Investigation of the effect of the melatonin agonist agomelatine on cerebral ischemia parameters in an experimental subarachnoid hemorrhage model

Subarachnoid hemorrhage (SAH) refers to bleeding that occurs within the subarachnoid space, usually due to arterial and rarely venous causes. Subsequent physiopathological events such as oxidative stress, neuroinflammation, and apoptosis lead to cerebral vasospasm (CV), a major cause of mortality and morbidity. The presence of blood and its products in the subarachnoid space, such as oxyhemoglobin (OxHb) released from erythrocytes, causes cerebral vasospasm through various direct and indirect pathways. These oxidative stress products damage the cell's main structures, including lipids, proteins, and nucleic acids, causing neuronal damage, cellular apoptosis, endothelial damage, and disruptions in the blood-brain barrier (BBB) through necrosis or apoptosis. The damage worsens due to delayed and insufficient antioxidant mechanisms. In this study, a total of 46 male Wistar albino rats were used, divided into 5 groups: control (n=8), SHAM (n=10), SAH (n=10), SAH+AGM (n=10), and AGM (n=8). In the SHAM group, 0.3 ml of saline was injected into the cisterna magna region, whereas in the SAH and SAH+AGM groups, 0.3 ml of autologous blood from the tail artery was injected to create an experimental SAH model. AGM was administered orally by gavage to the SAH+AGM and AGM groups for 7 days. The experiment ended with sacrifice 7 days after the last AGM administration. Brain tissue was sectioned into three parts for oxidative stress parameters (TAS, TOS, OSI), genetic (SIRT-1/PGC1α/Bcl-2/Bax), and histopathological (Caspase-3, TNF-α, VEGF) analyses. The study found that TOS and OSI values, indicators of oxidative stress, were significantly higher in the SAH group compared to the control, SHAM, and AGM groups, but significantly lower in the SAH+AGM group compared to the SAH group. TAS values were lower in the SAH group compared to the control, SHAM, and AGM groups but increased in the SAH+AGM group compared to these groups, with a significant increase in TAS expressions in the SAH+AGM group compared to the SAH group. PGC-1 alpha and SIRT-1 gene expressions significantly increased in the SAH+AGM group compared to the SAH group, indicating a positive effect of AGM. BAX expression decreased, and antiapoptotic BCL2 expression increased in the SAH+AGM group, suggesting that AGM reduces cell death. The results for VEGF (Vascular Endothelial Growth Factor), TNF-α (Tumor Necrosis Factor Alpha), and Cas-3 (Caspase-3) indicate that SAH causes significant pathological findings in the brain, and AGM treatments reduce these lesions.