title: The Na+/H+ exchanger-1 inhibitor cariporide prevents glutamate-induced necrotic neuronal death by inhibiting mitochondrial Ca2+ overload.
abstract: In the brain, Na+/H+ exchanger-1 (NHE-1) activation has a significant impact on ischemic injury, and, in recent studies, NHE-1 inhibition has been found to protect neurons from ischemic injury. This protective effect has been ascribed to the prevention of apoptosis, but neuronal cell death following ischemia is a consequence of both necrotic and apoptotic cell death. Here, we evaluated the ability of the potent NHE-1 inhibitor cariporide to prevent necrotic cell death in an in vitro model of excitotoxic neuronal death. Cariporide (100 nM) was found to reduce both glutamate-induced necrotic and apoptotic neuronal cell death. Ca2+ concentrations were observed to peak twice in cytosol and mitochondria in cultured neuronal cells after glutamate exposure, and cariporide was found to reduce the second Ca2+ concentration increase, but not the first. Furthermore, glutamate-mediated mitochondrial death pathways involving loss of mitochondrial membrane potential and reactive oxygen species (ROS) accumulation were found to be attenuated by cariporide. In addition, cariporide effectively prevented necrosis following exposure to glutamate and ameliorated the mitochondrial Ca2+ and ROS production increases implicated in necrotic cell death. These results suggest that NHE-1 participates in the necrotic cell death process and that its inhibition offers a means of preventing both necrosis and apoptosis.
authors.affiliation: College of Pharmacy, Ajou University, Suwon, Republic of Korea.
authors.forename: Bo Kyung
authors.initials: BK
authors.lastname: Lee
authors.forename: Yi-Sook
authors.initials: YS
authors.lastname: Jung
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D018698:Glutamic Acid / Q000633:toxicity; D006146:Guanidines / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011419:Propidium; D017382:Reactive Oxygen Species / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors; D013450:Sulfones / Q000494:pharmacology*
chemical_list: D017304:Annexin A5; D006146:Guanidines; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; D011419:Propidium; D018698:Glutamic Acid; C093373:cariporide; D007770:L-Lactate Dehydrogenase; D053148:Caspase 3; D002118:Calcium