Exploring cell membrane water exchange in aquaporin-4-deficient ischemic mouse brain using diffusion-weighted MRI

Takuya Urushihata,Nobuhiro Nitta,Makoto Higuchi,Yasuhiko Tachibana,Masato Yasui,Sayaka Shibata,Jeff Kershaw,Manami Takahashi,Hiroyuki Takuwa,Takayuki Obata

doi:10.1186/s41747-021-00244-y

Abstract

BackgroundAquaporin-4 is a membrane channel protein that is highly expressed in brain astrocytes and facilitates the transport of water molecules. It has been suggested that suppression of aquaporin-4 function may be an effective treatment for reducing cellular edema after cerebral infarction. It is therefore important to develop clinically applicable measurement systems to evaluate and better understand the effects of aquaporin-4 suppression on the living body.MethodsAnimal models of focal cerebral ischemia were created by surgically occluding the middle cerebral artery of wild-type and aquaporin-4 knockout mice, after which multi-b-value multi-diffusion-time diffusion-weighted imaging measurements were performed. Data were analyzed with both the apparent diffusion coefficient (ADC) model and a compartmental water-exchange model.ResultsADCs were estimated for five different b value ranges. The ADC of aquaporin-4 knockout mice in the contralateral region was significantly higher than that of wild-type mice for each range. In contrast, aquaporin-4 knockout mice had significantly lower ADC than wild-type mice in ischemic tissue for each b-value range. Genotype-dependent differences in the ADC were particularly significant for the lowest ranges in normal tissue and for the highest ranges in ischemic tissue. The ADCs measured at different diffusion times were significantly different for both genotypes. Fitting of the water-exchange model to the ischemic region data found that the water-exchange time in aquaporin-4 knockout mice was approximately 2.5 times longer than that in wild-type mice.ConclusionsMulti-b-value multi-diffusion-time diffusion-weighted imaging may be useful for in vivo research and clinical diagnosis of aquaporin-4-related diseases.

Highlights

Aquaporin-4 is a membrane channel protein that is highly expressed in brain astrocytes and facilitates the transport of water molecules
In studies using animal models, aquaporin-4 expression is sharply increased in ischemic brain edema [22, 23], and aquaporin-4 knockout or inhibitor administration has been shown to be effective in reducing cellular edema [8, 24,25,26]
apparent diffusion coefficient (ADC) were estimated for five different b value ranges: 0–2,000 s/mm2, which is used in general clinical practice; 500–2,000 s/mm2, where it is thought the effect of the intravoxel incoherent motion (IVIM) component is suppressed; and 2,000–4,000, 4,000–6,000, and 6,000–8,000 s/mm2, which are ranges where the restricted diffusion component is expected to be dominant

Summary

Introduction

Aquaporin-4 is a membrane channel protein that is highly expressed in brain astrocytes and facilitates the transport of water molecules. It has been reported that aquaporin-4 is involved in brain diseases such as ischemic stroke [7, 8], hydrocephalus [9, 10], Alzheimer’s disease [11,12,13], amyotrophic lateral sclerosis [14], traumatic brain injury [15], and epilepsy [16, 17]. These findings have led to the design of treatment strategies that target aquaporin4 [18, 19]. A clinically applicable method that can reliably evaluate changes in cytotoxic edema caused by aquaporin-4 inhibition is needed for the future development of suitable drugs and other therapies

Methods

Results

Conclusion