title: Effects of dantrolene on extracellular glutamate concentration and neuronal death in the rat hippocampal CA1 region subjected to transient ischemia.
abstract: BACKGROUND
  Excessive extracellular glutamate produced by cerebral ischemia has been proposed to initiate the cascade toward neuronal cell death. Changes in extracellular glutamate concentration are closely linked to changes in intracellular calcium ion concentration. Dantrolene inhibits calcium release from intracellular calcium stores. In this study, the authors investigated the effects of dantrolene on extracellular glutamate accumulation and neuronal degeneration in a rat model of transient global forebrain ischemia.
  
  
  METHODS
  Male Wistar rats weighing 230-290 g were anesthetized with halothane in nitrous oxide-oxygen and were subjected to 10 min of transient forebrain ischemia using a four-vessel occlusion technique. Fifteen minutes before ischemic injury, dantrolene sodium (5 mm), dimethyl sulfoxide as a vehicle for dantrolene, or artificial cerebrospinal fluid as a control was intracerebroventricularly administered (n = 8 in each group). In the hippocampal CA1 subfield, the extracellular glutamate concentration in vivo was measured during the periischemic period with a microdialysis biosensor, and the number of intact neurons was evaluated on day 7 after reperfusion.
  
  
  RESULTS
  Both dantrolene and dimethyl sulfoxide significantly reduced the ischemia-induced increase in glutamate concentration to a similar extent, i.e., by 53 and 51%, respectively, compared with artificial cerebrospinal fluid (P < 0.01). The number of intact hippocampal CA1 neurons (mean +/- SD; cells/mm) in dantrolene-treated rats (78 +/- 21) was significantly higher than that in artificial cerebrospinal fluid- (35 +/- 14; P < 0.001) and dimethyl sulfoxide-treated (56 +/- 11; P < 0.05) animals. Dimethyl sulfoxide also significantly increased the number of preserved neurons in comparison with artificial cerebrospinal fluid (P < 0.05).
  
  
  CONCLUSIONS
  Intracerebroventricular dantrolene prevents delayed neuronal loss in the rat hippocampal CA1 region subjected to transient ischemia; however, this neuroprotection cannot be accounted for only by the reduced concentrations of extracellular glutamate during ischemia.
authors.affiliation: Surgical Center and the Department of Anesthesiology, Kumamoto University School of Medicine, Honjo, Kumamoto, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Nakayama
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Yano
authors.forename: Kazuo
authors.initials: K
authors.lastname: Ushijima
authors.forename: Eiji
authors.initials: E
authors.lastname: Abe
authors.forename: Hidenori
authors.initials: H
authors.lastname: Terasaki
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D003620:Dantrolene / Q000008:administration & dosage / Q000494:pharmacology*; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D007276:Injections, Intraventricular; D002546:Ischemic Attack, Transient / Q000473:pathology*; D008297:Male; D017551:Microdialysis; D009125:Muscle Relaxants, Central / Q000008:administration & dosage / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000473:pathology
chemical_list: D009125:Muscle Relaxants, Central; D018696:Neuroprotective Agents; D018698:Glutamic Acid; D003620:Dantrolene; D004121:Dimethyl Sulfoxide