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Free Radical Research Jan 2021In the present study, we examined whether glutathione peroxidase-1 (GPx-1), a major HO scavenger in the brain, affects memory deficits induced by Aβ (1-42) in mice....
An adenoviral vector encoded with the GPx-1 gene attenuates memory impairments induced by β-amyloid (1-42) in GPx-1 KO mice via activation of M1 mAChR-mediated signalling.
In the present study, we examined whether glutathione peroxidase-1 (GPx-1), a major HO scavenger in the brain, affects memory deficits induced by Aβ (1-42) in mice. Treatment with 400 pmol/5 μl Aβ (1-42) (i.c.v.) resulted in a reduction of GPx-1 expression in wild-type (WT) mice. An Aβ (1-42)-induced reduction in acetylcholine (ACh) level was observed in the hippocampus. Treatment with Aβ (1-42) consistently resulted in reduced expression and activity of choline acetyltransferase (ChAT) and in an increase in expression and activity of acetylcholinesterase (AChE). Upon examining each of the muscarinic acetylcholine receptors (mAChRs) and nicotinic AChRs, we noted that Aβ (1-42) treatment selectively reduced the levels of M1 mAChR. In addition, Aβ (1-42) induced a significant reduction in phospho-cAMP response element-binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) expression. The cholinergic impairments induced by Aβ (1-42) were more pronounced in GPx-1 knockout mice than in WT mice. Importantly, an adenoviral vector encoded with the GPx-1 gene (Ad-GPx-1) significantly rescued Aβ (1-42)-induced cholinergic impairments in GPx-1 knockout mice. In addition, M1 mAChR antagonist dicyclomine significantly counteracted Ad-GPx-1-mediated increases in p-CREB and BDNF expression, as well as memory-enhancing effects in GPx-1 knockout mice, thus indicating that M1 mAChR might be a critical mediator for the rescue effects of Ad-GPx-1. Combined, our results suggest that GPx-1 gene protected against Aβ (1-42)-induced memory impairments activation of M1 mAChR-dependent CREB/BDNF signalling.
Topics: Acetylcholine; Adenoviridae; Amyloid beta-Peptides; Animals; Disease Models, Animal; Genetic Vectors; Glutathione Peroxidase; Hippocampus; Male; Memory Disorders; Mice; Mice, Knockout; Peptide Fragments; Receptor, Muscarinic M1; Signal Transduction; Glutathione Peroxidase GPX1
PubMed: 33222572
DOI: 10.1080/10715762.2020.1854455 -
Pharmacological Research Jan 2021Because observational studies often use imperfect measurements, results are prone to misclassification errors. We used as a motivating example the possible teratogenic... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
Because observational studies often use imperfect measurements, results are prone to misclassification errors. We used as a motivating example the possible teratogenic risks of antiemetic agents in pregnancy since a large observational study recently showed that first-trimester exposure to doxylamine-pyridoxine was associated with significantly increased risk of congenital malformations as a whole, as well as central nervous system defects, and previous observational studies did not show such associations. A meta-analysis on this issue was carried out with the aim to illustrate how differential exposure and outcome misclassifications may lead to uncertain conclusions.
METHODS
Medline, searched to October 2019 for full text papers in English. Summary Odds Ratios (ORs) with confidence intervals (CIs) were calculated using random-effect models. Probabilistic sensitivity analyses were performed for evaluating the extension of differential misclassification required to account for the exposure-outcome association.
RESULTS
Summary ORs were 1.02 (95 % CI, 0.92-1.15), 0.99 (0.82-1.19) and 1.25 (1.08-1.44) for overall congenital, cardiocirculatory, and central nervous system malformations respectively. By assuming exposure and outcome bias factor respectively of 0.95 (i.e., newborns with congenital defects had exposure specificity 5% lower than healthy newborns) and 1.12 (i.e., exposed newborns had outcome sensitivity 12 % higher than unexposed newborns), summary OR of central nervous system defects became 1.13 (95 % CI, 0.99-1.29) and 1.17 (95 % CI, 0.99-1.38).
CONCLUSION
Observational investigations and meta-analyses of observational studies need cautious interpretations. Their susceptibility to several, often sneaky, sources of bias should be carefully evaluated.
Topics: Abnormalities, Drug-Induced; Antiemetics; Dicyclomine; Doxylamine; Drug Combinations; Female; Humans; Nausea; Observational Studies as Topic; Odds Ratio; Pregnancy; Pyridoxine; Scientific Experimental Error; Uncertainty; Vomiting
PubMed: 33031909
DOI: 10.1016/j.phrs.2020.105229 -
The International Journal of... Apr 2022Parkinson's disease (PD) is a progressive neurodegenerative disorder. The major causative factors that progress the PD are age, genetic abnormalities, environmental...
