Mitigation of experimental ER stress and diabetes mellitus induced peripheral neuropathy by autophagy promoter, 6‐BIO

Abstract

Neuropathy occurs due to damage to the peripheral/central nervous system either due to injury, disease, or drug usage. Increased endoplasmic reticulum (ER) stress is observed in neuropathy. ER stress also leads to a block in autophagy amplifying neuropathic pain. 6‐Bromoindirubin‐3′‐oxime (6‐BIO) is an inhibitor of GSK‐3β which suppresses mTOR activity thereby increasing autophagy. Tunicamycin (TM)‐mediated ER stress and diabetic rat models were used to elucidate the role of ER stress and autophagy in mitigation of neuropathic pain by 6‐BIO. Pain was assessed by behavioral studies in ER stressed/diabetic rats having neuropathy. Western blotting, RT‐PCR, and fluorescence microscopy were used to assess the level of autophagy and ER stress after TM and 6‐BIO treatment in SH‐SY5Y neurons. Intraplantar injection of TM in rats led to peripheral neuropathy which was reduced upon 6‐BIO injection. 6‐BIO also reduced pain in animals exhibiting diabetic peripheral neuropathy. Modulation in the markers of autophagy (p‐mTOR, LC‐3, and SQSTM1/p62) shows that 6‐BIO induces autophagolysosome formation post TM treatment. Concomitantly, 6‐BIO reduces ER stress and c‐Fos expression—a neuronal activity and pain marker. Alleviation of pain by the inhibition of ER stress and increased formation of autolysosomes by 6‐BIO can be harnessed for treating peripheral neuropathy.