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The Journal of Venomous Animals and... 2024The bioactive peptides derived from snake venoms of the Viperidae family species have been promising as therapeutic candidates for neuroprotection due to their ability...
Activation of M1 muscarinic acetylcholine receptors by proline-rich oligopeptide 7a (
BACKGROUND
The bioactive peptides derived from snake venoms of the Viperidae family species have been promising as therapeutic candidates for neuroprotection due to their ability to prevent neuronal cell loss, injury, and death. Therefore, this study aimed to evaluate the cytoprotective effects of a synthetic proline-rich oligopeptide 7a (PRO-7a;
METHODS
Both cells were pre-treated for four hours with different concentrations of PRO-7a, submitted to HO-induced damage for 20 h, and then the oxidative stress markers were analyzed. Also, two independent neuroprotective mechanisms were investigated: a) L-arginine metabolite generation via argininosuccinate synthetase (AsS) activity regulation to produce agmatine or polyamines with neuroprotective properties; b) M1 mAChR receptor subtype activation pathway to reduce oxidative stress and neuron injury.
RESULTS
PRO-7a was not cytoprotective in C6 cells, but potentiated the HO-induced damage to cell integrity at a concentration lower than 0.38 μM. However, PRO-7a at 1.56 µM, on the other hand, modified HO-induced toxicity in PC12 cells by restoring cell integrity, mitochondrial metabolism, ROS generation, and arginase indirect activity. The α-Methyl-DL-aspartic acid (MDLA) and L-N-Nitroarginine methyl ester (L-Name), specific inhibitors of AsS and nitric oxide synthase (NOS), which catalyzes the synthesis of polyamines and NO from L-arginine, did not suppress PRO-7a-mediated cytoprotection against oxidative stress. It suggested that its mechanism is independent of the production of L-arginine metabolites with neuroprotective properties by increased AsS activity. On the other hand, the neuroprotective effect of PRO-7a was blocked in the presence of dicyclomine hydrochloride (DCH), an M1 mAChR antagonist.
CONCLUSIONS
For the first time, this work provides evidence that PRO-7a-induced neuroprotection seems to be mediated through M1 mAChR activation in PC12 cells, which reduces oxidative stress independently of AsS activity and L-arginine bioavailability.
PubMed: 38362565
DOI: 10.1590/1678-9199-JVATITD-2023-0043 -
PloS One 2015The link between off-target anticholinergic effects of medications and acute cognitive impairment in older adults requires urgent investigation. We aimed to determine...
The link between off-target anticholinergic effects of medications and acute cognitive impairment in older adults requires urgent investigation. We aimed to determine whether a relevant in vitro model may aid the identification of anticholinergic responses to drugs and the prediction of anticholinergic risk during polypharmacy. In this preliminary study we employed a co-culture of human-derived neurons and astrocytes (NT2.N/A) derived from the NT2 cell line. NT2.N/A cells possess much of the functionality of mature neurons and astrocytes, key cholinergic phenotypic markers and muscarinic acetylcholine receptors (mAChRs). The cholinergic response of NT2 astrocytes to the mAChR agonist oxotremorine was examined using the fluorescent dye fluo-4 to quantitate increases in intracellular calcium [Ca2+]i. Inhibition of this response by drugs classified as severe (dicycloverine, amitriptyline), moderate (cyclobenzaprine) and possible (cimetidine) on the Anticholinergic Cognitive Burden (ACB) scale, was examined after exposure to individual and pairs of compounds. Individually, dicycloverine had the most significant effect regarding inhibition of the astrocytic cholinergic response to oxotremorine, followed by amitriptyline then cyclobenzaprine and cimetidine, in agreement with the ACB scale. In combination, dicycloverine with cyclobenzaprine had the most significant effect, followed by dicycloverine with amitriptyline. The order of potency of the drugs in combination frequently disagreed with predicted ACB scores derived from summation of the individual drug scores, suggesting current scales may underestimate the effect of polypharmacy. Overall, this NT2.N/A model may be appropriate for further investigation of adverse anticholinergic effects of multiple medications, in order to inform clinical choices of suitable drug use in the elderly.
Topics: Amitriptyline; Astrocytes; Calcium; Cell Line, Tumor; Cholinergic Agents; Cholinergic Antagonists; Dicyclomine; Dose-Response Relationship, Drug; Glial Fibrillary Acidic Protein; Humans; Neurons; Oxotremorine; Receptors, Muscarinic; Tubulin
PubMed: 25738989
DOI: 10.1371/journal.pone.0118786 -
Journal of Ethnopharmacology Mar 2021The conventional naturopaths of Punjab Province (Pakistan) have trivial usage of Anagallis arvensis Linn.(Primulaceae) for cure of diarrhea, constipation, asthma as well...
