Expert opinion on therapeutic targetsOct 27, 2017

The water channel aquaporin-4 as a possible drug target in brain disorders

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 6, 2026

Abstract

A biologic called aquaporumab is in development for neuromyelitis optica, an autoimmune disease linked to AQP4 autoantibodies.

Aquaporin-4 (AQP4) is crucial for water transport in the brain and is associated with brain water balance and several neurological conditions.
Analysis of AQP4 knockout mice indicates its potential roles in neuroexcitation, glial scarring, and neuroinflammation.
There is speculation about the clinical utility of AQP4 modulators, particularly for early treatment of ischemic stroke.
Challenges in developing AQP4 inhibitors include poor druggability, the presence of homologous AQP isoforms, and the need for effective blood-brain barrier penetration.
Despite significant research efforts, no validated small-molecule AQP4 inhibitors have been advanced to date.

Simplified

Aquaporin-4 (AQP4) is a water transporting protein expressed at the plasma membrane of astrocytes throughout the central nervous system (CNS). Analysis of AQP4 knockout mice has suggested its broad involvement in brain water balance, neuroexcitation, glial scarring, neuroinflammation, and even neurodegenerative and neuropsychiatric disorders. Broad clinical utility of AQP4 modulators has been speculated. Area covered: This review covers the biology of AQP4, evidence for its roles in normal CNS function and neurological disorders, and progress in AQP4 drug discovery. Expert opinion: Critical examination of available data reduces the lengthy potential applications list to AQP4 inhibitors for early therapy of ischemic stroke and perhaps for reduction of glial scarring following CNS injury. Major challenges in identification and clinical development of AQP4 inhibitors include the apparent poor druggability of AQPs, the many homologous AQP isoforms with broad tissue distribution and functions, technical issues with water transport assays, predicted undesired CNS and non-CNS actions, and the need for high blood-brain barrier permeation. To date, despite considerable effort, validated small-molecule AQP4 inhibitors have not been advanced. However, a biologic ('aquaporumab') is in development for neuromyelitis optica, an autoimmune inflammatory demyelinating disease where CNS pathology is initiated by binding of anti-AQP4 autoantibodies to astrocyte AQP4.

Full Text

Full text is available at the source.

View Full Text ↗

Funding

Competing interests

Declaration of Interest. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

PubMed

The water channel aquaporin-4 as a possible drug target in brain disorders

Abstract

Full Text

Funding

Competing interests

You found one interesting study. We’ll send the next 7.

What Lands in Your Inbox Each Week:

Recent issues from the circadian biology brief