Window of opportunity for neuroprotection with an antioxidant, allene oxide synthase, after hypoxia-ischemia in adult male rats.

Abstract

Oxidative stress is an early event in the cascade leading in neuronal damage after hypoxic-ischemic (HI) brain injury. In the present study, we examined the dose response and window of opportunity for neuroprotection after HI injury with Allene Oxide Synthase (AOS), an anti-oxidative enzyme of the member of cytochrome P450 family. Adult male rats received intra-cerebro-ventricular infusions of either saline (vehicle) or AOS (1μg or 10μg or 100μg per rat, intracerebroventricular n=16 all groups) either 45min or 3h after unilateral HI brain injury. Brains were collected 5days later. The extent of brain damage, neuronal survival, apoptosis, and glial reactions were assessed in the striatum, hippocampus, and cortex. Allene Oxide Synthase was associated with reduced neuronal damage scores when given 45min, but not 3h, after HI injury (P<0.0001) in all brain regions. AOS treatment (10μg) improved neuronal survival in the striatum, cortex, and hippocampus (P<0.05, P<0.001) and reduced the microglia reaction (P<0.05) and numbers of caspase-3-positive cells in the hippocampus (P<0.01). Early blockade of oxidative stress after HI injury reduces inflammatory response, neuronal necrosis, and apoptosis. The neuroprotective effects of AOS were time of administration-dependent suggesting a relatively restricted window of opportunity for acute brain injury.