Evaluation of Acetylcholinesterase Activity in Diabetic Male Wistar Rats Treated with Glibenclamide

Diabetes is linked to cognitive decline via cholinergic neurodegeneration, and while neuronal loss cannot yet be halted, acetylcholinesterase inhibitors remain central to therapy. Glibenclamide, an antidiabetic sulfonylurea, was recently reported to potently inhibit acetylcholinesterase in vitro, suggesting potential for treating cognitive impairment. However, its in vivo activity on this enzyme remains underexplored. This study investigated the effects of orally administered glibenclamide on the peripheral and central cholinergic system in a diabetic rat model. Diabetes was induced in male Wistar rats by a single, intraperitoneal injection of 65 mg/kg streptozotocin (STZ). Diabetic animals were orally administered vehicle (distilled water) or glibenclamide (1.2, 5, or 20 mg/kg) for fourteen consecutive days. A normal, non-diabetic group also received the vehicle. Body weight and fasting blood glucose (FBG) were monitored. After training, memory was tested using the Y-maze and Morris water maze (MWM). On day 15, following the MWM probe trial, animals were euthanized, plasma and hippocampus homogenates assayed for acetylcholine (ACh), acetylcholinesterase (AChE), and insulin concentrations. STZ-induced hyperglycemia was associated with an increase in plasma AChE activity (control group, 0.15 ± 0.02 U/L vs diabetic control 0.4 ± 0.04 U/L, p =0.02), which was reduced by glibenclamide 20 mg/kg, p = 0.0319. Correspondingly, plasma ACh concentrations increased significantly in the glibenclamide 20 mg/kg group (p=0.004) without changes in brain cholinergic signalling despite improvement in short-term spatial memory as assessed in the Y-maze. Glibenclamide demonstrates a dose-dependent inhibitory effect on plasma acetylcholinesterase; further studies should assess its therapeutic potential for diabetic neuropathy.

Key Words: glibenclamide, acetylcholinesterase, cholinergic system, cognitive dysfunction, neuroprotection.