Metformin Improves Cognitive Function in a Rat Model of Global Cerebral Ischemia/Reperfusion Injury Via Inhibiting NF-kb Signaling Pathway and Caspase-1/NLRP3 Inflammasome.

Abstract

Ischemic stroke is among the important causes of death globally, with many survivors experiencing considerable cognitive deficits. This study explored metformin (Met)'s therapeutic effects in a global cerebral ischemia-reperfusion (I/R) injury model in male rats. One hundred and twelve rats randomly divided into four groups were subjected to a global cerebral I/R or sham surgery followed by 2 weeks of metformin treatment. We induced global cerebral ischemia in rats by employing a four-vessel occlusion (4VO) model, which lasted for 20 min. Before occlusion, just removing the small vessel clips and 72 h later, the EEG recording was done to establish the global cerebral ischemia. After 14 days of treatment with metformin, EEG recording and behavioral tests were conducted. After that, the hippocampus was harvested for biochemical analysis to evaluate potential inflammatory damages, NLRP3 inflammasome activity, and histopathological examinations in all tested groups. The I/R event caused impairment of the EEG and cognition. The inflammasome (NLRP3) complex activation is linked to a stroked damage in hippocampal and cortical cells, leading to memory deficits. Activation of NF-kB is associated with the overproduction of pro-inflammatory cytokines such as IL-1β and IL-18. Notably, 2 weeks of Met administration, following the I/R event demonstrated improvement in the EEG power as a therapeutic effect. It had a substantial impact on memory performance, led to a decrease in behaviors resembling memory impairment, and resulted in an increase in exploratory activities. The data indicate that the Met treatment alleviated cognitive impairments and decreased pro-inflammatory factors and inflammation.