Systemic Effects of Methotrexate upon the Peripheral Nerve Tissue

Methotrexate (MTX) is a widely used oncologic drug due to its antineoplastic and anti-inflammatory effects. Although its toxic effects on the central nervous system at high doses have long been known, its effects on the peripheral nervous system are less studied in the literature. This review discusses the systemic effects of MTX on peripheral nerve tissue at histopathological, biochemical, molecular, and behavioral levels. Experimental animal studies have shown that MTX administration leads to impaired nerve conduction, reduced myelin thickness, axonal degeneration, and increased glial activity. Moreover, elevated homocysteine levels due to disrupted folate metabolism, oxidative stress, the release of pro-inflammatory cytokines, and mitochondrial dysfunction are thought to be the main mechanisms underlying MTX-induced neurotoxicity. MTX-related peripheral neuropathies are often irreversible in clinical practice, but early diagnosis and appropriate pharmacological interventions may allow for recovery. This review aims to raise awareness by compiling current data on the effects of MTX on the peripheral nervous system, both in basic science and clinical applications.