Proton-sensitive cation channels and ion exchangers in ischemic brain injury: new therapeutic targets for stroke?
Ischemic brain injury results from complicated cellular mechanisms. The present therapy for acute ischemic stroke is limited to thrombolysis with the recombinant tissue plasminogen activator (rtPA) and mechanical recanalization. Therefore, a better understanding of ischemic brain injury is needed for the development of more effective therapies. Disruption of ionic homeostasis plays an important role in cell death following cerebral ischemia. Glutamate receptor-mediated ionic imbalance and neurotoxicity have been well established in cerebral ischemia after stroke. However, non-NMDA receptor-dependent mechanisms, involving acid-sensing ion channel 1a (ASIC1a), transient receptor potential melastatin 7 (TRPM7), and Na(+)/H(+) exchanger isoform 1 (NHE1), have recently emerged as important players in the dysregulation of ionic homeostasis in the CNS under ischemic conditions. These H(+)-sensitive channels and/or exchangers are expressed in the majority of cell types of the neurovascular unit. Sustained activation of these proteins causes excessive influx of cations, such as Ca(2+), Na(+), and Zn(2+), and leads to ischemic reperfusion brain injury. In this review, we summarize recent pre-clinical experimental research findings on how these channels/exchangers are regulated in both in vitro and in vivo models of cerebral ischemia. The blockade or transgenic knockdown of these proteins was shown to be neuroprotective in these ischemia models. Taken together, these non-NMDA receptor-dependent mechanisms may serve as novel therapeutic targets for stroke intervention.
Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA 30310, USA.
Tiandong
T
Leng
Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Yejie
Y
Shi
Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA 30310, USA. Electronic address: zxiong@msm.edu.
Zhi-Gang
ZG
Xiong
Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA; Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Educational and Clinical Center, Pittsburgh, PA 15213, USA. Electronic address: sund@upmc.edu.
Dandan
D
Sun
D062565:Acid Sensing Ion Channels / Q000378:metabolism*; D000818:Animals; D001930:Brain Injuries / Q000209:etiology / Q000503:physiopathology / Q000628:therapy; D002545:Brain Ischemia / Q000150:complications*; D027682:Cation Transport Proteins / Q000378:metabolism*; D006801:Humans; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D050053:TRPM Cation Channels / Q000378:metabolism
D062565:Acid Sensing Ion Channels; D027682:Cation Transport Proteins; C490998:SLC9A1 protein, human; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D050053:TRPM Cation Channels; C121934:TRPM2 protein, human
ASIC; Acidosis; Calcium; NHE1; TRPM7; Zinc