C-Glucosyl Xanthone derivative Mangiferin downregulates the JNK3 mediated caspase activation in Almal induced neurotoxicity in differentiated SHSY-5Y neuroblastoma cells.

INTRODUCTION: C-Glucosyl Xanthone derivatives were assessed to inhibit the JNK3 mediated Caspase pathway in Almal (Aluminum Maltolate) induced neurotoxicity in SHSY-5Y cells. METHODS: Mangiferin was selected among 200 C-Glucosyl Xanthones based on molecular interaction, docking score (-10.22 kcal/mol), binding free energy (-71.12 kcal/mol), ADME/tox properties and by molecular dynamic studies. Further, it was noticed that glycone moiety of Mangiferin forms H-bond with ASN 194, SER 193, GLY 76, and OH group in the first position of the aglycone moiety shows interaction at Met 149 which is exceptionally crucial for JNK3 inhibitory activity. RESULTS AND DISCUSSION: Mangiferin (0.5, 1, 10, 20 and 30 µM) and standard SP600125 (20 µM) treatment increased the cell survival rate against Almal 200 µM, with EC50 of Mangiferin (8 µM) and standard SP600125 (4.9 µM) respectively. Mangiferin significantly impedes kinase activation, indicating suppression of JNK3 signaling with IC50 (98.26 nM). Mangiferin (10 and 15 µM) dose-dependently inhibits the caspase 3, 8, and 9 enzyme activation in comparison to Almal group. CONCLUSION: Mangiferin demonstrated neuroprotection in SHSY-5Y cells against apoptosis induced by Almal by adapting the architecture of the neurons and increasing their density. Among all Xanthone derivatives, Mangiferin could improve neuronal toxicity by inhibiting JNK3 and down-regulating the Caspase activation.

3-O-Acetyl-11-keto-ß-boswellic acid ameliorates acquired, consolidated and recognitive memory deficits through the regulation of hippocampal PPAR γ, MMP9 and MMP2 genes in dementia model.

Pentacyclic Phytomolecule 3-O-Acetyl-11-keto-ß-boswellic acid (AKBA) from Frankincense family has proven for the neuroprotection and recognized as an orphan drug for the treatment of cerebral edema. Nonetheless, AKBA have promising indications with Peroxisome proliferator activated receptor gamma (PPARγ) associated to cognitive function not deliberated so far. In order to substantiate the potential role of AKBA on memory function, we examine the contribution of PPARγ activation and its downstream process. Modified method of scopolamine induced dementia rats were treated with AKBA (5, 10&15 mg/kg,i.p) and Donepezil (2.5 mg/kg,i.p). Scopolamine induced short term spatial, working memory and recognition memory impairment was reversed significantly after AKBA treatment. AKBA administration diminished the Acetylcholine esterase (AchE) activity and preserved brain GABA and glutamate mediated neuronal excitability. Further, gene expression study reveals AKBA ameliorates the memory impairment via activating PPARγ and its downstream regulators, matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9) genes in hippocampus. This study concludes that the treatment with AKBA can be a novel Phyto-molecule of interest for treating dementia via up-regulating hippocampus genes mediated cholinergic activation.

3-O-Acetyl-11-keto-ß-boswellic acid ameliorates chronic unpredictable mild stress induced HPA axis dysregulation in relation with glutamate/GABA aberration in depressive rats.

Overt expression of brain glucocorticoid receptor (GR) leads to elevation of glutamate release causes cerebral excitotoxicity which in turn produce neuropsychological disorders. The aim of our work is to study the consequence of 3-O-Acetyl-11-keto-ß-boswellic acid (AKBA) on chronic unpredictable mild stress (CUMS) induced HPA axis dysregulation in relative to glutamate and GABA irregularity in depressive rats. AKBA (5, 10 &15mg/kg) was administered for 28 days parallel with CUMS induction in rats. Behavioural studies, tail suspension test (TST), open field exploratory (OFT) and forced swim test (FST) were performed. Biochemical studies including plasma corticosterone, glutamate GABA and glutamic acid decarboxylase (GAD) enzyme activity were studied. Glucocorticoid receptor expression and brain histology were studied to observe the effect of AKBA. CUMS induction results in depressive state of the animals were confirmed by the sucrose preference test. The administration of AKBA significantly reduced the immobility time and improved the exploratory behaviour. Plasma corticosterone and brain glutamate level was decreased and GABA level were increased significantly evident with GAD activation in AKBA-treated animals, further confirmed with decreased GR expression improves architecture of prefrontal cortex region. Correlation study illustrates behavioural improvements undeviating the biochemical alteration and GR expression after AKBA treatment during depression. AKBA significantly reversed the CUMS-induced glutamate/GABA abnormalities through the adaptation of central HPA axis regulation. Hence this study concludes that AKBA can be a better alternative to treat depressive disorders.