Kisspeptin-10 Preserves the Blood-Brain Barrier's Integrity Post-Stroke by Augmenting Claudin-10 Expression

The integrity of the Blood-Brain Barrier (BBB) is crucial in the pathophysiological progression of acute ischemic stroke (AIS). However, the potential of Kisspeptin-10 (Kp-10), with its antioxidant and anti-inflammatory properties, has not been explored experimentally in the context of stroke management. This study aimed to investigate the neurovascular protective effects of Kp-10 following cerebral ischemia using both in vivo and in vitro models. A middle cerebral artery occlusion (MCAO) model was established in C57BL/6 mice, followed by Kp-10 administration. Neurological deficits (Longa score), infarct volume (TTC staining), BBB permeability (14C-Sucrose), and Claudin-10 expression (qRT-PCR and immunohistochemistry) were assessed to evaluate the therapeutic effects of Kp-10. Human brain microvascular endothelial cells (HBMVECs) were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) to mimic ischemic conditions. Endothelial permeability, oxidative stress (OS), and nuclear factor erythroid 2-related factor 2 (Nrf2) levels were evaluated. Nrf2 silencing was performed to validate its role in Kp-10-mediated protection. Initially, we observed a significant reduction in Kp-10 expression within the cortical tissue of mice subjected to MCAO. Subsequent administration of Kp-10 not only alleviated neurological deficits but also significantly mitigated blood-brain barrier (BBB) dysfunction following stroke induction, as evidenced by reduced 14C-sucrose leakage. Furthermore, Kp-10 treatment led to an upregulation of Claudin-10 expression in the post-stroke cortical region. In our in vitro experiments, we employed HBMVECs exposed to OGD/R to simulate ischemic conditions. We found that Kp-10 effectively reduced OGD/R-induced endothelial permeability by enhancing Claudin-10 expression. Additionally, Kp-10 exhibited antioxidant capabilities by decreasing mitochondrial reactive oxygen species (ROS) levels, increasing superoxide dismutase (SOD) activity, and upregulating nuclear factor erythroid 2-related factor 2 (Nrf2) expression. Notably, when Nrf2 was knocked down in HBMVECs, the protective effects of Kp-10 on endothelial permeability and Claudin-10 expression were abolished, indicating that the beneficial actions of Kp-10 are mediated through the Nrf2 pathway. In conclusion, our findings suggest that Kp-10 holds promise as a therapeutic strategy to preserve BBB integrity and promote neuroprotection following stroke, acting primarily via the Nrf2 signalling pathway. These findings suggest that Kp-10 may represent a promising therapeutic strategy for preserving BBB integrity following ischemic stroke.