# Alcohol Promotes Waste Metabolites Clearance in the CNS

> **NIH NIH R21** · NEW JERSEY INSTITUTE OF TECHNOLOGY · 2020 · $179,711

## Abstract

Abstract:
Application is submitted here in response to PA-17-296. The efficient clearance of waste metabolites is compromised in
the brain due to lack of lymphatic system and cerebrospinal fluid (CSF) is not able to clear large size waste metabolites.
Recent discovery of glymphatic system is able to transport small size water-soluble waste metabolites directly to
perivenous space by aquaporin-4 water channels of the astrocyte end-feet. Thus, unravelling the mechanisms of clearing
large size waste metabolites in the CNS become significant for therapeutic prevention of neurological diseases associated
with entangled proteins. Here, we propose to address the clearance mechanisms of fluorescent labeled -amyloid protein
from interstitial fluid to perivascular space or from CSF subarachnoid into perivenous drainage through perivascular
clearance path. We propose that this dynamic perivascular-perivenous drainage path is significantly promoted by low
dose alcohol (ethanol), and not by high dose or chronic alcohol use. Our working hypothesis is that activation of cerebral
arterial endothelial specific nitric oxide synthase (eNOS) by alcohol (5 mM) led to generation of a potent vasodilator
nitric oxide, which mediates the interactive reactivity of endothelial-smooth muscle cells and subsequent inter-convective
movement of waste metabolites towards perivascular space. We will address the hypothesis, first, by establishing the
existence of perivascular clearance path and how alcohol promotes this drainage path, and second by evaluating the
underlying molecular mechanisms of perivascular clearance by alcohol-elicited endothelial NO that promotes endothelial-
smooth muscle cells dilative reactivity and subsequent waste metabolites clearance. Knowledge gained from this project
is expected to bear a significant impact for possible prevention of neurological disorders such as cerebral amyloid
angiopathy and Alzheimer's disease.

## Key facts

- **NIH application ID:** 9956122
- **Project number:** 1R21AA028340-01
- **Recipient organization:** NEW JERSEY INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** James Haorah
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $179,711
- **Award type:** 1
- **Project period:** 2020-04-10 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9956122

## Citation

> US National Institutes of Health, RePORTER application 9956122, Alcohol Promotes Waste Metabolites Clearance in the CNS (1R21AA028340-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9956122. Licensed CC0.

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