Minocycline reduces traumatic brain injury-mediated caspase-1 activation, tissue damage, and neurological dysfunction

OBJECTIVE: Caspase-1 plays an important functional role mediating neuronal cell death and dysfunction after experimental traumatic brain injury (TBI) in mice. Minocycline, a derivative of the antibiotic tetracycline, inhibits caspase-1 expression. This study investigates whether minocycline can amel iorate TBI-mediated injury in mice. METHODS: Brains from mice subjected to traumatic brain injury underwent imm unohistochemical analyses for caspase-1, caspase-3, and a neuronal specific marker (NeuN). Minocycline- and saline-treated mice subjected to traumatic brain injury were compared with respect to neurological function, lesion v olume, and interleukin-lp production. RESULTS: Immunohistochemical analysis revealed that activated caspase-1 and caspase-3 are present in neurons 24 hours after TBI. Intraperitoneal admin istration of minocycline 12 hours before or 30 minutes after TBI in mice re sulted in improved neurological function when compared with mice given sali ne control, as assessed by Rotarod performance 1 to 4 days after TBI. The l esion volume, assessed 4 days after trauma, was significantly decreased in mice treated with minocycline before or after trauma when compared with sal ine-treated mice. Caspase-1 activity, quantified by measuring mature interl eukin-1 beta production by enzyme-linked immunosorbent assay, was considera bly increased in mice that underwent TBI, and this increase was significant ly diminished in minocycline-treated mice. CONCLUSION: We show for the first time that caspase-1 and caspase-3 activit ies localize specifically within neurons after experimental brain trauma. F urther, these results indicate that minocycline is an effective pharmacolog ical agent for reducing tissue injury and neurological deficits that result from experimental TBI, likely through a caspase-1-dependent mechanism. The se results provide an experimental rationale for the evaluation of minocycl ine in human trauma patients.