Enhancing Glymphatic Transport via Vasopressin: Implications for Neurodegenerative Disease and Drug Delivery
Eman Hamed1, Mingxiao Zhang2, Shreyan Majumdar2, Harsha Namburi2, Hanifa Mohammed2, Jennifer Mitchell2, Martha Gillette2
1New York University, 2University of Illinois at Urbana Champaign
Objective:
This study investigates whether arginine vasopressin modulates glymphatic flow in a circadian-dependent manner and restores flow after circadian disruption in the hippocampus. Using Glymph-FIT, a novel model for slow-flow DCE-MRI, we also assess the effects of AVP and V1A receptor antagonist Relcovaptan on glymphatic dynamics.
Background:
The glymphatic system clears metabolic waste from the brain via CSF flow through perivascular spaces, regulated by aquaporin-4 channels. Impaired glymphatic function is linked to neurodegenerative diseases like Alzheimer’s. Arginine vasopressin, a neuropeptide involved in fluid homeostasis, may modulate glymphatic flow.
Design/Methods:
Using confocal microscopy and/or DCE-MRI, we assessed AVP and Relcovaptan effects on glymphatic transport in Long-Evans/BluGill rats. Intracisternal injection of MultiHance® was given at 1.6 µL/min. Imaging was done using 9.4T scanner with 3D T1-weighted FLASH sequences for 2 hours. Images were processed with ITK-SNAP and registered to Waxholm Atlas. Glymph-FIT, quantified tracer kinetics in whole brain and hippocampal regions.
Results:
AVP enhanced glymphatic flow in the hippocampus, with diurnal variation observed. AVP also downregulated AQP4 expression in the hippocampus. After circadian disruption, glymphatic flow was diminished within the hippocampus. AVP restored glymphatic flow following circadian disruption. Glymphatic peak intensity increased using V1A receptor blockade by Relcovaptan, indicating possible partial AVP effects via alternative pathways. Whole-brain and hippocampal MRI analyses revealed significant increases in peak signal intensity under both AVP and Relcovaptan, confirming modulatory effects on glymphatic dynamics.
Conclusions:
AVP enhances glymphatic flow in the hippocampus in a circadian-dependent manner, modulating CSF transport and AQP4 expression. V1A receptor blockade enhanced glymphatic peak signal intensity, suggesting alternative vasopressin pathways. These findings position AVP signaling as a potential target for improving glymphatic clearance, drug delivery, and neurodegenerative outcomes. Glymph-FIT effectively captured slow glymphatic dynamics, supporting its utility in future brain clearance research.
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