Impaired Flow: Glymphatic Dysfunction in Ischemic Stroke and the Influence of Sex.

Abstract

The glymphatic system, essential for the clearance of metabolic waste from the brain, plays a complex role in the context of ischemic stroke (IS), influencing both the acute phase and long-term recovery. Following IS, impairment in cerebrospinal fluid (CSF) flow and in the clearance of neurotoxic substances, such as beta-amyloid and tau proteins, is observed. This dysfunction contributes to the accumulation of waste products in the brain parenchyma, increasing the risk of complications such as post-stroke dementia and depression. Several mechanisms are involved in this process, including perivascular space dilation, changes in aquaporin-4 expression and polarization, and the presence of reactive astrogliosis, all of which further compromise glymphatic function. These factors are also directly associated with the development of cerebral edema, a critical complication that exacerbates the severity of IS. Moreover, growing evidence suggests that biological sex may influence the glymphatic system's response to IS. Studies indicate that women may exhibit a more efficient glymphatic response, potentially mediated by hormones such as estrogen, which could offer greater protection against the deleterious effects of cerebral ischemia. However, further research is needed to confirm this hypothesis and to better understand the mechanisms underlying this sex-based difference. This review article aims to compile and critically discuss current evidence regarding the role of the glymphatic system in IS pathophysiology, also highlighting potential sex-related differences and their implications for future therapeutic approaches.