Resveratrol prevents lipopolysaccharide-induced cognitive impairment in rats through regulation of hippocampal GluA1-containing AMPA receptors

Background: Evidence suggests that dysregulation in AMPA-type glutamate receptors (AMPA-Rs) has been associated with the pathogenesis of Alzheimer’s disease (AD), especially during its early phase. Hence, the present study was performed to elucidate the impact of resveratrol (RV) on hippocampal expression of AMPA-Rs in a rat model of AD.

Methods: A rat model of cognitive deficits was developed by a stereotactic intracerebroventricular infusion of lipopolysaccharide (LPS) in male Wistar rats (n=24). The LPS+RV30 group (n=12) received intraperitoneal injections of RV (30 mg/kg) at 30 min, 12 h, and 24 h before LPS injection. Meanwhile, the model (LPS) and sham (SO) groups only were treated with the vehicle solution (normal saline containing 1% ethanol). One day after the LPS infusion, the mRNA expressions of AMPA-Rs subunits (Gria1-4) were evaluated by RT–PCR. In addition, hippocampal levels of lipid peroxidation, superoxide dismutase, and nitric oxide were assessed. Seven days after the LPS challenge, the remaining animals (n=6, each group) were subjected to the Y-maze task, and the expression and localization of GluA1-containing AMPA-Rs in their hippocampi were investigated immunohistochemically.

Results: Pretreatment with RV prevented LPS-induced cognitive dysfunction in rats and enhanced their working memory performance. Moreover, RV could moderately prevent oxidant-antioxidant imbalance in rats’ hippocampi. RT-PCR results revealed that the hippocampal mRNA expression of the Gria1 was significantly reduced, while the expressions of Gria2 and Gria3 were increased in LPS-challenged rats. RV significantly modulated the alteration in the Gria1 mRNA expression; however, it could not influence the Gria2 and Gria3 mRNA expressions. The immunohistochemical assessment showed a significantly reduced immunoreactivity for GluA1- containing AMPA-Rs in all hippocampal subfields of the LPS group, and RV could effectively ameliorate the alteration.

Conclusion: This study is the first to report that RV could modulate GluA1-containing AMPA-Rs dysregulation in a rat AD model.