Jha Ruchira M, Rani Anupama, Desai Shashvat M, Raikwar Sudhanshu, Mihaljevic Sandra, Munoz-Casabella Amanda, Kochanek Patrick M, Catapano Joshua, Winkler Ethan, Citerio Giuseppe, Hemphill J Claude, Kimberly W Taylor, Narayan Raj, Sahuquillo Juan, Sheth Kevin N, Simard J Marc
Department of Neurology, Barrow Neurological Institute and St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
Department of Translational Neuroscience, Barrow Neurological Institute and St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
Int J Mol Sci. 2021 Nov 2;22(21):11899. doi: 10.3390/ijms222111899.
Sulfonylurea receptor 1 (SUR1) is a member of the adenosine triphosphate (ATP)-binding cassette (ABC) protein superfamily, encoded by Abcc8, and is recognized as a key mediator of central nervous system (CNS) cellular swelling via the transient receptor potential melastatin 4 (TRPM4) channel. Discovered approximately 20 years ago, this channel is normally absent in the CNS but is transcriptionally upregulated after CNS injury. A comprehensive review on the pathophysiology and role of SUR1 in the CNS was published in 2012. Since then, the breadth and depth of understanding of the involvement of this channel in secondary injury has undergone exponential growth: SUR1-TRPM4 inhibition has been shown to decrease cerebral edema and hemorrhage progression in multiple preclinical models as well as in early clinical studies across a range of CNS diseases including ischemic stroke, traumatic brain injury, cardiac arrest, subarachnoid hemorrhage, spinal cord injury, intracerebral hemorrhage, multiple sclerosis, encephalitis, neuromalignancies, pain, liver failure, status epilepticus, retinopathies and HIV-associated neurocognitive disorder. Given these substantial developments, combined with the timeliness of ongoing clinical trials of SUR1 inhibition, now, another decade later, we review advances pertaining to SUR1-TRPM4 pathobiology in this spectrum of CNS disease-providing an overview of the journey from patch-clamp experiments to phase III trials.
磺脲类受体1（SUR1）是三磷酸腺苷（ATP）结合盒（ABC）蛋白超家族的成员，由Abcc8编码，被认为是通过瞬时受体电位褪黑素4（TRPM4）通道介导中枢神经系统（CNS）细胞肿胀的关键介质。该通道大约在20年前被发现，正常情况下在中枢神经系统中不存在，但在中枢神经系统损伤后会转录上调。2012年发表了一篇关于SUR1在中枢神经系统中的病理生理学和作用的全面综述。从那时起，对该通道在继发性损伤中所起作用的理解在广度和深度上呈指数级增长：在多种临床前模型以及包括缺血性中风、创伤性脑损伤、心脏骤停、蛛网膜下腔出血、脊髓损伤、脑出血、多发性硬化症、脑炎、神经恶性肿瘤、疼痛、肝功能衰竭、癫痫持续状态、视网膜病变和HIV相关神经认知障碍在内的一系列中枢神经系统疾病的早期临床研究中，抑制SUR1-TRPM4已被证明可减轻脑水肿和出血进展。鉴于这些重大进展，再加上目前正在进行的SUR1抑制临床试验的及时性，现在，在又一个十年之后，我们回顾了在这一系列中枢神经系统疾病中与SUR1-TRPM4病理生物学相关的进展——概述了从膜片钳实验到III期试验的历程。
