Alcohol promotes waste clearance in the CNS via brain vascular reactivity

The efficient clearance of the interstitial waste metabolites is essential for the normal maintenance of brain homeostasis. The brain lacks the lymphatic clearance system. Thus, the drainage of waste metabolites in the brain is dependent on a slow flow of cerebrospinal fluid (CSF) system. Glymphatic system claims the direct bulk flow transport of small size water-soluble waste metabolites into to the perivenous space by aquaporin-4 water channels of the astrocyte end-feet, but it did not address the diffusive clearance of large size waste metabolites. Here, we addressed the clearance mechanisms of large size waste metabolites from interstitial fluid to perivascular space as well as from CSF subarachnoid into perivascular space via the paravascular drainage. A low dose ethanol acting as a potent vasodilator promotes the dynamic clearance of waste metabolites through this perivascular-perivenous drainage path. We observed that ethanol-induced increased in vascular endothelial and smooth muscle cell reactivity regulated the enhanced clearance of metabolites. Here, activation of endothelial specific nitric oxide synthase (eNOS) by ethanol and generation of vasodilator nitric oxide mediates the interactive reactivity of endothelial-smooth muscle cells and subsequent diffusion of the CNS waste metabolites towards perivascular space. Detection of tracer dye (waste metabolite) in the perivenous space and in the blood samples further confirmed the improved clearance of waste metabolites through this unraveled interstitial-perivascular-perivenous clearance path. Our results suggest that alcohol intake at low-dose levels may promote clearance of neurological disease associated entangled proteins.