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.