The neuroprotective effect of pterostilbene on oxaliplatin-induced peripheral neuropathy via its anti-inflammatory, anti-oxidative and anti-apoptotic effects: Comparative study with celecoxib

Oxaliplatin is one of the first-line drugs in solid tumors treatment. However, neuropathy is a devastating side effect leading to poor compliance and treatment cessation. The current study explored pterostilbene plausible neuroprotective effects aiming to ascertain the potential mechanisms involved in relieving oxaliplatin-induced peripheral neuropathy (OIPN) and investigating whether pterostilbene and celecoxib combination could show better relief. Rats were divided into six groups; control, pterostilbene (40 mg/kg/day, p.o. for 5 weeks), oxaliplatin (4 mg/kg, i.p. twice per week for 4.5 weeks), celecoxib (30 mg/kg/day, p.o. for 5 weeks) and combination of pterostilbene and celecoxib. Behavioral tests and histopathological analysis of sciatic nerves were done. MAPKs, cytokines, COX-2, and PGE2 gene and protein expressions were estimated using qRT-PCR, western, and ELISA techniques. Malondialdehyde (MDA) and total antioxidant capacity (TAC) were assessed by colorimetric assay while apoptotic markers by immunohistochemical analysis and qRT-PCR. The study revealed that pterostilbene and celecoxib averted oxaliplatin-induced behavioral and motor impairments along with restoration of histopathological changes. Moreover, pterostilbene and celecoxib have significantly attenuated sciatic nerve: p38 MAPK, JNK, ERK1/2, NF-κB, COX-2, PGE2, TNF-α, and interleukins levels. Pterostilbene and celecoxib have reduced caspase-3, Bax, and MDA while increasing Bcl-2 level and TAC. Altogether, Pterostilbene mitigates OIPN by interrupting the vicious cycle of inflammation, oxidation, and apoptosis. Furthermore, pterostilbene and celecoxib show comparable attenuation on MAPKs cascades, inflammatory cytokines, oxidative and apoptotic markers. Likewise, co-administration of pterostilbene and celecoxib shows further relief of neuropathic pain.