Ethnopharmacological basis for folkloric claims of Anagallis arvensis Linn. (Scarlet Pimpernel) as prokinetic, spasmolytic and hypotensive in province of Punjab, Pakistan.
ETHNOPHARMACOLOGICAL RELEVANCE
The conventional naturopaths of Punjab Province (Pakistan) have trivial usage of Anagallis arvensis Linn.(Primulaceae) for cure of diarrhea, constipation, asthma as well as hypertension.
AIM
Present research was focused to discover comprehensive mechanism of spasmogenic, spasmolytic, bronchorelaxant and hypotensive folkloric usage of Anagallis arvensis Linn..
METHODOLOGY
The crude extract of Anagallis arvensis Linn. (Aa.Cr) & its (aqueous & organic) portions tested in-vitro on isolated jejunum, ileum, trachea, aorta, paired atria preparations as well as in-vivo in mice & normotensive anaesthetized rats. The responses have been noted by transducers (isotonic & isometric) coupled to Power Lab.
RESULT
Anagallis arvensis Linn. (Aa.Cr; crude aqueous-alcoholic extract) produced contractile action at low concentrations but relaxant action was observed by increasing concentrations on spontaneous contractions of isolated jejunum of rabbit. But, pre-treatment of tissue with atropine prior extract caused suppression of contractile effect indicating presence of cholinergic muscarinic response of Aa.Cr. It also triggered relaxation of high Potassium -stimulated contractions of jejunum with subsequent non-parallel right move in Ca CRCs. Moreover, Aa.Cr relaxed carbachol - & high Potassium - stimulated contractions in trachea of rabbit but observed relaxant effect was powerful against CCh (1 μM)- stimulated contractions with rightside parallel move of CCh-curves succeeded by non-parallel move, like Dicyclomine, having dual activities. The Aa.Cr also showed relaxant result on Phenylephrine and High Potassium -prompted contractions in endothelium intact aorta. The fractionation revealed segregations of contractile & relaxant effects in relevant aqueous & organic portions. The Intravenous administration of Aa.Cr to ketamine-diazepam anaesthetized normo-tensive albino rats resulted in decreased MABP, SBP & DBP. The Aa.Cr applied negative (-) inotropic & chronotropic action on paired atria. The Aa.Cr also exhibited anti-diarrheal action in mice against castor oil prompted diarrhea and also mitigated distance covered by charcoal meal in gastrointestinal tract in a manner comparable with loperamide.
CONCLUSION
These results revealed presence of CCB and selective muscarinic agonist activity in Aa.Cr, hence validating folkloric practice of Anagallis arvensis Linn. in diarrhea, constipation, asthma & hypertension.
Topics: Anagallis; Animals; Bronchodilator Agents; Ethnopharmacology; Female; Folklore; Gastrointestinal Agents; In Vitro Techniques; Male; Medicine, Traditional; Mice, Inbred BALB C; Muscarinic Agonists; Muscle Relaxation; Muscle, Smooth; Muscle, Smooth, Vascular; Pakistan; Parasympatholytics; Plant Extracts; Rabbits; Rats, Sprague-Dawley; Vasodilation; Vasodilator Agents; Mice; Rats
PubMed: 33246113
DOI: 10.1016/j.jep.2020.113634 -
BMC Pregnancy and Childbirth Nov 2016Nausea and vomiting of pregnancy (NVP) affects up to 80% of expecting mothers. In April 2013 the FDA approved the delayed-release combination of doxylamine succinate and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Nausea and vomiting of pregnancy (NVP) affects up to 80% of expecting mothers. In April 2013 the FDA approved the delayed-release combination of doxylamine succinate and pyridoxine hydrochloride (Diclegis®) for NVP, based in part, on the results of a phase III randomized trial demonstrating the efficacy of this drug combination [study drug marketed under the trade name Diclectin® in Canada and Diclegis® in the United States] compared to placebo in pregnant women. Study drug dosing occurred for 14 days, which is substantially longer than what has been performed in similar studies. The objective of this study was to evaluate, through secondary analysis, whether the primary measure of efficacy can be demonstrated after five days of treatment.
