Mesencephalic astrocyte-derived neurotrophic factor (MANF): A novel therapeutic target for chemotherapy-induced peripheral neuropathy via regulation of integrated stress response and neuroinflammation

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) represents a severe complication, impacting up to 90% of cancer patients administered with chemotherapeutic agents such as oxaliplatin. The purpose of our study was to examine the potential role and therapeutic efficacy of Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF), given its recognized neuroprotective and immunomodulatory properties in diverse neurological disorders. Utilizing an oxaliplatin-induced CIPN mouse model, we investigated MANF expression in the dorsal root ganglia (DRG) and spinal cord, and evaluated the impacts of AAV-mediated MANF overexpression on CIPN. Our findings revealed substantial downregulation of MANF expression in both the DRG and spinal cord of CIPN inflicted mice, with MANF majorly localized in neurons as opposed to glial cells. Intrathecal administration of AAV-MANF preceding oxaliplatin treatment yielded several beneficial results. MANF overexpression diminished mechanical hypersensitivity and decreased Calcitonin Gene-Related Peptide (CGRP) expression in DRG and the spinal dorsal horn. These enhancements were concomitant with modulation of the integrated stress response (ISR) and neuroinflammation. Intervention with AAV-MANF effectively regulated ISR markers (BiP, CHOP, and p-eIF2α), mitigated activation of microglia and astrocytes in the DRG and spinal dorsal horn, and inhibited NFκB and ERK inflammatory signaling pathways. To conclude, our study underscores the potential of MANF as a viable therapeutic target for CIPN, manifesting its ability to modulate ISR and neuroinflammation. These insights recommend that continued exploration of MANF-centered approaches could facilitate the advancement of more efficacious interventions for this incapacitating chemotherapy complication.