sated mice. Taken together these results indicate that, in a satiated condition, a tonic α1 adrenergic action on the DRN neurons inhibits food intake and that exogenous NE administered to the DRN acts on α2 adrenergic receptors to increase food intake. These data reinforce the intricate neuronal functioning of the DRN and its effects on feeding.
Topics: Rats; Mice; Male; Animals; Dorsal Raphe Nucleus; Norepinephrine; Neurons; Prazosin; Eating
PubMed: 38266779
DOI: 10.1016/j.bbr.2024.114872 -
Daru : Journal of Faculty of Pharmacy,... Jun 2024Dexamethasone-induced neurotoxicity has been previously reported. However, the molecular mechanisms are still not completely understood.
Adrenergic receptors blockade alleviates dexamethasone-induced neurotoxicity in adult male Wistar rats: Distinct effects on β-arrestin2 expression and molecular markers of neural injury.
BACKGROUND
Dexamethasone-induced neurotoxicity has been previously reported. However, the molecular mechanisms are still not completely understood.
OBJECTIVES
The current work aimed to investigate the modulatory effects of α- and β-adrenergic receptors on dexamethasone-induced neurotoxicity in rats focused on changes in β-arrestin2 and molecular markers of neural injury in cerebral cortex.
METHODS
Male Wistar rats were subcutaneously injected with dexamethasone (10 mg/kg/day) for 7 days to induce neural injury in the cerebral cortex. The experiment involved 5 groups: control, dexamethasone, carvedilol, propranolol, and doxazosin. In the last 3 groups, drugs were given 2 hours before dexamethasone injection. At the end of experiment, brain samples were collected for measurement of brain derived neurotrophic factor (BDNF), glial fibrillary acidic protein (GFAP), kinase activity of protein kinase B (Akt), diacylglycerol (DAG), α-smooth muscle actin (α-SMA), Smad3, β-amyloid and phospho-tau protein levels in addition to histopathological examination of brain tissue using hematoxylin-eosin, Nissl, and Sirius red stains. Moreover, β-arrestin2 levels in the cerebral cortex were measured using immunohistochemical examination.
RESULTS
Dexamethasone slightly reduced brain weight and significantly decreased BDNF, Akt kinase activity and β-arrestin2 but markedly induced degeneration of cortical neurons and significantly increased GFAP, DAG, α-SMA, Smad3, β-amyloid and phospho-tau protein levels compared to controls. Carvedilol, propranolol, and doxazosin reversed all dexamethasone-induced molecular changes and slightly ameliorated the histopathological changes. Carvedilol significantly increased brain weight and β-arrestin2 levels compared to dexamethasone, propranolol, and doxazosin groups.
CONCLUSION
blocking α- and/or β-adrenergic receptors alleviate dexamethasone-induced neurotoxicity despite their distinct effects on β-arrestin2 levels in the cerebral cortex.
Topics: Animals; Male; Rats; Adrenergic Antagonists; beta-Arrestin 2; Biomarkers; Brain-Derived Neurotrophic Factor; Carvedilol; Cerebral Cortex; Dexamethasone; Doxazosin; Neurotoxicity Syndromes; Propranolol; Rats, Wistar
PubMed: 37966585
DOI: 10.1007/s40199-023-00490-y -
Brain Research Jul 20241-(Phenylselanyl)-2-(p-tolyl)indolizine (MeSeI) is a selenoindolizine with an antidepressant-like effect in mice by regulation of the serotonergic system. This study...
1-(Phenylselanyl)-2-(p-tolyl)indolizine: A selenoindolizine with potential antidepressant-like activity in mice mediated by the modulation of dopaminergic and noradrenergic systems.
1-(Phenylselanyl)-2-(p-tolyl)indolizine (MeSeI) is a selenoindolizine with an antidepressant-like effect in mice by regulation of the serotonergic system. This study investigated the involvement of dopaminergic and noradrenergic systems in the antidepressant-like action of MeSeI. For this purpose, Swiss male mice were pretreated with different antagonists, after 15 min, the MeSeI was administrated by intragastric (i.g.) via; after 30 min, the mouse behavior was assessed in the forced swimming test (FST). The action of MeSeI on the activity of monoamine oxidase (MAO) was determined. The pretreatment of mice with haloperidol (0.05 mg/kg, intraperitoneally, i.p.; non-selective dopamine receptor antagonist), sulpiride (50 mg/kg, i.p.; D receptor antagonist), yohimbine (1 mg/kg, i.p.; α receptor antagonist), and propranolol (2 mg/kg, i.p.; non-selective β receptor antagonist), inhibited the anti-immobility action of MeSeI (50 mg/kg, i.g.) in the FST. This blocking effect was not observed when SCH23390 (0.01 mg/kg, i.p.; D receptor antagonist), and prazosin (1 mg/kg, i.p.; α receptor antagonist) were administered. The coadministration of subeffective doses of bupropion (3 mg/kg. i.g.; dopamine and noradrenaline reuptake inhibitor) and MeSeI (0.5 mg/kg. i.g.) reduced the immobility time in the FST. Furthermore, MeSeI inhibited MAO-A and B activities in vitro and ex vivo tests. These results suggest that MeSeI exerts its antidepressant-like effect via regulation of the D, α, and β receptors and the inhibition of MAO-A and B activities. Molecular docking investigations corroborated these results. This study provides comprehensive insights into the antidepressant-like mechanism of MeSeI in mice, suggesting its potential as a novel antidepressant candidate.