METHODS
Women suffering from NVP were randomized to receive Diclegis® (n = 131) or placebo (n = 125) for 14 days at doses ranging from two to four tablets a day, based on a pre-specified titration protocol. The primary efficacy endpoint was the change in the validated Pregnancy-Unique Quantification of Emesis (PUQE) score at baseline versus Day 15 between Diclegis®-treated and placebo-treated women. For the present study, the change in PUQE score between baseline and Day 15 (end of the study) was compared to the changes observed for Days 3, 4, and 5.
RESULTS
The use of delayed-release doxylamine succinate and pyridoxine hydrochloride tablets show improved NVP symptom control as compared to placebo on Days 3,4 and 5, with sustained efficacy until the end of the trial.
CONCLUSION
A four day study drug dosing trial with Diclegis® is sufficient to document efficacy, as the results are similar to those achieved after 14 study drug dosing days. The benefit seen at the earlier time validates drug efficacy and minimizes the natural course of improvement.
TRIAL REGISTRATION
CTR No. NCT006 14445 2007.
Topics: Antiemetics; Delayed-Action Preparations; Dicyclomine; Doxylamine; Drug Combinations; Female; Humans; Morning Sickness; Pregnancy; Pyridoxine; Time Factors
PubMed: 27881103
DOI: 10.1186/s12884-016-1172-9 -
Journal of Translational Medicine Apr 2015Solena heterophylla Lour. has traditionally been used in the management of diseases pertaining to gastrointestinal, respiratory and vascular system and present study was...
BACKGROUND
Solena heterophylla Lour. has traditionally been used in the management of diseases pertaining to gastrointestinal, respiratory and vascular system and present study was undertaken to validate its traditional uses.
METHODS
The aqueous ethanolic extract of Solena heterophylla Lour (Sh.Cr) was tested in-vitro on isolated rabbit jejunum, tracheal and aorta preparations. The responses of tissues were recorded using isotonic transducers coupled with PowerLab data acquisition system.
RESULTS
The aqueous ethanolic extract of Solena heterophylla Lour (Sh.Cr) (0.03-1.0 mg/ml) on application to spontaneous contractions in isolated rabbit jejunum preparation exerted relaxant effect through decrease in magnitude and frequency of contractions, caused relaxation of K(+)(80 mM)-induced contractions and shifted the Ca(2+) concentration response curves toward right in isolated rabbit jejunum preparations in a manner similar to verapamil (a standard Ca(2+) channel blocker), thus confirming its Ca(2+) channel blocking activity. The Sh.Cr also caused relaxation of carbachol (1 μM)- and K(+)(80 mM)-induced contractions in isolated rabbit tracheal preparations in a manner comparable to dicyclomine.
CONCLUSIONS
The observed relaxant effect may be outcome of anti-muscarinic and Ca(2+) channel blocking activities. The Sh.Cr (0.03-1.0 mg/ml) against phenyephrine (1 μM)- and K(+)(80 mM)-induced contractions in isolated rabbit aortic preparations exerted a relaxant effect, possibly through Ca(2+) channel blocking activity. These findings provide a rationale for the folkloric uses of the plant in the management of ailments pertaining to gastrointestinal, respiratory and vascular system.
Topics: Animals; Aorta; Calcium Channels; Carbachol; Cardiovascular Diseases; Cucurbitaceae; Female; Gastrointestinal Diseases; In Vitro Techniques; Jejunum; Male; Plant Extracts; Rabbits; Respiration Disorders; Trachea
PubMed: 25925396
DOI: 10.1186/s12967-015-0470-8 -
BMC Pregnancy and Childbirth Mar 2015Nausea and vomiting of pregnancy (NVP) is the most common medical condition in pregnancy, affecting up to 80% of expecting mothers. In April 2013 the FDA approved the... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Nausea and vomiting of pregnancy (NVP) is the most common medical condition in pregnancy, affecting up to 80% of expecting mothers. In April 2013 the FDA approved the delayed release combination of doxylamine succinate and -pyridoxine hydrochloride (Diclegis®) for NVP, following a phase 3 randomized trial in pregnant women. The fetal safety of this medication has been proven by numerous studies. However, because it is the only FDA-approved medication for NVP that is likely to be used by a large number of pregnant women, its maternal safety is an important public health question. The Objective is to evaluate the maternal safety of doxylamine succinate -pyridoxine hydrochloride delayed-release preparation (Diclegis® as compared to placebo.
