Aquaporins in brain edema

Abstract

Brain edema is a common feature of brain injuries, which leads to increased intracranial pressure (ICP) and ischemia that worsen outcome. Current management of edema focuses on reduction of ICP, but there are no treatments targeting the molecular players directly involved in edema process. The perivascular astrocyte endfeet are critical in maintaining brain homeostasis with ionic and water exchange; in this context, aquaporins (AQPs), astrocyte water channels, have emerged as privileged targets for edema modulation. However, AQPs can facilitate either accumulation or drainage of water, depending on the osmotic gradients between extra‐intracellular space; and thus inhibition of AQPs leads to different outcomes depending on specific tissue characteristics and time post‐injury. Most of this knowledge has been gathered from the study of AQP4, the best characterized AQP and the one that has the biggest impact on water movement. In addition to the level of expression, the ratio of AQP4 isoforms (m1, m23 or mz), the spatial distribution of AQP4 into orthogonal arrays of particles, and the interaction of AQP4 with neighboring ionic channels and gap junctions could directly impact edema formation. Although there are no specific AQP4 pharmacological blockers, the development of AQP4 siRNA offers a promising therapeutic tool. Given the complex dynamics of AQP4, therapies targeting AQP4 should carefully take into account the particular features of the injury (e.g., hemorrhagic vs. non‐hemorrhagic) and different times after injury (e.g., phase of edema formation vs. resolution).

Cerebrospinal fluid flow. Part 2. Aquaporins and their role in CNS water homeostasis

“…Ряд недавних исследований подтвердили участие AQP4 в активности Ca 2+ -сигнальной системы в астроцитах [86]. Ингибирование синтеза AQP4 угнетает вызванную гипоосмотическим http://theunj.org экспрессии AQP4 [96]. По мнению Ying Hsu и соавт., на этом этапе AQP4 облегчает удаление избытка жидкости из паренхимы мозга [98].…”

“…Как отмечено выше, AQP4 играет важную роль в морфогенезе отека мозга, что подробно изучено при моделировании нокаута гена AQP4 [96]. Согласно современным представлениям, отек мозга можно условно разделить на три основных этапа: аноксический или бескислородный, ионный и вазогенный [56].…”

17th international conference on Brain Edema and Cellular Injury

“…These molecular mechanisms might contribute to the pathological accumulation of water in the brain after injury. In this regard, astrocytic water channels, aquaporins (AQPs), have been proposed to be a key player in water accumulation and thought to be a potential candidate for drug development to limit edema formation post‐injury (Clement, Rodriguez‐Grande, & Badaut, ). Due to the molecular complexity of injury, water channel inhibition is not suitable at all time points or in all injury subtypes.…”

“…Due to the molecular complexity of injury, water channel inhibition is not suitable at all time points or in all injury subtypes. Moreover, AQP4 is coupled with other ionic channels or with gap junctions and participate in water accumulation and in neuroinflammation, adding another layer of intricacy (Clement, Rodriguez‐Grande, & Badaut, ). In the theme of edema and neuroinflammation, several preclinical studies that identify molecular targets in the potential treatment of TBI are discussed in a review by Sulhan and collaborators (Sulhan, Lyon, Shapiro, & Huang, ).…”

Aquaporin Expression, Regulation and Function in the Intervertebral Disc

“…The expression of specific AQP isoforms within specific tissues also alludes to their potential roles. AQPs have been shown to regulate many processes such as cell volume regulation ; cell structure and adhesion (Varadaraj and Kumari, 2018); cell migration and proliferation (Papadopoulos, Saadoun and Verkman, 2008); water homeostasis in the kidney (Hasler et al, 2008); blood-brain barrier function (Clément, Rodriguez-Grande and Badaut, 2018); lens function (Schey et al, 2017); fluid secretion (Ramli et al, 2019); sperm motility (Laforenza et al, 2016;Fujii et al, 2018); and glycerol metabolism (Méndez-Giménez et al, 2018). As such, alteration to AQP expression and function has also been implicated in the pathophysiology of many disorders, including: renal water imbalance (Kortenoeven and Fenton, 2014); brain oedema (Clément, Rodriguez-Grande and Badaut, 2018); cataract formation (Biswas et al, 2014); infertility (Kasimanickam et al, 2017); and cancer metastasis (Marlar et al, 2017) (Day et al, 2014).…”