The effect of agmatine on nervous system degeneration induced by the use of methotrexate in rats

Objective: One of the common side effects of chemotherapeutic treatment is neurodegeneration, including central nervous system neurotoxicity and peripheral neuropathy. This study aims to investigate the therapeutic efficacy of Agmatine (AgM) on Methotrexate (MTX)-induced neurotoxicity and peripheral neuropathy. Materials and Methods: Male Wistar albino rats were divided into four groups, namely control, MTX, AgM and MTX-AgM (n=10). MTX was administered at a weekly dose of 37.5 mg/kg (intraperitoneal) for 3 weeks. Then, AgM was administered at a 40 mg/kg dose twice a day for 7 days. Nociceptive pain perception and behavioral alterations were determined via sciatic functional index (SFI), water maze, rotarod and open field tests. Electrophysiological recordings were collected and expression levels of some apoptotic and mitophagic markers and tissue histopathology were assessed. Results: MTX administration resulted in a decreased axon diameter, myelin sheath thickness and myelinated nerve fiber diameter in sciatic nerves, which produced a decrease in nociceptive pain perception, nerve conduction velocity and SFI score. An increase in axon diameter, myelinated sheath thickness, nociceptive pain perception, nerve conduction velocity and SFI score were observed in MTX-AgM group. The decreased locomotor activity, learning and memory skills upon MTX administration were increased with AgM treatment. MTX administration led to a slight increase in the apoptotic pathway triggering and did not altered mitophagic pathway initiation, while AgM administration suppressed apoptosis. The MTX-induced degenerative changes observed in the spinal cord thoracic region were improved upon AgM administration. Conclusion: AgM was observed to possess a promising therapeutic efficacy on MTX-induced neurodegeneration. Keywords: Methotrexate, Agmatine, Sciatic nerve, Spinal Cord, Peripheral Neuropathy, Neurodegeneration.