The Neuroprotective Effects of the Modulation of Glycogen Synthase Kinase-3 in Diabetic Encephalopathy Through Pharmacological and Genetic Means

Diabetes is a major medical problem, with complications such as nephropathy, retinopathy and neuropathy shortening life span and impairing quality of life. One of these complications of chronic diabetes, diabetic encephalopathy, is characterized by deficient cognition and may progress to an Alzheimer's disease-like condition over time. The primary pathogenic mechanisms underlying diabetic encephalopathy include impaired insulin signaling and hyperglycemia. Deficient insulin signaling results in an over-activation of glycogen synthase kinase-3 (GSK3) leading to an increase in amyloid-beta (A[beta]) protein and the hyper-phosphorylation of the structural protein tau. In an effort to combat the cognitive decline seen in chronic diabetes, we treated streptozotocin (STZ)-diabetic mice with one of two drugs: AR-A014418, a GSK3 inhibitor, or TX14(A), a neuropeptide derived from prosaposin that possesses both GSK3 inhibitory and neuroprotective properties. DN-GSK3 mice, a model expressing inactive GSK3[beta], were used to compare the effects of endogenous versus pharmacological inhibition. Treatment with AR- A014418 was sufficient to prevent the development of cognitive deficits while TX14(A) was able to both prevent and reverse them. No prevention of cognitive decline was seen with endogenous inhibition of GSK3. These results may open a new avenue for treatment to prevent or ameliorate some of the detrimental effects of diabetic encephalopathy and Alzheimer's diseas