Celastrus paniculatus oil ameliorates NF-KB mediated neuroinflammation and synaptic plasticity in the scopolamine-induced cognitive impairment rat model.

BACKGROUND AND AIM: Traditionally, Celastrus paniculatus Willd. (CP) oil has been utilized as a tranquilizer and memory enhancer. The present study investigated the neuropharmacological activity and efficacy of CP oil in ameliorating scopolamine-induced cognitive impairment in rats. EXPERIMENTAL PROCEDURE: Cognitive deficiency was induced in rats by administration of scopolamine (2 mg/kg intraperitoneal injection) for a period of 15 days. Donepezil served as a reference drug and CP oil was tested as both preventive and curative treatments. Animals' behaviour was assessed through the Morris water maze (MWM), novel object preference (NOR), and conditioned avoidance (CA) tests. Oxidative stress parameters, bioamine concentration (dopamine, noradrenaline, and 5-hydroxytryptamine), nerve growth factor (NGF), interleukin-6 (IL-6), nuclear factor kappa B (NF-кB), and tumor necrosis factor-alpha (TNFα) were estimated. Synaptophysin immunohistochemistry was performed. RESULTS: Our results showed that CP oil ameliorated behavioural deficits. It reduced latency to find a hidden platform in MWM. Reduced novel object exploration time and discrimination index (p < 0.05) in the NOR. Reduced step-down latency and normalized conditioned avoidance response (p < 0.001) in the CA test. CP oil increased dopamine, serotonin, norepinephrine, superoxide dismutase (SOD), glutathione, and catalase levels. It decreased malondialdehyde (MDA), acetylcholinesterase activity, IL-6, NF-кB (P < 0.001), TNFα, and NGF levels. Treatment showed approximate typical reactivity to synaptophysin. CONCLUSION: Our data is suggestive that CP oil treatment improves behavioural test outcomes, increases biogenic amine concentration, and decreases acetylcholinesterase activity, and neuroinflammatory biomarkers. It also restores synaptic plasticity. It thus improves cognitive functions against scopolamine-induced amnesia in rats by improving cholinergic function.

Insights of Valacyclovir in Treatment of Alzheimer's Disease: Computational Docking Studies and Scopolamine Rat Model.

BACKGROUND: Alzheimer's Disease (AD) impairs memory and cognitive functions in the geriatric population and is characterized by intracellular deposition of neurofibrillary tangles, extracellular deposition of amyloid plaques, and neuronal degeneration. Literature suggests that latent viral infections in the brain act as prions and promote neurodegeneration. Memantine possesses both anti-viral and N-methyl-D-aspartate (NMDA) receptor antagonistic activity. OBJECTIVES: This research was designed to evaluate the efficacy of antiviral agents, especially valacyclovir, a prodrug of acyclovir in ameliorating the pathology of AD based on the presumption that anti-viral agents targeting the Herpes Simplex Virus (HSV) can have a protective effect on neurodegenerative diseases like Alzheimer's disease. METHODS: Thus, we evaluated acyclovir's potential activity by in-silico computational docking studies against acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and beta-secretase 1 (BACE-1). These findings were further evaluated by in-vivo scopolamine-induced cognitive impairment in rats. Two doses of valacyclovir, a prodrug of acyclovir (100 mg/kg and 150 mg/kg orally) were tested. RESULTS: Genetic Optimisation for Ligand Docking scores and fitness scores of acyclovir were comparable to donepezil. Valacyclovir improved neurobehavioral markers. It inhibited AChE and BuChE (p<0.001) enzymes. It also possessed disease-modifying efficacy as it decreased the levels of BACE-1 (p<0.001), amyloid beta 1-42 (p<0.001), amyloid beta 1-40 (p<0.001), phosphorylatedtau (p<0.001), neprilysin (p<0.01), and insulin-degrading enzyme. It ameliorated neuroinflammation through decreased levels of tumour necrosis factor α (p<0.001), nuclear factor-kappa B (p<0.001), interleukin 6 (p<0.001), interleukin 1 beta (p<0.001), and interferon-gamma (p<0.001). It also maintained synaptic plasticity and consolidated memory. Histopathology showed that valacyclovir could restore cellular density and also preserve the dentate gyrus. CONCLUSION: Valacyclovir showed comparable activity to donepezil and thus can be further researched for the treatment of Alzheimer's disease.

Alzheimer's disease: a scoping review of biomarker research and development for effective disease diagnosis.

INTRODUCTION: Alzheimer's disease (AD) is regarded as the foremost reason for neurodegeneration that prominently affects the geriatric population. Characterized by extracellular accumulation of amyloid-beta (Aß), intracellular aggregation of hyperphosphorylated tau (p-tau), and neuronal degeneration that causes impairment of memory and cognition. Amyloid/tau/neurodegeneration (ATN) classification is utilized for research purposes and involves amyloid, tau, and neuronal injury staging through MRI, PET scanning, and CSF protein concentration estimations. CSF sampling is invasive, and MRI and PET scanning requires sophisticated radiological facilities which limit its widespread diagnostic use. ATN classification lacks effectiveness in preclinical AD. AREAS COVERED: This publication intends to collate and review the existing biomarker profile and the current research and development of a new arsenal of biomarkers for AD pathology from different biological samples, microRNA (miRNA), proteomics, metabolomics, artificial intelligence, and machine learning for AD screening, diagnosis, prognosis, and monitoring of AD treatments. EXPERT OPINION: It is an accepted observation that AD-related pathological changes occur over a long period of time before the first symptoms are observed providing ample opportunity for detection of biological alterations in various biological samples that can aid in early diagnosis and modify treatment outcomes.