BACKGROUND
Parkinson's disease (PD) is a progressive neurodegenerative disorder. The major causative factors that progress the PD are age, genetic abnormalities, environmental factors and degeneration of dopamine neurons in substantia nigra. PD normally exerts a tonic inhibitory effect on striatal cholinergic interneurons. Anticholinergics act by normalizing the disequilibrium between striatal dopamine and acetylcholine-resulted reduction in tremors.
OBJECTIVE
This study sought to evaluate the anti-Parkinson potential of dicyclomine in haloperidol (HAL)- and paraquat (PQT)-induced Parkinsonism models in mice.
MATERIALS AND METHODS
Sixty albino mice were divided into six groups ( = 10) for each model. Group I: received distilled water 1 mL/kg, Group II: diseased group received HAL (1 mg/kg) for consecutive 21 days and PQT (2 mg/kg) every three days for three weeks, Group III: treated with sinemet (20 mg/kg), Group IV-VI: received 40, 80 and 160 mg/kg dose of dicyclomine, respectively, for consecutive 21 days. The effect of treatments on spontaneous locomotor activity and motor co-ordination was evaluated by using open field, rotarod, actophotometer and light and dark box tests. Cataleptic behavior was estimated by the block method and triple horizontal bar apparatus. Biochemical markers of oxidative stress and levels of neurotransmitters were estimated.
RESULTS
Findings from this study showed that dicyclomine at highest dose level of 160 mg/kg prevented HAL- and PQT-induced PD through enhancement of antioxidant defense system.
CONCLUSION
The study concluded that dicyclomine could be the potential drug in the management of Parkinsonism.
Topics: Animals; Dicyclomine; Disease Models, Animal; Dopamine; Haloperidol; Mice; Paraquat; Parkinson Disease, Secondary; Parkinsonian Disorders; Substantia Nigra
PubMed: 32847457
DOI: 10.1080/00207454.2020.1815732 -
Evidence-based Complementary and... 2020Aqueous-methanolic crude extracts of Flaxseed (Fs.Cr) and Flaxseed oil were tested against 6% acetic acid- (AA-) induced colitis in BALB/c mice. Microscopic damage...
MATERIALS AND METHODS
Aqueous-methanolic crude extracts of Flaxseed (Fs.Cr) and Flaxseed oil were tested against 6% acetic acid- (AA-) induced colitis in BALB/c mice. Microscopic damage parameters of the hematoxylin and eosin-stained and periodic acid-Schiff-alcian blue-stained sections of the colon were scored to be assessed. Possible antispasmodic mechanism was studied on isolated rabbit jejunum, while antibacterial activity was assessed for microbes implicated in IBD.
RESULTS
In AA-induced colitis, Flaxseed oil was found to be more effective in reducing mortality and colonic ulcers than Fs.Cr at 500 mg/kg dose. Fs.Cr was more efficacious in increasing mucin content as compared to oil, exhibiting slightly greater anti-inflammatory effect (50% vs 35%) and reducing depth of lesion (55% vs 42.31%, respectively). Antispasmodic activity of Fs.Cr (0.03 and 0.1 mg/ml) was mediated by phosphodiesterase inhibitors (PDEI, possibly PDE-4 subtype) with a resultant increase in cAMP levels. Flaxseed oil PDEI activity was mild (1 and 3 mg/ml). Fs.Cr (0.1 and 0.3 mg/ml) was potent in exhibiting anticholinergic activity, similar to dicyclomine, whereas Flaxseed oil showed anticholinergic effect at 1 and 3 mg/ml. Flaxseed oil (9 and 14 g/ml) was bactericidal against enteropathogenic (EPEC), enterotoxigenic (ETEC), and enteroaggregative (EAEC), whereas Fs.Cr exhibited bactericidal effect against EPEC at 100 g/ml.
CONCLUSIONS
Results of this study, taken together with previous studies, suggest that Flaxseed possesses anti-inflammatory, antibacterial, and antispasmodic action through multiple pathways and thus offers promising potential to be developed for IBD.
PubMed: 32765633
DOI: 10.1155/2020/7974835 -
Pediatrics Aug 2020A central tension in pediatric research ethics arises from our desire to protect children from harm while also allowing progress toward discoveries that could improve...
A central tension in pediatric research ethics arises from our desire to protect children from harm while also allowing progress toward discoveries that could improve child health. A prime example of this tension is research on a controversial yet increasingly common practice: the use of cannabis by women to treat nausea and vomiting of pregnancy. Studies of cannabis use in pregnancy face a combination of ethical hurdles because of the inclusion of pregnant women and involvement of a schedule I controlled substance. Given the growing need for research on the safety and efficacy of cannabis for nausea and vomiting of pregnancy, we reflect on the multiple historical contexts that have contributed to the challenge of studying cannabis use during pregnancy and make a case for the ethical rationale for such research.
