The long-term goal of our research is to understand the cellular mechanisms underlying cerebral ischemic damage and provide insights for development of effective treatment for stroke. Our previous studies demonstrate that a Na-dependent Cl transporter plays an important role in disruption of ion homeostasis in cerebral ischemia and contributes to cytotoxic edema and ischemic damage. In this study, we will investigate the role of Na/H exchanger isoform 1 (NHE1) in ischemic damage. It is unknown whether NHE1 activity contributes to ion perturbation in cerebral ischemia and whether inhibition of NHE1 is neuroprotective against ischemic brain damage. Our preliminary study revealed that NHE1 is essential in regulation of pHi in astrocytes and neurons. Either pharmacological inhibition or genetic ablation of NHE1 activity delayed pHi regulation and significantly reduced Na+ accumulation in astrocytes and neurons following in vitro ischemia (oxygen and glucose deprivation, OGD). Moreover inhibition of NHE1 with a potent inhibitor HOE 642 reduced infarct volume by 40% following focal ischemia. The cellular mechanisms underlying this protection are not well understood. Therefore, an extensive study of NHE1 in cerebral ischemia is warranted. We hypothesize that NHE1 activity in astrocytes and neurons is stimulated following focal ischemia. Excessive stimulation of NHE1 will lead to the intracellular Na+ overload, which in turn can cause the rise of intracellular Ca2+ (through reduced Ca efflux and/or increased Ca influx via the reversed Na/Ca exchange). Thus, NHE1 activity contributes to cerebral ischemic damage in part by disruption of intracellular Na+ and Ca2+ homeostasis. These hypotheses will be tested by three Aims: 1. Determine the role of NHE1 in pHi regulation, intracellular Na+ and Ca2+ overload, swelling, and cell damage in astrocytes following OGD. 2. Investigate the contribution of NHE1 to ischemic neuronal death. 3. Investigate whether pharmacological inhibition and genetic ablation of NHE1 reduces brain damage in mice following transient focal ischemia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS048216-04
Application #
7342903
Study Section
Special Emphasis Panel (ZRG1-CDIN (01))
Program Officer
Golanov, Eugene V
Project Start
2005-02-04
Project End
2009-05-14
Budget Start
2008-01-01
Budget End
2009-05-14
Support Year
4
Fiscal Year
2008
Total Cost
$185,976
Indirect Cost
Name
University of Wisconsin Madison
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Begum, Gulnaz; Song, Shanshan; Wang, Shaoxia et al. (2018) Selective knockout of astrocytic Na+ /H+ exchanger isoform 1 reduces astrogliosis, BBB damage, infarction, and improves neurological function after ischemic stroke. Glia 66:126-144
Dong, Shuying; Maniar, Shelly; Manole, Mioara D et al. (2018) Cerebral Hypoperfusion and Other Shared Brain Pathologies in Ischemic Stroke and Alzheimer's Disease. Transl Stroke Res 9:238-250
Yin, Yan; Sun, George; Li, Eric et al. (2017) ER stress and impaired autophagy flux in neuronal degeneration and brain injury. Ageing Res Rev 34:3-14
Zhao, Hanshu; Carney, Karen E; Falgoust, Lindsay et al. (2016) Emerging roles of Na?/H? exchangers in epilepsy and developmental brain disorders. Prog Neurobiol 138-140:19-35
Boscia, Francesca; Begum, Gulnaz; Pignataro, Giuseppe et al. (2016) Glial Na(+) -dependent ion transporters in pathophysiological conditions. Glia 64:1677-97
Zhu, Wen; Carney, Karen E; Pigott, Victoria M et al. (2016) Glioma-mediated microglial activation promotes glioma proliferation and migration: roles of Na+/H+ exchanger isoform 1. Carcinogenesis 37:839-851
Chang, He Benny; Gao, Xin; Nepomuceno, Rachel et al. (2015) Na(+)/H(+) exchanger in the regulation of platelet activation and paradoxical effects of cariporide. Exp Neurol 272:11-6
Leng, Tiandong; Shi, Yejie; Xiong, Zhi-Gang et al. (2014) Proton-sensitive cation channels and ion exchangers in ischemic brain injury: new therapeutic targets for stroke? Prog Neurobiol 115:189-209
Cengiz, Pelin; Kintner, Douglas B; Chanana, Vishal et al. (2014) Sustained Na+/H+ exchanger activation promotes gliotransmitter release from reactive hippocampal astrocytes following oxygen-glucose deprivation. PLoS One 9:e84294
Cong, Damin; Zhu, Wen; Shi, Yejie et al. (2014) Upregulation of NHE1 protein expression enables glioblastoma cells to escape TMZ-mediated toxicity via increased H? extrusion, cell migration and survival. Carcinogenesis 35:2014-24

Showing the most recent 10 out of 39 publications