METHODS
We randomized women suffering from NVP to receive Diclegis® (n = 131) or placebo (n = 125) for 14 days at doses ranging from 2-4 tablets a day, based on a pre-specified titration protocol response to symptoms. Adverse events were collected through patient diaries, clinical examination and laboratory testing.
RESULTS
Doxylamine succinate 10 mg and pyridoxine hydrochloride 10 mg use was not associated with an increased rate of any adverse event over placebo, including CNS depression, gastrointestinal or cardiovascular involvement.
CONCLUSIONS
Doxylamine succinate-pyridoxine hydrochloride delayed release combination is safe and well tolerated by pregnant women when used in the recommended dose of up to 4 tablets daily in treating nausea and vomiting of pregnancy.
TRIAL REGISTRATION
Clinical Trial Registration No: NCT00614445 .
Topics: Adult; Antiemetics; Delayed-Action Preparations; Dicyclomine; Double-Blind Method; Doxylamine; Drug Combinations; Drug Monitoring; Female; Histamine H1 Antagonists; Humans; Nausea; Pregnancy; Pregnancy Complications; Pyridoxine; Treatment Outcome; Vitamin B Complex; Vomiting
PubMed: 25884778
DOI: 10.1186/s12884-015-0488-1 -
PloS One 2015Pyrus pashia Buch.-Ham. ex D. Don. has been used conventionally by many communities in the Himalayan region for the management of gastrointestinal, respiratory, and...
BACKGROUND
Pyrus pashia Buch.-Ham. ex D. Don. has been used conventionally by many communities in the Himalayan region for the management of gastrointestinal, respiratory, and vascular complications. Set against this background, this study was carried out to justify the scientific basis to validate folkloric uses of fruits of Pyrus pashia Buch.-Ham. ex D. Don. (Pp.Cr) in traditional systems of medicine.
METHODS
The crude ethanol extract of fruits of Pyrus pashia Buch.-Ham. ex D. Don. (Pp.Cr) was tested in vitro on isolated rabbit jejunum, tracheal, and aorta preparations. The responses of tissues were recorded using isotonic transducers coupled with a PowerLab data acquisition system.
RESULTS
The Pp.Cr on application (0.01-5.0 mg/ml) to isolated rabbit jejunum preparation exhibited relaxation through decrease in magnitude and frequency of spontaneous contractions. The Pp.Cr also exerted a relaxant (0.01-5.0 mg/ml) effect on K+ (80 mM) induced contractions in isolated rabbit jejunum preparations and caused shifting of the Ca2+ curves (1.0-3.0 mg/ml) toward right in a manner similar to that of verapamil (3 μM), possibly suggesting presence of Ca2+ channel blocking activity. Subsequently, Pp.Cr in a concentration-dependent fashion (0.01-10.0 mg/ml) caused relaxation of CCh (1 μM) and K+ (80 mM) induced contractions in isolated rabbit tracheal preparations in a manner comparable to that of dicyclomine, suggesting that the observed relaxant effect is likely to be mediated through antimuscarinic and/or Ca2+ channel blocking activities. Moreover, when evaluated against isolated rabbit aortic preparations, the Pp.Cr in concentrations up to 10 mg/ml exhibited a contractile response that was found to be abolished subsequent to pretreatment of isolated tissue preparation with cyproheptadine (1 μM), phentolamine (1 μM), and losartan (1 μM), suggesting that Pp.Cr may have some α-adrenergic, muscarinic, serotonergic, and angiotensin II activities.
CONCLUSIONS
The aqueous ethanolic extract of Pyrus pashia (Pp.Cr) exhibited spasmolytic, bronchodilator, and vaso-constrictive activities possibly through different mechanisms. The spasmolytic and bronchodilator activities are likely to be mediated through blockade of Ca2+ channels, while vasoconstrictive activity may be due to presence of a α-adrenergic, muscarinic, serotonergic, and angiotensin II agonistic component.
Topics: Animals; Aorta; Ethanol; Fruit; Jejunum; Medicine, Traditional; Phytotherapy; Plant Extracts; Pyrus; Rabbits; Trachea
PubMed: 25786248
DOI: 10.1371/journal.pone.0118605 -
Journal of Alzheimer's Disease : JAD 2015Indirect modulation of cholinergic activity by cholinesterase inhibition is currently a widely established symptomatic treatment for Alzheimer's disease (AD). Selective...
