Epigallocatechin gallate ameliorates oxaliplatin-induced peripheral neuropathy via upregulation of IGF-1 signaling and suppression of neuroinflammation

Abstract

Chemotherapy-Induced Peripheral Neuropathy (CIPN) is a severe neurological complication characterized by persistent pain and sensory dysfunction. This study investigated the role of Insulin-like Growth Factor-1 (IGF-1) signaling in the pathogenesis of oxaliplatin-induced CIPN and evaluated the therapeutic potential of Epigallocatechin gallate (EGCG). Using an oxaliplatin-induced CIPN mouse model, we examined IGF-1 expression in dorsal root ganglia (DRG) and spinal cord, and assessed the therapeutic effects of intraperitoneal EGCG (50 mg/kg/day) administration. Oxaliplatin induced mechanical hypersensitivity and significantly reduced IGF-1 protein levels, predominantly localized in neurons, within both DRG and spinal cord, while IGF-1 receptor (IGF1R) expression remained unchanged. Daily EGCG administration significantly attenuated oxaliplatin-induced mechanical hypersensitivity and restored neuronal IGF-1 expression in these tissues. These therapeutic effects were accompanied by robust anti-neuroinflammatory actions. EGCG treatment significantly reduced oxaliplatin-induced microglia/macrophage activation (Iba-1 positive cells) in both DRG and spinal dorsal horn (SDH). Furthermore, EGCG suppressed the phosphorylation of NFκB, p38 MAPK (notably in Iba-1 positive cells), and ERK, key inflammatory signaling molecules. EGCG also reversed the oxaliplatin-induced increase in phosphorylated CREB and diminished expression of the pain marker Calcitonin Gene-Related Peptide (CGRP). Interestingly, the phosphorylation of AKT, a common downstream effector of IGF-1, was not significantly altered by EGCG treatment in this model. In conclusion, our study demonstrates EGCG's therapeutic potential in CIPN by enhancing neuronal IGF-1 signaling and suppressing neuroinflammation through the modulation of NFκB, p38 MAPK, ERK, and CREB pathways. These findings highlight EGCG as a promising candidate for CIPN management, warranting further investigation.