The aquaporin-4 water channel as a potential drug target in neurological disorders

Abstract

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.

The Pattern of AQP4 Expression in the Ageing Human Brain and in Cerebral Amyloid Angiopathy

“…Responses within the brain through expression of AQP4 appear to be lost with advancement of disease to severe CAA. A clear picture of how the pattern of immunocytochemistry of AQP4 changes in the grey and white matter in health and disease will advance our knowledge of how best to target AQP4 for rebalancing levels of fluid and solutes in the brain in CAA and Alzheimer's disease [47].…”

Regulation of AQP4 in the Central Nervous System

“…While 13 unique AQPs have been identified in the human body thus far, aquaporin-4 (AQP4) has become an interesting therapeutic target in various neurological disorders, due to its variety of functions and widespread expression in the nervous system [3]. AQP4 is the predominant water channel protein in the mammalian brain [4], and is expressed in astrocytes throughout the central nervous system [5]. In particular, AQP4 is located at the end-feet of astrocytic processes [6], which allows it to control nervous system water homeostasis via its involvement in water movement across the blood brain barrier [7].…”

“…In cerebral edema and ischemia, AQP4 expression is increased [15,16], and inhibition of AQP4 activity, either by knockout or pretreatment with an inhibitor has been shown to cause a reduction in edema size and formation [7,[17][18][19]. However, in vasogenic edema the loss of AQP4 activity actually aggravates the condition, due to the loss of ability to remove excess water from the brain tissue [2,5,16]. In glioblastomas and astrocytomas, AQP4 is upregulated and redistributed, showing a loss of polarized distribution in the end-feet of high grade tumors [12,[20][21][22].…”

“…Finally, AQP4 has been shown to have many roles in Alzheimer's disease, including possibly mediating the clearance of amyloid-β [36][37][38][39], and AQP4 deficiency leads to impaired learning and memory via disruption of both the glutamate transport pathway and K + ion homeostasis [40][41][42][43]. With the increase in interest in AQP4 as a potential therapeutic target [1,5,16,19], and the implications AQP4 activity has on many neurological disorders [7,14,[16][17][18][21][22][23]25,[30][31][32][33][34]42,43], it is important to have a clear understanding of the myriad of ways in which AQP4 is known to be regulated.…”

Experimental animal models of aquaporin‐4‐IgG‐seropositive neuromyelitis optica spectrum disorders: progress and shortcomings

“…32]. AQP4 is considered to be an attractive drug target for various neurological conditions such as ischemic stroke, though at present there are no validated AQP4 inhibitors .…”