Indirect modulation of cholinergic activity by cholinesterase inhibition is currently a widely established symptomatic treatment for Alzheimer's disease (AD). Selective activation of certain muscarinic receptor subtypes has emerged as an alternative cholinergic-based amyloid-lowering strategy for AD, as selective muscarinic M1 receptor agonists can reduce amyloid-β (Aβ) production by shifting endoproteolytic amyloid-β protein precursor (AβPP) processing toward non-amyloidogenic pathways. In this study, we addressed the hypothesis that acute stimulation of muscarinic M1 receptors can inhibit Aβ production in awake and freely moving AβPP transgenic mice. By combining intracerebral microdialysis with retrodialysis, we determined hippocampal Aβ concentrations during simultaneous pharmacological modulation of brain M1 receptor function. Infusion with a M1 receptor agonist AF102B resulted in a rapid reduction of interstitial fluid (ISF) Aβ levels while treatment with the M1 antagonist dicyclomine increased ISF Aβ levels reaching significance within 120 minutes of treatment. The reduction in Aβ levels was associated with PKCα and ERK activation resulting in increased levels of the α-secretase ADAM17 and a shift in AβPP processing toward the non-amyloidogenic processing pathway. In contrast, treatment with the M1 receptor antagonist dicyclomine caused a decrease in levels of phosphorylated ERK that was independent of PKCα, and led to an elevation of β-secretase levels associated with increased amyloidogenic AβPP processing. The results of this study demonstrate rapid effects of in vivo M1 receptor modulation on the ISF pool of Aβ and suggest that intracerebral microdialysis with retrodialysis is a useful technical approach for monitoring acute treatment effects of muscarinic receptor modulators on AβPP/Aβ metabolism.
Topics: Actins; Amyloid Precursor Protein Secretases; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Aspartic Acid Endopeptidases; Dicyclomine; Dose-Response Relationship, Drug; Female; Gene Expression Regulation; Hippocampus; Mice; Mice, Transgenic; Microdialysis; Muscarinic Agonists; Muscarinic Antagonists; Quinuclidines; Receptor, Muscarinic M1; Statistics, Nonparametric; Thiophenes
PubMed: 25881909
DOI: 10.3233/JAD-150152 -
Journal of Clinical Pharmacology Jul 2015Nausea and vomiting of pregnancy (NVP) is a common gestational condition. This is the first study to compare the use of vitamin B6 (pyridoxine) versus Diclectin... (Comparative Study)
Comparative Study
Nausea and vomiting of pregnancy (NVP) is a common gestational condition. This is the first study to compare the use of vitamin B6 (pyridoxine) versus Diclectin (doxylamine succinate-pyridoxine HCl) for NVP symptoms. Participants were pregnant women with NVP who used either pyridoxine or doxylamine succinate-pyridoxine HCl for ≥4 days prior to calling the Motherisk NVP Helpline. Women receiving pyridoxine only (n = 80) were matched to a woman taking doxylamine succinate-pyridoxine HCl only (n = 80), accounting for potential confounders and baseline level of NVP, measured by the Pregnancy Unique Quantification of Emesis (PUQE) score. Change in NVP severity after a week of therapy with either pyridoxine or doxylamine succinate-pyridoxine HCl was quantified using the PUQE-24 scale, which describes NVP symptoms 24 hours prior to their call. Doxylamine succinate-pyridoxine HCl use found a significant reduction in PUQE score, compared with pyridoxine (+0.5 versus -0.2, P < .05; negative denotes worsening). This association was especially prominent in women with more severe symptoms, where doxylamine succinate-pyridoxine HCl use saw a mean improvement of 2.6 versus 0.4 with pyridoxine (P < .05). As well, doxylamine succinate-pyridoxine HCl use was associated with fewer women experiencing moderate to severe scores after a week of treatment, compared with the pyridoxine group (7 versus 17, P < .05), despite similar baseline PUQE scores.
Topics: Adult; Antiemetics; Cohort Studies; Dicyclomine; Doxylamine; Drug Combinations; Female; Humans; Morning Sickness; Pregnancy; Prospective Studies; Pyridoxine; Severity of Illness Index; Treatment Outcome
PubMed: 25663469
DOI: 10.1002/jcph.480 -
Journal of the Neurological Sciences Feb 2018
Topics: Aged; Cerebral Amyloid Angiopathy; Cognition Disorders; Female; Fluorodeoxyglucose F18; Humans; Positron-Emission Tomography; Social Behavior; White Matter
PubMed: 29406906
DOI: 10.1016/j.jns.2018.01.001