TIGAR alleviates cognitive impairment in rats with chronic cerebral hypoperfusion by suppressing oxidative stress and pyroptosis

Background: It is postulated that oxidative stress and pyroptosis, which are induced by chronic cerebral hypoperfusion (CCH), contribute to the pathogenesis of vascular cognitive impairment (VCI). The protective role of TIGAR in neurologic illnesses has been the subject of extensive examination, yet its role in models of CCH-induced cognitive impairment remains unexplored. The objective of this study was to ascertain whether TIGAR is a neuroprotective agent in rats with CCH that reduces oxidative stress and pyroptosis. Methods: A CCH model was established in rats through the use of bilateral common carotid artery occlusion (BCCAO). The effects of TIGAR on cognitive function and anxiety-depressive behaviors in rats with CCH were examined. To this end, the Y-maze and open field tests were employed. Nissl and hematoxylin-eosin (H&E) staining were used to assess histologic changes in the CA1 area of the hippocampus. Hippocampal glutathione (GSH) activity, malondialdehyde (MDA) content, and NADPH/NADP+ ratio were measured using the WST-8 colorimetric method to assess oxidative stress. The expression of TIGAR and pyroptosis-related proteins was assessed by western blotting. Results: A model of CCH-induced cognitive impairment was successfully established. Four weeks after BCCAO, cerebral blood flow returned to normal in the rats, and cognitive impairment and anxiety-depression-like behavior developed. In rats with CCH, MDA levels increased, GSH activity and NADPH/NADP+ ratio decreased, and pyroptosis-related protein expression increased. The pathologic findings indicated that there was an exacerbation of neuronal injury in the CA1 area of the hippocampus and that the cells were loosely arranged. In rats with CCH, overexpression of TIGAR reduced pyroptosis-associated protein expression while increasing MDA content, GSH activity, and NADPH/NADP+ ratio. It promoted neuronal cell survival, and improved cognitive function and anxiety-depression-like behavior. Conclusion: Overexpression of TIGAR reduced CCH-induced oxidative stress and pyroptosis and ameliorated cognitive dysfunction and anxiety-depression-like behavior in rats. These findings suggest that TIGAR counteracts oxidative stress and prevents pyroptosis, making it a promising target for the treatment of VCI.