PHOSPHOINOSITIDE 3-KINASE INHIBITOR AS605240 AMELIORATES STREPTOZOTOCIN-INDUCED ALZHEIMER'S DISEASE LIKE SPORADIC DEMENTIA IN EXPERIMENTAL RATS

The quest for chemical entities able to curb the action of the phosphoinositide 3-kinase, (PI3K)/protein kinase B (AKT) signaling pathways is evolving as a potential therapeutic strategy for the treatment and/or prevention of neurodegenerative disorders including Alzheimer's disease (AD). In this study, the effects of a PI3K inhibitor, AS605240 on cognitive dysfunction and antioxidative defense parameters against intra-cerebroventricular-streptozotocin (ICV-STZ)-induced rat model of sporadic AD was evaluated. ICV administration of a single dose of STZ (3 mg/kg) was performed to induce behavioral and biochemical changes in rats using the stereotaxic technique. Animals were administered with varying doses of AS605240 (5, 10 and 15 mg/kg) orally, 1 h before ICV-STZ on day 1 and continued once daily for four weeks. The behavioral parameters (passive avoidance and Morris water maze), antioxidative defense parameters, amyloid-beta (A beta) protein expression by Western blotting and immunostaining technique were estimated in brain tissue. AS605240 dose-dependently and significantly (p < 0.05 and p < 0.01 and p < 0.001) improved ICV-STZ-induced cognitive impairment and attenuated the altered antioxidative related parameters including superoxide dismutase, lipid peroxidation, glutathione and nitrite levels. Further, the increased A beta protein expression levels in brain tissue were markedly restored with AS605240 treatment. In conclusion, our study demonstrated that AS605240 exhibited immense potential in attenuating STZ-induced sporadic AD features in rats and may be developed as a therapeutic agent in the treatment and management of sporadic AD.