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Biomedicine & Pharmacotherapy =... Jul 2024Therapeutic options for Alzheimer's disease are limited. Dual compounds targeting two pathways concurrently may enable enhanced effect. The study focuses on tacrine...
Therapeutic options for Alzheimer's disease are limited. Dual compounds targeting two pathways concurrently may enable enhanced effect. The study focuses on tacrine derivatives inhibiting acetylcholinesterase (AChE) and simultaneously N-methyl-D-aspartate (NMDA) receptors. Compounds with balanced inhibitory potencies for the target proteins (K1578 and K1599) or increased potency for AChE (K1592 and K1594) were studied to identify the most promising pro-cognitive compound. Their effects were studied in cholinergic (scopolamine-induced) and glutamatergic (MK-801-induced) rat models of cognitive deficits in the Morris water maze. Moreover, the impacts on locomotion in the open field and AChE activity in relevant brain structures were investigated. The effect of the most promising compound on NMDA receptors was explored by in vitro electrophysiology. The cholinergic antagonist scopolamine induced a deficit in memory acquisition, however, it was unaffected by the compounds, and a deficit in reversal learning that was alleviated by K1578 and K1599. K1578 and K1599 significantly inhibited AChE in the striatum, potentially explaining the behavioral observations. The glutamatergic antagonist dizocilpine (MK-801) induced a deficit in memory acquisition, which was alleviated by K1599. K1599 also mitigated the MK-801-induced hyperlocomotion in the open field. In vitro patch-clamp corroborated the K1599-associated NMDA receptor inhibitory effect. K1599 emerged as the most promising compound, demonstrating pro-cognitive efficacy in both models, consistent with intended dual effect. We conclude that tacrine has the potential for development of derivatives with dual in vivo effects. Our findings contributed to the elucidation of the structural and functional properties of tacrine derivatives associated with optimal in vivo pro-cognitive efficacy.
Topics: Animals; Tacrine; Cholinesterase Inhibitors; Receptors, N-Methyl-D-Aspartate; Male; Rats; Dizocilpine Maleate; Maze Learning; Cognition; Rats, Wistar; Acetylcholinesterase; Scopolamine; Excitatory Amino Acid Antagonists; Memory
PubMed: 38823278
DOI: 10.1016/j.biopha.2024.116821 -
Experimental Gerontology Aug 2024Chronic stress (CS) is critically involved in the Alzheimer's disease (AD) pathogenesis resulting in cognitive disturbance. Also, amyloid precursor protein (APP) related...
Quercetin ameliorates cognitive deficit, expression of amyloid precursor gene, and pro-inflammatory cytokines in an experimental models of Alzheimer's disease in Wistar rats.
Chronic stress (CS) is critically involved in the Alzheimer's disease (AD) pathogenesis resulting in cognitive disturbance. Also, amyloid precursor protein (APP) related gens, pro-inflammatory cytokines, and stress increases AD-related pathogenesis through increasing APP, all are important players in the development of AD. Herein, we explore the possible neuroprotective and anti-amnestic effect of quercetin (QUER) on cognitive deficits induced by scopolamine (SCOP) in stressed rats. Stress induction was performed by exposed of rats to 2-h chronic restraint stress for 10 days. Then rats were supplemented with QUER (25 mg/kg/day oral gavage, for 1 month). Ratswere submitted to intraperitoneal (i.p.) injection of SCOP (1 mg/kg) during the final 9 days of QUER supplementation to induce dementia like condition. Following the interventions, behavioral tests [elevated plus maze (EPM) and novel object recognition memory (NORM)] was examined to analysis the cognitive functions. Meanwhile, prefrontal cortex (PFC) and hippocampus of brain were used for gene expression and biochemical studies. Also, the plasma corticosterone (CORT) level was measured. We established that administration of QUER ameliorated the SCOP-related memory impairment. Also, QUER decreased stress related anxiety like behaviors in the EPM. QUER also altered the interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels in both PFC and hippocampus of SCOP treated rats in stress and non-stress conditions. We found that QUER increased APP and amyloid precursor-like protein 2 (APLP2) mRNA expression in both non-stress and stressed rats. Also, our findings imply that QUER suppress the effect of SCOP on cognitive functions. Moreover, decreased APP mRNA expression in the hippocampus were observed following pretreatment of rats with QUER in both stress and non-stress groups. Given that decreased amyloid beta (Aβ) expression in the hippocampus of stressed rats, it can be proposed that elevations in APP mRNA expression by QUER activates non-amyloidogenic pathways leading to reduction in Aβ levels. However, our findings indicate that QUER can be a therapeutic candidate, which exerts an anti-amnesic property against SCOP-induced memory decline. On the other hand, prior QUER administration in stress condition could be a promising approach against AD prevention.
