Neuroprotective Effect of Umbelliferone Against Chemotherapy-Induced Neurotoxicity in Rats via Alteration of NF-κB, PPAR-δ, and Mitochondrial Apoptosis Pathways.

Chemotherapy-induced peripheral neuropathy (CIPN) is a prevalent and debilitating adverse effect associated with the use of different anticancer drugs such as platinum compounds, taxanes, vinca alkaloids, and proteasome inhibitors. In the current experimental study, we investigate the neuroprotective effects of umbelliferone against oxaliplatin (OXA)-induced peripheral neuropathy in rats. Intraperitoneal administration of OXA (4 mg/kg) was used for induction of neurotoxicity in the rats. The rats subsequently received the oral administration of umbelliferone at a dose of 2.5, 5, and 10 mg/kg. The mechanical withdrawal threshold (MWT), cold allodynia testing, nerve conduction activity, body weight, cerebrum weight, cerebrum index, acetylcholinesterase (AchE), total protein, nitric oxide (NO), antioxidant, inflammatory cytokines, apoptosis, and inflammatory parameters were estimated. The different mRNA expressions were measured in the brain tissue. Umbelliferone treatment improved the MWT and reduced the cold allodynia. Umbelliferone significantly (P < 0.001) improved the nerve conduction velocity, along with the body weight, cerebrum weight, cerebrum index, and altered the levels of acetylcholinesterase (AchE), total protein, and nitric oxide (NO). Umbelliferone treatment altered the level of antioxidant parameters (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione (GSH), malonaldehyde (MDA)); inflammatory cytokines (interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), IL-10, IL-18); inflammatory parameters (cyclooxygenase-2 (COX-2), inducible nitric oxide synthetase (iNOS), prostaglandin E (PGE), nuclear factor kappa B (NF-κB)); apoptosis parameters (caspase-3, caspase-9, Bcl-2 Associated X protein (Bax), B-cell lymphoma 2 (Bcl-2), Bax/Bcl-2 ratio). Umbelliferone treatment altered the mRNA expression paraoxonase (PON)-1, PON-2, PON-3, and peroxisome proliferator-activated receptor δ (PPAR-δ). The findings clearly showed the neuroprotective effect of umbelliferone against OXA-induced neurotoxicity in rats via alteration of NF-κB, PPAR-δ, and mitochondrial apoptosis pathways.