2-Cyclopropylimino-3-methyl-1,3-thiazoline Hydrochloride Protects Against Beta-amyloid-induced Activation of the Apoptotic Cascade in Cultured Cortical Neurons

Abstract

Aggregated beta-amyloid, implicated in the pathogenesis of Alzheimer's disease (AD), induces neurotoxicity by evoking a cascade of oxidative damage-dependent apoptosis in neurons. We investigated the molecular mechanisms underlying the protective effect of 2-cyclopropylimino-3-methyl-1,3-thiazoline hydrochloride (KHG26377) against the beta-amyloid (A beta(25-35))-induced primary cortical neuronal cell neurotoxicity. Treatment with KHG26377 attenuated the A beta(25-35)-induced apoptosis by decreasing the Bax/Bcl-2 ratio and suppressing the activation of caspase-3. A marked increase in calcium influx and in the level of reactive oxygen species together with a decrease in glutathione levels was found after A beta(25-35) exposure; however, KHG26377 treatment reversed these changes in a concentration-dependent manner. In addition, KHG26377 significantly suppressed A beta(25-35)-induced toxicity concomitant with a reduction in the activation of extracellular signal-regulated kinases 1 and 2 and nuclear factor kappa B. The KHG26377-induced protection of neuronal cells against A beta toxicity was also mediated by suppressing the expression of glycogen synthase kinase-3 beta, increasing the levels of beta-catenin, and reducing the levels of phosphorylated tau. Our findings suggest that KHG26377 may modulate the neurotoxic effects of beta-amyloid and provide a rationale for treatment of AD.