Effect of saroglitazar 2 mg and 4 mg on glycemic control, lipid profile and cardiovascular disease risk in patients with type 2 diabetes mellitus: a 56-week, randomized, double blind, phase 3 study (PRESS XII study).

BACKGROUND: The potential for PPAR agonists to positively affect risk of cardiovascular disease in patients with type 2 diabetes (T2DM) is of persistent attention. The PRESS XII study primarily aimed to evaluate the efficacy and safety of saroglitazar (2 mg and 4 mg) as compared to pioglitazone 30 mg on glycemic control in patients with type 2 diabetes mellitus. METHODS: In this randomized double-blind study, patients with T2DM [glycosylated hemoglobin (HbA1c) ≥ 7.5%] were enrolled from 39 sites in India. Patients received once-daily doses of either saroglitazar or pioglitazone (1:1:1 allocation ratio) for a total of 24 weeks. Patients were continued in a double blind extension period for an additional 32 weeks. Efficacy evaluations of glycemic parameters [HbA1c (Primary endpoint at week 24), FPG and PPG] and other lipid parameters (TG, LDL-C, VLDL-C, HDL-C, TC, Non HDL-C, Apo A1 and Apo B) were conducted at week 12, 24 and 56 and compared to the baseline levels. The efficacy analyses were performed by using paired t-test and ANCOVA model. RESULTS: A total of 1155 patients were enrolled in this study. The baseline characteristics were similar between the three treatment groups. The within group mean (± SD) change in HbA1c (%) from baseline of the saroglitazar (2 mg and 4 mg) and pioglitazone treatment groups at week 24 were: - 1.38 ± 1.99 for saroglitazar 2 mg; - 1.47 ± 1.92 for saroglitazar 4 mg and - 1.41 ± 1.86 for pioglitazone, respectively. Statistically significant reduction from baseline in HbA1c was observed in each treatment group at week 24 with p-value < 0.016. There was a significant reduction in TG, LDL-C, VLDL-C, TC and Non HDL-C with a significant increase in HDL-C from baseline levels (< 0.016). Most of the AE's were 'mild' to 'moderate' in severity and were resolved by the completion of the study. CONCLUSIONS: Saroglitazar effectively improved glycemic control and lipid parameters over 56 weeks in patients of T2DM receiving background metformin therapy and has a promising potential to reduce the cardiovascular risk in T2DM patients. Trial registration CTRI/2015/09/006203, dated 22/09/2015.

An ayurvedic proprietary herbal preparation, Calci-7, prevents ovariectomy-induced osteoporosis in rats.

INTRODUCTION: CALCI-7 (CA) is an ayurvedic proprietary medicine, used to treat osteoporosis in postmenopausal women. However, scientific proof for its anti-osteoporotic effect and mechanism of action remain unclear due to which present study was under taken. MATERIALS AND METHODS: Ovariectomy was performed to induce osteoporosis. Rats were given CA 100 mg/kg, p.o. and estrogen 0.0563 mg/kg, i.m. once a day from day 1 to day 42. Animals were weighed weekly for body weight variation. At the end of 42 days treatment, urine and the blood samples were collected for analysis of calcium, phosphorus and alkaline phosphatase. Immediately, after sample collection, the uterus was carefully removed and weighed. Results were analysed using ANOVA. RESULTS: CA treatment to ovariectyomized (OVX) rats showed significant improvement in body weight, increased levels of calcium and phosphorus levels in serum while levels were found to be decreased in urine as compared to OVX group. The significant increase in uterine weight and femur length were observed in treatment groups. In the histopathological examination bone structure showed a normal structure with lacuna and various lamellae without any damage or porosity in bone in the formulation and estrogen-treated group. CONCLUSION: The present findings are strongly suggestive that CA possesses comparable efficacy to estrogen and thus can be useful in the postmenopausal osteoporosis.

Anti-Viral Agents in Neurodegenerative Disorders: New Paradigm for Targeting Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disease affecting geriatric populations for which several causes have been proposed. These include a relationship with known pathogens although the exact nature of such a relationship remains uncertain. Herpes simplex virus-1 has been proposed as potential cause of AD because of its ability to form ß amyloid(Aß) and neurofibrillary tangles due to tau hyperphosphorylation and action of beta & gamma secretase on amyloid precursor protein(APP) together with genetic association with apolipoprotein-E4(ApoE-Ɛ4), which points out to latent Herpes Simplex virus-1 as an agent causing AD. There are numerous studies that linked HSV-1 with AD like anti-HSV-1 IgM antibodies, nectin-2, heme oxygenase-1, phosphorylated eukaryotic initiation factor-2A, caspase-8 and nucleus-specific alteration of raphe neurons. Various possible mechanisms by which HSV-1 might lead to development of AD such as ApoE, ß-amyloid, tau phosphorylation, inflammation and oxidative stress are also discussed. Thus, this review discusses patent information and a strong relationship between latent HSV-1 and AD and also proposes antiviral therapy for AD.