Topics: Animals; Quercetin; Alzheimer Disease; Rats, Wistar; Male; Disease Models, Animal; Rats; Cytokines; Hippocampus; Amyloid beta-Protein Precursor; Stress, Psychological; Cognitive Dysfunction; Scopolamine; Neuroprotective Agents; Corticosterone; Prefrontal Cortex; Cognition
PubMed: 38821324
DOI: 10.1016/j.exger.2024.112466 -
Emergencias : Revista de La Sociedad... Jun 2024
Topics: Humans; Emergency Service, Hospital; Psychoses, Substance-Induced; Male; Adult; Tropicamide; Female
PubMed: 38818988
DOI: 10.55633/s3me/026.2023 -
BMC Cardiovascular Disorders May 2024Despite their continued use, the effectiveness and safety of vasopressors in post-cardiac arrest patients remain controversial. This study examined the efficacy of... (Meta-Analysis)
Meta-Analysis
BACKGROUND & OBJECTIVE
Despite their continued use, the effectiveness and safety of vasopressors in post-cardiac arrest patients remain controversial. This study examined the efficacy of various vasopressors in cardiac arrest patients in terms of clinical, morbidity, and mortality outcomes.
METHODS
A comprehensive literature search was performed using online databases (MeSH terms: MEDLINE (Ovid), CENTRAL (Cochrane Library), Embase (Ovid), CINAHL, Scopus, and Google Scholar) from 1997 to 2023 for relevant English language studies. The primary outcomes of interest for this study included short-term survival leading to death, return of spontaneous circulation (ROSC), survival to hospital discharge, neurological outcomes, survival to hospital admission, myocardial infarction, and incidence of arrhythmias.
RESULTS
In this meta-analysis, 26 studies, including 16 RCTs and ten non-RCTs, were evaluated. The focus was on the efficacy of epinephrine, vasopressin, methylprednisolone, dopamine, and their combinations in medical emergencies. Epinephrine treatment was associated with better odds of survival to hospital discharge (OR = 1.52, 95%CI [1.20, 1.94]; p < 0.001) and achieving ROSC (OR = 3.60, 95% CI [3.45, 3.76], P < 0.00001)) over placebo but not in other outcomes of interest such as short-term survival/ death at 28-30 days, survival to hospital admission, or neurological function. In addition, our analysis indicates non-superiority of vasopressin or epinephrine vasopressin-plus-epinephrine therapy over epinephrine monotherapy except for survival to hospital admission where the combinatorial therapy was associated with better outcome (0.76, 95%CI [0.64, 0.92]; p = 0.004). Similarly, we noted the non-superiority of vasopressin-plus-methylprednisolone versus placebo. Finally, while higher odds of survival to hospital discharge (OR = 3.35, 95%CI [1.81, 6.2]; p < 0.001) and ROSC (OR = 2.87, 95%CI [1.97, 4.19]; p < 0.001) favoring placebo over VSE therapy were observed, the risk of lethal arrhythmia was not statistically significant. There was insufficient literature to assess the effects of dopamine versus other treatment modalities meta-analytically.
