Morphologic aspects of ethanol-induced changes in the glymphatic system and their effect on nervous system func-tion

The glymphatic system, a perivascular network responsible for the exchange of cerebrospinal (CSF) and interstitial (ISR) fluids, plays a critical role in the clearance of metabolic wastes, particularly neurotoxic proteins such as β-amyloid and microtubule-associated protein tau (MAPT). Disruption of its function is commonly associated with neurodegenerative diseases, including Alzheimer's disease. However, ethanol (C₂H₅OH), a widespread neurotoxic substance, has also been shown to cause profound structural and functional changes in the central nervous system (CNS); in particular, its effect on the glymphatic system cannot be ruled out, which is still poorly understood. This review examines ethanol-induced morpho-histological changes in the glymphatic pathways, focusing on astrocyte integrity, aquaporin-4 (AQP4) mislocalization, perivascular inflammation, and vascular dysfunction. A systematic review of available studies shows that ethanol consumption leads to redistribution of AQP4 away from perivascular astrocytic endings, impairing glymphatic flow and reducing the efficiency of waste clearance. Thus, histopathologic evidence suggests ethanol-induced gliosis (pathologic overgrowth of glial cells in the CNS), neuroinflammation, and oxidative stress further exacerbate glymphatic dysfunction. In addition, ethanol disrupts basic mechanisms of sleep, which in turn as a process is a critical regulator of glymphatic activity; thereby exacerbating the adverse effects on CNS homeostasis. These mechanisms suggest a potential link between chronic ethanol exposure and accelerated progression of neurodegenerative diseases associated with glymphatic dysfunction. Despite the accumulating evidence of ethanol's neurotoxicity, studies directly addressing its effects on the glymphatic system at the tissue-cellular level remain scarce. Future research, which is extremely promising, should focus on elucidating the reversibility of ethanol-induced glymphatic disturbances and identifying potential pharmacological and behavioral interventions to mitigate their effects. Understanding these interrelationships of these processes, as well as their overall analysis and awareness, is necessary for the development of targeted neuroprotective strategies, especially in populations with chronic alcohol use.