Differential Effects of Pentoxifylline on Learning and Memory Impairment Induced by Hypoxic-ischemic Brain Injury in Rats

Objective: Hypoxic-ischemic (HI) brain injury in the human perinatal period often leads to significant long-term neuro-behavioral dysfunction in the cognitive and sensory-motor domains. Using a neonatal HI injury model (unilateral carotid ligation followed by hypoxia) in postnatal day seven rats, the present study investigated the long-term effects of HI and potential behavioral protective effect of pentoxifylline. Methods: Seven-day-old rats underwent right carotid ligation, followed by hypoxia (FiO2 = 0.08). Rats received pentoxifylline immediately after and again 2 hours after hypoxia (two doses, 60-100 mg/kg/dose), or serum physiologic. Another set of seven-day-old rats was included to sham group exposed to surgical stress but not ligated. These rats were tested for spatial learning and memory on the simple place task in the Morris water maze from postnatal days 77 to 85. Results: HI rats displayed significant tissue loss in the right hippocampus, as well as severe spatial memory deficits. Low-dose treatment with pentoxifylline resulted in significant protection against both HI-induced hippocampus tissue losses and spatial memory impairments. Beneficial effects are, however, negated if pentoxifylline is administered at high dose. Conclusion: These findings indicate that unilateral HI brain injury in a neonatal rodent model is associated with cognitive deficits, and that low dose pentoxifylline treatment is protective against spatial memory impairment.