CONCLUSION
This meta-analysis indicated that only epinephrine yielded superior outcomes among vasopressors than placebo, albeit limited to survival to hospital discharge and ROSC. Additionally, we demonstrate the non-superiority of vasopressin over epinephrine, although vasopressin could not be compared to placebo due to the paucity of data. The addition of vasopressin to epinephrine treatment only improved survival to hospital admission.
Topics: Humans; Vasoconstrictor Agents; Treatment Outcome; Out-of-Hospital Cardiac Arrest; Risk Factors; Return of Spontaneous Circulation; Male; Middle Aged; Female; Aged; Time Factors; Cardiopulmonary Resuscitation; Epinephrine; Recovery of Function; Risk Assessment; Vasopressins; Patient Discharge; Adult
PubMed: 38816786
DOI: 10.1186/s12872-024-03962-4 -
Scientific Reports May 2024Dietary trans 10, cis 12-conjugated linoleic acid (t10c12-CLA) is a potential candidate in anti-obesity trials. A transgenic mouse was previously successfully...
Dietary trans 10, cis 12-conjugated linoleic acid (t10c12-CLA) is a potential candidate in anti-obesity trials. A transgenic mouse was previously successfully established to determine the anti-obesity properties of t10c12-CLA in male mice that could produce endogenous t10c12-CLA. To test whether there is a different impact of t10c12-CLA on lipid metabolism in both sexes, this study investigated the adiposity and metabolic profiles of female Pai mice that exhibited a dose-dependent expression of foreign Pai gene and a shift of t10c12-CLA content in tested tissues. Compared to their gender-match wild-type littermates, Pai mice had no fat reduction but exhibited enhanced lipolysis and thermogenesis by phosphorylated hormone-sensitive lipase and up-regulating uncoupling proteins in brown adipose tissue. Simultaneously, Pai mice showed hepatic steatosis and hypertriglyceridemia by decreasing gene expression involved in lipid and glucose metabolism. Further investigations revealed that t10c10-CLA induced excessive prostaglandin E2, adrenaline, corticosterone, glucagon and inflammatory factors in a dose-dependent manner, resulting in less heat release and oxygen consumption in Pai mice. Moreover, fibroblast growth factor 21 overproduction only in monoallelic Pai/wt mice indicates that it was sensitive to low doses of t10c12-CLA. These results suggest that chronic t10c12-CLA has system-wide effects on female health via synergistic actions of various hormones.
Topics: Animals; Female; Fibroblast Growth Factors; Mice, Transgenic; Mice; Linoleic Acids, Conjugated; Corticosterone; Dinoprostone; Glucagon; Epinephrine; Thermogenesis; Male; Lipid Metabolism; Adipose Tissue, Brown; Fatty Liver; Lipolysis; Hypertriglyceridemia; Adiposity
PubMed: 38816541
DOI: 10.1038/s41598-024-63282-7 -
BMJ Open May 2024To determine the prevalence, causes and risk factors associated with visual impairment (VI) in the Nirmal district of Telangana, India, using extended Rapid Assessment...
OBJECTIVE
To determine the prevalence, causes and risk factors associated with visual impairment (VI) in the Nirmal district of Telangana, India, using extended Rapid Assessment of Visual Impairment (RAVI) methodology.
DESIGN
Cross-sectional study.
SETTING
Community setting.
PARTICIPANTS
Participants aged ≥16 years were enumerated from 90 randomly selected clusters and 4629/5400 (85.7%) participants were examined. Presenting visual acuity (VA) was assessed using a Snellen chart with E optotypes at a 6 m distance. Near vision was assessed binocularly using an N notation chart with tumbling E optotypes at a 40 cm distance. An anterior segment examination done followed by distance direct ophthalmoscopy at 50 cm. Non-mydriatic fundus images were obtained. VI was defined as presenting VA worse than 6/12 in the better eye. The prevalence of VI in the current study was compared with a RAVI study conducted in 2014 to assess the trends in VI among those aged ≥40 years.