Topics: Animals; Male; Mice; Antidepressive Agents; Organoselenium Compounds; Monoamine Oxidase; Dopamine; Dopamine Antagonists; Swimming; Norepinephrine; Receptors, Dopamine; Depression; Motor Activity
PubMed: 38561086
DOI: 10.1016/j.brainres.2024.148904 -
Journal of Clinical Sleep Medicine :... Feb 2024Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by dream-enactment behaviors that emerge during a loss of REM sleep atonia. Untreated RBD carries...
UNLABELLED
Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by dream-enactment behaviors that emerge during a loss of REM sleep atonia. Untreated RBD carries risks for physical injury from falls or other traumatic events during dream enactment as well as risk of injury to the bed partner. Currently, melatonin and clonazepam are the mainstay pharmacological therapies for RBD. However, therapeutic response to these medications is variable. While older adults are most vulnerable to RBD, they are also particularly vulnerable to the adverse effects of benzodiazepines, including increased risk of falls, cognitive impairment, and increased risk of Alzheimer disease. Prazosin is a centrally active alpha-1 adrenergic receptor antagonist often prescribed for trauma nightmares characterized by REM sleep without atonia in patients with posttraumatic stress disorder. We report a case of successful RBD management with prazosin in a patient in whom high-dose melatonin was ineffective. Although there was no observable reduction in dream-enactment behaviors with high-dose melatonin, the possibility of a synergistic effect of prazosin combined with melatonin cannot be ruled out. This case report supports further evaluation of prazosin as a potential therapeutic for RBD.
CITATION
Cho Y, Iliff JJ, Lim MM, Raskind M, Peskind E. A case of prazosin in treatment of rapid eye movement sleep behavior disorder. . 2024;20(2):319-321.
Topics: Humans; Aged; Melatonin; REM Sleep Behavior Disorder; Prazosin; Clonazepam; Stress Disorders, Post-Traumatic
PubMed: 37882640
DOI: 10.5664/jcsm.10888 -
The Journal of Physiology May 2024Na1.7 plays a crucial role in inducing and conducting action potentials in pain-transducing sensory nociceptor fibres, suggesting that Na1.7 blockers could be effective...
Na1.7 plays a crucial role in inducing and conducting action potentials in pain-transducing sensory nociceptor fibres, suggesting that Na1.7 blockers could be effective non-opioid analgesics. While SCN9A is expressed in both sensory and autonomic neurons, its functional role in the autonomic system remains less established. Our single neuron rt-PCR analysis revealed that 82% of sympathetic neurons isolated from guinea-pig stellate ganglia expressed Na1.7 mRNA, with Na1.3 being the only other tetrodotoxin-sensitive channel expressed in approximately 50% of neurons. We investigated the role of Na1.7 in conducting action potentials in postganglionic sympathetic nerves and in the sympathetic adrenergic contractions of blood vessels using selective Na1.7 inhibitors. Two highly selective Na1.7 blockers, GNE8493 and PF 05089771, significantly inhibited postganglionic compound action potentials by approximately 70% (P < 0.01), with residual activity being blocked by the Na1.3 inhibitor, ICA 121431. Electrical field stimulation (EFS) induced rapid contractions in guinea-pig isolated aorta, pulmonary arteries, and human isolated pulmonary arteries via stimulation of intrinsic nerves, which were inhibited by prazosin or the Na1 blocker tetrodotoxin. Our results demonstrated that blocking Na1.7 with GNE8493, PF 05089771, or ST2262 abolished or strongly inhibited sympathetic adrenergic responses in guinea-pigs and human vascular smooth muscle. These findings support the hypothesis that pharmacologically inhibiting Na1.7 could potentially reduce sympathetic and parasympathetic function in specific vascular beds and airways. KEY POINTS: 82% of sympathetic neurons isolated from the stellate ganglion predominantly express Na1.7 mRNA. Na1.7 blockers inhibit action potential conduction in postganglionic sympathetic nerves. Na1.7 blockade substantially inhibits sympathetic nerve-mediated adrenergic contractions in human and guinea-pig blood vessels. Pharmacologically blocking Na1.7 profoundly affects sympathetic and parasympathetic responses in addition to sensory fibres, prompting exploration into the broader physiological consequences of Na1.7 mutations on autonomic nerve activity.
