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.