An Na+/H+ exchanger inhibitor suppresses cellular swelling and neuronal death induced by glutamate in cultured cortical neurons.
We examined the effects of a selective Na+/H+ exchanger inhibitor, SM-20220 (N-(aminoiminomethyl)-1-methyl-1H-indole-2-carboxamide methanesulfonate), on neuronal death induced by glutamate in rat cortical neurons. Morphological changes in neurons were observed with a differential interference contrast microscope, and cellular swelling was analysed. Neuronal death was assessed by staining the cell with propidium iodide. The intracellular calcium concentration ([Ca2+]i) and the intracellular pH were measured by fluorescence imaging with fluo-3/AM as an indicator for [Ca2+]i and BCECF/AM for pH, respectively. SM-20220 (0.3 to 30 nM) dose-dependently attenuated glutamate (300 microM)-induced neuronal death in a dose-dependent fashion over 6 hours, and inhibited acute cellular swelling following glutamate (100 microM) exposure. SM-20220 suppressed the persistent [Ca2+]i increase following glutamate (500 microM) exposure, and inhibited intracellular acidification induced by glutamate (1 mM). The activation of the Na+/H+ exchanger system may enhance the progress of cerebral damage and oedema following glutamate exposure. SM-20220, a Na+/H+ exchanger inhibitor, suppressed neuronal death and cellular swelling induced by glutamate through inhibition of both Ca2+ influx and acidification in neurons.
Yamamoto
S
S
Photon Medical Research Centre, Hamamatsu University School of Medicine, Hamamatsu, Japan. seijiy@hama-med.ac.jp
Matsumoto
Y
Y
Suzuki
Y
Y
Tsuboi
T
T
Terakawa
S
S
Ohashi
N
N
Umemura
K
K
D000577:Amides / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D007425:Intracellular Membranes / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D009994:Osmolar Concentration; D051381:Rats; D017208:Rats, Wistar; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013997:Time Factors
D000577:Amides; D007211:Indoles; C401341:SM 20220; D017923:Sodium-Hydrogen Exchangers; D018698:Glutamic Acid; D002118:Calcium