The cholinergic anti-inflammatory pathway is one of the putative biochemical pathways that link diabetes with Alzheimer disease. Hence, here we aimed to verify the potential antidiabetic effect and to unveil the possible mechanisms of galantamine, a clinically approved acetylcholinesterase (AChE) inhibitor used in Alzheimer disease. Additionally, we evaluated its effect as an add-on therapy with vildagliptin.
Material and Methods
The neonatal streptozotocin (n5-STZ) rat model was adopted and the diabetic animals were treated with galantamine (2.5, 5, 10 mg/kg), vildagliptin (5,10, 30 mg/kg) or both (5 and 10 mg/kg, respectively) for 4 weeks.
Galantamine leveled off the n5-STZ-induced elevation in body weight, food intake, and serum levels of glucose, fructosamine, ALT/AST, and the lipid profile (triglycerides, cholesterol, free fatty acids) assessed in serum, liver, and muscle. Besides, it increased the insulin level, HDL-C and % α-cell function, in a pattern similar to that of vildagliptin. Additionally, galantamine confirmed its antioxidant (nuclear factor-erythroid-2-related factor 2, total antioxidant capacity, lipid peroxide), anti-inflammatory (NF-κB, TNF-α) and anti-apoptotic (caspase-3 and cytochrome c) capabilities by altering the n5-STZ effect on all of the aforementioned parameters. Galantamine mediated its effect via improving the insulin (phosphorylated insulin receptor, p-AKT, GLUT4, GLUT2) and the Wnt/α-catenin (p-GSK-3α, α-catenin) signaling pathways. Galantamine, as expected, lowered dose dependently the n5-STZ-induced activation of AChE in brain, muscle and liver; nevertheless, the vildagliptin effect was limited to the brain enzyme. On almost all tested parameters, the galantamine effects surpassed that of vildagliptin, while combining both drugs showed the best effect.
The present results clearly prove that galantamine modulated glucose/lipid profile partly through its anti-cholinesterase, anti-oxidant, anti-apoptotic and anti-inflammatory properties, along with the improvement of both insulin and Wnt/α-catenin signaling pathways. Additionally, galantamine can be strongly considered as a potential antidiabetic agent and as an add-on therapy.
H S El-Abhar, Faculty of Pharmacy, Cairo University, Kasr El-Aini Str., 11562 Cairo, Egypt. [email protected]