Investigating tacrolimus-induced neurotoxicity and ibudilast as a drug repositioning candidate for neuroprotection

<p>Tacrolimus (TAC) is a common cause of neurotoxicity in clinical settings, yet its precise mechanisms and protective interventions remain elusive. This study aimed to elucidate TAC-induced neurotoxicity and evaluate the neuroprotective effects of ibudilast (IBU), a drug initially used for asthma, as a potential drug repositioning candidate.</p><p>In vitro experiments using SH-SY5Y cells demonstrated dose-dependent apoptotic cell death induced by TAC, which was mitigated by IBU treatment. Subsequently, in vivo experiments were performed by subcutaneous administration of TAC (2.5 or 5.0 mg/kg/day) for 14 days to Wistar rats, and administrating IBU (7.5 mg/kg/day) intraperitoneally once daily, commencing 2 days prior to TAC. Neurotoxic behavior was scored from 0 to 3 according to the severity of tremors, seizures, or irritability at pre-treatment, day 8, and day 15. Results revealed significant chronic neurotoxicity in the TAC (5 mg/kg/day) group on day 15, which was ameliorated by IBU administration. A histopathological assay of excised brains using Nissl and TUNEL staining demonstrated neuronal damage primarily in the cerebral cortex and CA1 region of the hippocampus, with sparing of the CA3 region, dendrite gyrus, and cerebellum. Co-administration of IBU notably attenuated these neuronal cell death. In conclusion, our findings suggest that TAC penetration into the brain and subsequent neuronal damage in the cortex and CA1 region underlie TAC-induced neurotoxicity. Furthermore, IBU emerges as a promising protective agent against this adverse event.</p>