Involvement of NMDA receptors in the beneficial effects of pioglitazone on scopolamine-induced memory impairment in mice

IntroductionPioglitazone, a peroxisome proliferator activated receptor γ (PPARγ) agonist, is widely used in clinical medicine as a treatment for type 2 diabetes and is recently proved to have beneficial effects on improving cognition in early stages of Alzheimer's disease (AD). Moreover, it has been shown that pioglitazone reduces N-methyl-d-aspartate (NMDA, a glutamate agonist) mediated calcium currents and transients. Since enhanced calcium transients are present in AD models, we tested the hypothesis whether pioglitazone manifests its acquisition memory enhancement role through glutamatergic pathway.Material and methodsMemory performance was evaluated in a two-trial recognition Y-maze test and passive avoidance in mice. Pioglitazone (20 or 40 mg/kg, p.o.) was administered 2 h before each trial, NMDA (75 mg/kg i.p.), 15 min before pioglitazone, and scopolamine, an M1 (muscarinic) receptor antagonist (0.3 or 1.0 mg/kg i.p.) and MK-801 (dizocilpine) (0.01, 0.03 or 0.1 mg/kg, i.p.), the highly selective, non-competitive NMDA antagonist – 30 min beforehand.Results(1) We induced the memory impairment by scopolamine or MK-801 before trials. (2) Pioglitazone did not improve the memory impairment induced by MK-801. (3) Pioglitazone significantly improved the memory impairment induced by scopolamine. (4) Subeffective dose of MK-801 nullified the beneficial effects of pioglitazone in scopolamine induced memory impaired mice. (5) NMDA promoted the effects of subeffective dose of pioglitazone on memory impaired by scopolamine.DiscussionIn conclusion, the present study suggests that glutamatergic pathway is involved in the pioglitazone induced memory performance.

► Pioglitazone improves the acquisition of memory impairment induced by scopolamine.
► NMDA promotes the effects of pioglitazone on memory impaired by scopolamine.
► MK-801 nullifies the effects of pioglitazone on scopolamine memory impaired mice.
► Glutaminergic pathway is involved in pioglitazone induced memory performance.