Neuroprotective Effects of Semaglutide in Cyclophosphamide-Induced Neuropathy: Restoring SIRT1/AMPK, PI3K/AKT/mTOR, and Antioxidant Pathways

Abstract

Cyclophosphamide (CP), a widely used chemotherapeutic agent, often induces chemotherapy‑induced peripheral neuropathy (CIPN). CP metabolism generates acrolein, a reactive aldehyde that promotes oxidative stress, lipid peroxidation, mitochondrial dysfunction, and NF‑κB–mediated neuroinflammation, while impairing PI3K/AKT/mTOR signaling. These processes drive axonal degeneration, demyelination, and neuronal apoptosis, highlighting the need for novel therapies. This study examined the neuroprotective effects of semaglutide, a glucagon‑like peptide‑1 (GLP‑1) receptor agonist, in a rat model of CP‑induced neuropathy. Wistar rats were assigned to control, CP (200 mg/kg, IP), or CP plus semaglutide (12–40 µg/kg, SC every three days). Motor and sensory functions were assessed using rotarod, hot plate, tail flick, and cold allodynia tests. Sciatic nerves were analyzed for oxidative stress markers (GSH, SOD, MDA), inflammatory cytokines (TNF‑α, IL‑6), apoptotic regulators (Caspase‑3, BAX, Bcl‑2), and signaling proteins (SIRT1, AMPK, PI3K, AKT, mTOR). Histopathology and immunohistochemistry evaluated structural integrity and Nrf2/p‑AKT expression. CP caused marked motor incoordination (‑31.3% rotarod latency) and sensory hypersensitivity (thermal: ‑60.7%; cold: ‑46.6%; tail flick: ‑31.4%). Semaglutide dose‑dependently reversed these deficits, with the higher dose restoring near‑normal function. Mechanistically, semaglutide reduced oxidative stress, upregulated SIRT1 and AMPK, suppressed TNF‑α and IL‑6, rebalanced apoptotic markers, and restored PI3K/AKT/mTOR signaling. Histology confirmed protection against edema and demyelination, while immunohistochemistry showed recovery of Nrf2 and p‑AKT. Overall, semaglutide provides multimodal neuroprotection against CP‑induced neuropathy, supporting its potential as a therapeutic candidate for CIPN.