PRIMARY OUTCOME
Prevalence, causes and risk factors for VI.
RESULTS
Among those examined, 55% were women, 53% had at least school-level education, 2.3% self-reported diabetes and 8.7% self-reported hypertension. The prevalence of VI was 8.81% (95% CI 8.01% to 9.67%). Overall, uncorrected refractive errors (49.5%) were the leading cause of VI, followed by cataracts (40.2%) and posterior segment diseases (4.9%). Among those aged ≥40 years, the prevalence of VI declined by 19.3% compared with the 2014 baseline study (from 20.2% to 16.3%; p<0.01).
CONCLUSION
The extended RAVI study conducted in the Nirmal district showed a considerable decline in the prevalence of VI. Targeted interventions are needed to provide adequate eye care for the high-risk groups in this district.
Topics: Humans; Cross-Sectional Studies; India; Female; Male; Middle Aged; Adult; Prevalence; Risk Factors; Aged; Young Adult; Adolescent; Visual Acuity; Vision Disorders; Cataract
PubMed: 38816051
DOI: 10.1136/bmjopen-2023-083199 -
Biomedicine & Pharmacotherapy =... Jul 2024Alzheimer's disease (AD) presents a significant challenge due to its prevalence and lack of cure, driving the quest for effective treatments. Anshen Bunao Syrup, a...
Alzheimer's disease (AD) presents a significant challenge due to its prevalence and lack of cure, driving the quest for effective treatments. Anshen Bunao Syrup, a traditional Chinese medicine known for its neuroprotective properties, shows promise in addressing this need. However, understanding its precise mechanisms in AD remains elusive. This study aimed to investigate Anshen Bunao Syrup's therapeutic potential in AD treatment using a scopolamine-induced AD rat model. Assessments included novel-object recognition and Morris water maze tasks to evaluate spatial learning and memory, alongside Nissl staining and ELISA analyses for neuronal damage and biomarker levels. Results demonstrated that Anshen Bunao Syrup effectively mitigated cognitive dysfunction by inhibiting amyloid-β and phosphorylation Tau aggregation, thereby reducing neuronal damage. Metabolomics profiling of rats cortex revealed alterations in key metabolites implicated in tryptophan and fatty acid metabolism pathways, suggesting a role in the therapeutic effects of Anshen Bunao Syrup. Additionally, ELISA and correlation analyses indicated attenuation of oxidative stress and immune response through metabolic remodeling. In conclusion, this study provides compelling evidence for the neuroprotective effects of Anshen Bunao Syrup in AD models, shedding light on its potential as a therapeutic agent for AD prevention and treatment.
Topics: Animals; Alzheimer Disease; Neuroprotective Agents; Disease Models, Animal; Male; Cognitive Dysfunction; Rats; Drugs, Chinese Herbal; Rats, Sprague-Dawley; Oxidative Stress; Amyloid beta-Peptides; Maze Learning; Scopolamine; tau Proteins; Morris Water Maze Test
PubMed: 38810401
DOI: 10.1016/j.biopha.2024.116754 -
Nutrients May 2024Polymethoxyflavonoids, such as nobiletin (abundant in Citrus depressa), have been reported to have antioxidant, anti-inflammatory, anticancer, and anti-dementia effects,...
