Pioglitazone improves learning and memory in a rat model of cholinergic dysfunction induced by scopolamine, the roles of oxidative stress and neuroinflammation

Alzheimer's disease (AD) is a major neurodegenerative disorder characterized by progressive cognitive decline. Among various experimental models, scopolamine-induced amnesia is widely used to mimic memory dysfunction. Pioglitazone (PG), a thiazolidinedione derivative, has recently demonstrated neuroprotective potential in neurodegenerative conditions. This study aimed to evaluate the potential benefits of PG in mitigating scopolamine-induced cholinergic dysfunction and the associated memory and learning deficits in male Wistar rats. Fifty male Wistar rats were randomly assigned to five groups: (1) Control, (2) Scopolamine, and (3-5) three treatment groups receiving daily injections of PG at doses of 20, 40, or 60 mg/kg for three weeks in addition to scopolamine administration. Cognitive impairment was induced using scopolamine in all groups except the control. Cognitive function was assessed using the Morris water maze (MWM) and passive avoidance (PA) tests. Biochemical analyses were conducted to measure malondialdehyde (MDA), superoxide dismutase (SOD), total thiol levels, and acetylcholinesterase (AChE) activity in the cortex and hippocampus. Additionally, mRNA expression levels of inflammatory markers (TNF-alpha, IL-1 beta, IL-6) were evaluated in the hippocampus. Scopolamine induced cognitive impairment, increased MDA levels and AChE activity, decreased SOD activity and thiol levels, and elevated mRNA expression of inflammatory cytokines. PG significantly reversed these effects by enhancing performance in the MWM and PA tests, reducing MDA levels and AChE activity, and increasing SOD activity and total thiol concentration. Additionally, PG downregulated TNF-alpha, IL-1 beta, and IL-6 expression in brain tissue. The present behavioral and neurochemical findings suggest that PG ameliorates scopolamine-induced memory impairment by reducing oxidative stress and neuroinflammation while enhancing cholinergic function.