Evaluation of the neuroprotective effect of donepezil in type 2 diabetic rats

Recent studies raise the possibility that donepezil can delay the progression of Alzheimer's disease (AD). This research evaluated the efficacy of donepezil in an animal model with brain insulin resistance and AD-like alterations. Rats were fed with high-fat/high-fructose (HF/Hfr) diet during the study period (17 weeks) and received one injection of streptozotocin (STZ) (25 mg/kg) after 8 weeks of starting the study. Diabetic (T2D) rats were treated with donepezil (4 mg/kg; p.o.) or vehicle for 8 weeks after STZ injection. The influence of donepezil on AD-related behavioral, biochemical, and neuropathological changes was investigated in T2D rats. Treatment of diabetic rats with donepezil led to a significant decrease in both amyloid-β deposition and the raised hippocampal activity of cholinesterase (ChE). It significantly increased the suppressed glutamate receptor expression (AMPA GluR1 subunit and NMDA receptor subunits NR1, NR2A, NR2B). It also improved cognitive dysfunction in the passive avoidance and the Morris water maze tests. However, donepezil treatment did not significantly decrease the elevated levels of P-tau, caspase-3, GSK-3β, MDA, TNF-α, and IL-1β in the hippocampus of diabetic rats. Also, it did not restore the suppressed levels of glutathione and superoxide dismutase in the brain of these rats. Moreover, donepezil did not alter the elevated serum level of glucose, insulin, and total cholesterol. These findings suggest that donepezil treatment could ameliorate learning and memory impairment in T2D rats through reversal of some of the AD-related alterations, including reduction of amyloid-β burden and ChE activity as well as restoration of glutamate receptor expression. However, lack of any significant effect on P-tau load, oxidative stress, neuroinflammation, and insulin resistance raises the question about the ability of donepezil to delay the development or arrest the progression of T2D-induced AD and it is still a matter of debate that requires further studies.