Polymethoxyflavonoids, such as nobiletin (abundant in Citrus depressa), have been reported to have antioxidant, anti-inflammatory, anticancer, and anti-dementia effects, and are also a circadian clock modulator through retinoic acid receptor-related orphan receptor (ROR) α/γ. However, the optimal timing of nobiletin intake has not yet been determined. Here, we explored the time-dependent treatment effects of nobiletin and a possible novel mechanistic idea for nobiletin-induced circadian clock regulation in mice. In vivo imaging showed that the PER2::LUC rhythm in the peripheral organs was altered in accordance with the timing of nobiletin administration (100 mg/kg). Administration at ZT4 (middle of the light period) caused an advance in the peripheral clock, whereas administration at ZT16 (middle of the dark period) caused an increase in amplitude. In addition, the intraperitoneal injection of nobiletin significantly and potently stimulated corticosterone and adrenaline secretion and caused an increase in expression in the peripheral tissues. Nobiletin inhibited phosphodiesterase (PDE) 4A1A, 4B1, and 10A2. Nobiletin or rolipram (PDE4 inhibitor) injection, but not SR1078 (RORα/γ agonist), caused acute expression in the peripheral tissues. Thus, the present study demonstrated a novel function of nobiletin and the regulation of the peripheral circadian clock.
Topics: Animals; Flavones; Circadian Clocks; Mice; Male; Corticosterone; Period Circadian Proteins; Epinephrine; Mice, Inbred C57BL; Nuclear Receptor Subfamily 1, Group F, Member 1; Circadian Rhythm
PubMed: 38794729
DOI: 10.3390/nu16101491 -
Journal of Yeungnam Medical Science May 2024This case report is a unique case of solar retinopathy following antidepressant-induced mydriasis and highlights the need for comprehensive ophthalmic evaluation in...
This case report is a unique case of solar retinopathy following antidepressant-induced mydriasis and highlights the need for comprehensive ophthalmic evaluation in patients treated with medications having mydriatic effects. A 49-year-old female patient who had received long-term antidepressant therapy presented with bilateral visual impairment after prolonged sun exposure. Fundoscopy confirmed solar retinopathy, which was attributed to drug-induced mydriasis. Medication adjustments and sun protection strategies led to full visual recovery, underscoring the importance of interdisciplinary awareness. This case emphasizes the challenges associated with the simultaneous management of psychiatric and ophthalmic conditions and highlights the need for routine ophthalmic evaluation of patients prescribed antidepressants with reported ocular side effects.
PubMed: 38778720
DOI: 10.12701/jyms.2024.00213 -
Brazilian Journal of Medical and... 2024Arthritis has important cardiovascular repercussions. Phenylephrine-induced vasoconstriction is impaired in rat aortas in the early phase of the adjuvant-induced...
Arthritis has important cardiovascular repercussions. Phenylephrine-induced vasoconstriction is impaired in rat aortas in the early phase of the adjuvant-induced arthritis (AIA), around the 15th day post-induction. Therefore, the present study aimed to verify the effects of AIA on hyporesponsiveness to phenylephrine in rat aortas. AIA was induced by intradermal injection of Mycobacterium tuberculosis (3.8 mg/dL) in the right hind paw of male Wistar rats (n=27). Functional experiments in isolated aortas were carried out 15 days after AIA induction. Morphometric and stereological analyses of the aortas were also performed 36 days after the induction of AIA. AIA did not promote structural modifications in the aortas at any of the time points studied. AIA reduced phenylephrine-induced contraction in endothelium-intact aortas, but not in endothelium-denuded aortas. However, AIA did not change KCl-induced contraction in either endothelium-intact or denuded aortas. L-NAME (non-selective NOS inhibitor), 1400W (selective iNOS inhibitor), and ODQ (guanylyl cyclase inhibitor) reversed AIA-induced hyporesponsiveness to phenylephrine in intact aortas. 7-NI (selective nNOS inhibitor) increased the contraction induced by phenylephrine in aortas from AIA rats. In summary, the hyporesponsiveness to phenylephrine induced by AIA was endothelium-dependent and mediated by iNOS-derived NO through activation of the NO-guanylyl cyclase pathway.
Topics: Animals; Male; Phenylephrine; Rats, Wistar; Arthritis, Experimental; Nitric Oxide; Vasoconstriction; Endothelium, Vascular; Vasoconstrictor Agents; Rats; Aorta
PubMed: 38775546
DOI: 10.1590/1414-431X2024e13304