PubMed: 38743485
DOI: 10.1113/JP286538 -
Heliyon May 2024- Cocaine use disorder (CUD) is a complex disease. Several studies have shown the efficacy of multitarget drugs used to treat CUD. Here we compare the efficacy of...
PURPOSE
- Cocaine use disorder (CUD) is a complex disease. Several studies have shown the efficacy of multitarget drugs used to treat CUD. Here we compare the efficacy of mirtazapine (MIR), pindolol (PIN), fluoxetine (FLX), risperidone (RIS), trazodone (TRZ), ziprasidone (ZPR), ondansetron (OND), yohimbine (YOH), or prazosin (PRZ), to reduce long-term cocaine-induced locomotor activity and the expression of cocaine-induced locomotor sensitization in rats.
METHODS
- The study consists of four experiments, which were divided into four experimental phases. Induction (10 days), cocaine withdrawal (30 days), expression (10 days), and post-expression phase (10 days). Male Wistar rats were daily dosed with cocaine (10 mg/kg; i.p.) during the induction and post-expression phases. During drug withdrawal, the MIR, PIN, FLX, RIS, TRZ, ZPR, OND, YOH, or PRZ were administered 30 min before saline. In the expression, the multitarget drugs were administered 30 min before cocaine. After each administration, locomotor activity for each animal was recorded for 30 min.During the agonism phase, in experiment four, 8-OH-DPAT, DOI, CP-809-101, SR-57227A, or clonidine (CLO) was administered 30 min before MIR and 60 min before cocaine. After each administration, locomotor activity for each animal was recorded for 30 min.
RESULTS
-MIR, FLX, RIS, ZPR, OND, or PRZ attenuated the cocaine-induced locomotor activity and cocaine locomotor sensitization. PIN, TRZ, and YOH failed to decrease cocaine locomotor sensitization. At the optimal doses used, PIN, FLX, RIS, TRZ, ZPR, OND, YOH, or PRZ failed to attenuate long-term cocaine locomotor activation. MIR generated a decrease in cocaine-induced locomotor activity of greater magnitude and duration than the other multitarget drugs evaluated.
CONCLUSION
- At the optimal doses of multitarget drugs evaluated, MIR was the multitarget drug that showed the greatest long-term cocaine-induced behavior effects compared to other multitarget drugs.
PubMed: 38726128
DOI: 10.1016/j.heliyon.2024.e29979 -
Proceedings of the National Academy of... Feb 2024The drug terazosin (TZ) binds to and can enhance the activity of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) and can increase ATP levels. That finding...
The drug terazosin (TZ) binds to and can enhance the activity of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) and can increase ATP levels. That finding prompted studies of TZ in Parkinson's disease (PD) in which decreased neuronal energy metabolism is a hallmark feature. TZ was neuroprotective in cell-based and animal PD models and in large epidemiological studies of humans. However, how TZ might increase PGK1 activity has remained a perplexing question because structural data revealed that the site of TZ binding to PGK1 overlaps with the site of substrate binding, predicting that TZ would competitively inhibit activity. Functional data also indicate that TZ is a competitive inhibitor. To explore the paradoxical observation of a competitive inhibitor increasing enzyme activity under some conditions, we developed a mass action model of TZ and PGK1 interactions using published data on PGK1 kinetics and the effect of varying TZ concentrations. The model indicated that TZ-binding introduces a bypass pathway that accelerates product release. At low concentrations, TZ binding circumvents slow product release and increases the rate of enzymatic phosphotransfer. However, at high concentrations, TZ inhibits PGK1 activity. The model explains stimulation of enzyme activity by a competitive inhibitor and the biphasic dose-response relationship for TZ and PGK1 activity. By providing a plausible mechanism for interactions between TZ and PGK1, these findings may aid development of TZ or other agents as potential therapeutics for neurodegenerative diseases. The results may also have implications for agents that interact with the active site of other enzymes.
Topics: Humans; Animals; Phosphoglycerate Kinase; Prazosin; Parkinson Disease; Glycolysis
PubMed: 38377207
DOI: 10.1073/pnas.2318956121