P3‐290: Neuroprotective effects of hypoxic preconditioning on streptozotocin‐induced animal model of sporadic Alzheimer's disease

Cerebral metabolic changes accompanying an “insulin-resistant brain state” have been hypothesized to form the core of the neurodegenerative events that occur in sporadic Alzheimer's disease (sAD) pathology. This study was conducted to evaluate the effect of hypoxic preconditioning (HP), one of the most powerful mechanisms of protection, on cognition, cerebral energy metabolism and oxidative status in the intracerebroventricular (icv) streptozotocin (STZ)-induced model of sAD. For this purpose, male Wistar rats were randomly divided into four groups: 1- Control (sham operation/vehicle administration); 2- STZ (bilateral icv injection of STZ at the dose of 3mg/Kg); 3- HP (exposure to brief periods of moderate hypoxia (10% O2 for 2 hours) during 3 days, followed by sham operation/vehicle administration); 4- HP + STZ (as group 3, but submitted to icvSTZ injection). The severe deficits in learning and memory resulting from icvSTZ administration were antagonized by HP. HP was also able to attenuate icvSTZ-induced increased neuroinflammation and oxidative stress, reflected by increased glial fibrillary acidic protein (GFAP) immunoreactiviy, nitrites and malondialdehyde levels as well as decreased antioxidant defenses. Enhanced acetyl cholinesterase activity was also observed in icvSTZ rats indicating the occurrence of cholinergic dysfunction, an effect prevented by HP. Moreover, HP significantly protected against energy hypo metabolism and mitochondrial impairment induced by icvSTZ. Collectively, these results demonstrate that the deleterious effects icvSTZ can be prevented by HP, suggesting that the clarification of the mechanisms underlying HP protective effects may offer new therapeutic opportunities to counteract the cognitive decline and metabolic alterations associated with sAD.