Investigation of the neuroprotective potential of ranolazine at different doses in an experimental cerebral ischemia reperfusion injury model in rats.

Introduction and Aim: Cerebral ischemia is defined as the inability to provide sufficient oxygenation to neural tissue, meet its metabolic demands, and remove toxic metabolites due to a reduction or complete cessation of blood flow to the brain. Ischemic stroke is a significant cause of morbidity and mortality. The majority of ischemic strokes occur in regions supplied by the middle cerebral artery (MCA). Due to the limited use of mechanical thrombectomy and tissue plasminogen activator, efforts are being made to expand new treatment protocols. In this context, we investigated whether Ranolazine, an antianginal drug, has neuroprotective effects at different doses in rats subjected to ischemia-reperfusion (IR) injury induced by the Intraluminal Middle Cerebral Artery Occlusion (iMCAO) model. Materials and Methods: In this study, 47 male Sprague Dawley rats weighing 250 ± 20 g were used (n=10). The rats were randomly divided into 5 groups: Sham Operated, MCAO, MCAO+RAN10, MCAO+RAN30, and MCAO+RAN50. In the groups subjected to the MCAO model, ischemia was induced for 90 minutes, followed by reperfusion. The first doses of Ranolazine were administered after reperfusion, and subsequent doses were given intraperitoneally at 24-hour intervals for a total of 21 days. At the end of the experiment, the rats were sacrificed via intracardiac blood collection to obtain serum and brain tissues. Sections obtained from the brain tissues were stained with Hematoxylin & Eosin, and changes that occurred secondary to IR injury in the MCA irrigation area were evaluated. The damage in the sections was scored as the number of apoptotic cells and the severity of neuronal degeneration. Additionally, serum levels of APELA, APL13, and SIRT1 were analyzed using ELISA method. Results: In our study, histopathological examination of the cerebrum of sacrificed rats revealed normal neuroglial tissue and a low number of apoptotic cells in the Sham Operated group. Hemorrhage, neurodegeneration, increased apoptotic cells and chronic dystrophic calcification were observed in the ischemia group. In the treatment groups, particularly in the MCAO+RAN50 group, neurodegenerative damage was more severe. SIRT1, APELA, and APL 13 serum levels were correlated with the histopathological findings and statistically evaluated. A significant correlation was observed between the histopathological data and the serum ELISA results. Conclusion: The effects of Ranolazine on cerebral ischemia-reperfusion injury were investigated, and all results were evaluated. No neuroprotective effects of Ranolazine were observed; instead, it was found to cause greater degeneration at higher doses. Key words: MCAO, Ranolazin, SIRT1, APELA, APL13