Topics: Antiemetics; Dicyclomine; Doxylamine; Drug Approval; Drug Combinations; Ethics, Research; Female; Humans; Medical Marijuana; Morning Sickness; Ondansetron; Pediatrics; Pregnancy; Pregnant Women; Pyridoxine; Research Subjects; Teratogens; Thalidomide
PubMed: 32737240
DOI: 10.1542/peds.2020-0818R -
Indian Journal of Anaesthesia Apr 2020
PubMed: 32489212
DOI: 10.4103/ija.IJA_848_19 -
ELife May 2020Invasive fungal infections cause 1.6 million deaths annually, primarily in immunocompromised individuals. Mortality rates are as high as 90% due to limited treatments....
Invasive fungal infections cause 1.6 million deaths annually, primarily in immunocompromised individuals. Mortality rates are as high as 90% due to limited treatments. The azole class antifungal, fluconazole, is widely available and has multi-species activity but only inhibits growth instead of killing fungal cells, necessitating long treatments. To improve treatment, we used our novel high-throughput method, the overlap method (O2M) to identify drugs that interact with fluconazole, either increasing or decreasing efficacy. We identified 40 molecules that act synergistically (amplify activity) and 19 molecules that act antagonistically (decrease efficacy) when combined with fluconazole. We found that critical frontline beta-lactam antibiotics antagonize fluconazole activity. A promising fluconazole-synergizing anticholinergic drug, dicyclomine, increases fungal cell permeability and inhibits nutrient intake when combined with fluconazole. In vivo, this combination doubled the time-to-endpoint of mice with meningitis. Thus, our ability to rapidly identify synergistic and antagonistic drug interactions can potentially alter the patient outcomes.
Topics: Animals; Antifungal Agents; Cryptococcosis; Cryptococcus neoformans; Drug Antagonism; Drug Evaluation, Preclinical; Drug Synergism; Female; Fluconazole; High-Throughput Screening Assays; Humans; Meningitis, Cryptococcal; Mice; Mycoses; Structure-Activity Relationship
PubMed: 32367801
DOI: 10.7554/eLife.54160 -
The Medical Letter on Drugs and... Mar 2020
PubMed: 32324174
DOI: No ID Found -
The Medical Letter on Drugs and... Mar 2020
Topics: Constipation; Diarrhea; Gastrointestinal Agents; Humans; Irritable Bowel Syndrome
PubMed: 32324172
DOI: No ID Found -
Saudi Pharmaceutical Journal : SPJ :... Mar 2020, a plant belonging to the family Lamiaceae, is endemic to Ethiopia. In Ethiopian traditional medicine, has been used for the treatment of several respiratory-related...
, a plant belonging to the family Lamiaceae, is endemic to Ethiopia. In Ethiopian traditional medicine, has been used for the treatment of several respiratory-related disorders. The present study was designed to evaluate the bronchodilatory and antimicrobial activities of leaves crude extract (Of.Cr). Ex-vivo experiments were conducted on guinea-pig trachea provided with physiological oxygenated buffer solution using emkaBath setup. The crude extract was analyzed by gas chromatography-mass spectrometry. Of.Cr, showed the presence of terpenes, fragrance components, saponins, and higher fatty acids. Of.Cr when tested on contracted tracheal chains with carbamylcholine (CCh, 1 µM) and high K (80 mM) produced relaxation by showing higher potency against CCh with incomplete inhibition of high K. Dicyclomine, used as a positive control, also showed selectively higher potency to inhibit CCh when compared with its effect against K. In the anticholinergic curves, Of.Cr at 1 mg/mL deflected CCh-induced concentration-response curves (CRCs) competitively to the right like dicyclomine (0.03 µM) and atropine whereas a higher dose of Of.Cr (3 mg/mL) produced a non-parallel shift in the CCh curves like a higher dose of dicyclomine (0.1 µM). In the calcium channel inhibitory assay, Of.Cr at 3 & 5 mg/mL, deflected CRCs of Ca to the right like verapamil, used as positive control. Of.Cr, at concentrations (1-3 mg/mL) increases cAMP levels in isolated tracheal homogenates, similar to positive control phosphodiesterase inhibitor (papaverine). When tested for antibacterial activity against standard and clinical strains, Of.Cr was found more active (MIC 475 µg/ml) against S. aureus (NCTC 6571), while the maximum inhibition (MIC 625 µg/ml) was observed by the extract when tested against MRSA. These results determine the mechanistic pathways of the observed bronchodilatory effect of with a combination of anticholinergic and dual inhibition of phosphodiesterase and voltage-gated Ca channels.
PubMed: 32194329
DOI: 10.1016/j.jsps.2020.01.007