Window of Opportunity for Neuroprotection with an Antioxidant, Allene Oxide Synthase, after Hypoxia-Ischemia in Adult Male Rats

Abstract

Aims: 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. Methods: Adult male rats received intra-cerebro-ventricular infusions of either saline (vehicle) or AOS (1 μg or 10 μg or 100 μg per rat, intracerebroventricular n = 16 all groups) either 45 min or 3 h after unilateral HI brain injury. Brains were collected 5 days later. The extent of brain damage, neuronal survival, apoptosis, and glial reactions were assessed in the striatum, hippocampus, and cortex. Results: Allene Oxide Synthase was associated with reduced neuronal damage scores when given 45 min, but not 3 h, after HI injury (P < 0.0001) in all brain regions. AOS treatment (10 μg) 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). Conclusions: 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. © 2012 Blackwell Publishing Ltd.