Nakayama Ryosuke, Yano Toshiyuki, Ushijima Kazuo, Abe Eiji, Terasaki Hidenori
Surgical Center and the Department of Anesthesiology, Kumamoto University School of Medicine, Honjo, Kumamoto, Japan.
Anesthesiology. 2002 Mar;96(3):705-10. doi: 10.1097/00000542-200203000-00029.
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.
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.
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).
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.
脑缺血产生的过量细胞外谷氨酸被认为会引发导致神经元细胞死亡的级联反应。细胞外谷氨酸浓度的变化与细胞内钙离子浓度的变化密切相关。丹曲林抑制细胞内钙库释放钙。在本研究中，作者在短暂性全脑缺血大鼠模型中研究了丹曲林对细胞外谷氨酸积累和神经元变性的影响。
体重230 - 290 g的雄性Wistar大鼠用氟烷在一氧化二氮 - 氧气中麻醉，采用四血管闭塞技术进行10分钟的短暂性前脑缺血。在缺血损伤前15分钟，脑室内注射丹曲林钠（5 mM）、作为丹曲林溶剂的二甲基亚砜或作为对照的人工脑脊液（每组n = 8）。在海马CA1亚区，在缺血期周围用微透析生物传感器测量体内细胞外谷氨酸浓度，并在再灌注后第7天评估完整神经元的数量。
丹曲林和二甲基亚砜均显著降低了缺血诱导的谷氨酸浓度升高，程度相似，即分别比人工脑脊液降低了53%和51%（P < 0.01）。丹曲林处理的大鼠海马CA1完整神经元数量（平均值±标准差；细胞/mm）为（78 ± 21），显著高于人工脑脊液处理组（35 ± 14；P < 0.001）和二甲基亚砜处理组（56 ± 11；P < 0.05）。与人工脑脊液相比，二甲基亚砜也显著增加了保存神经元的数量（P < 0.05）。
脑室内注射丹曲林可预防短暂性缺血大鼠海马CA1区的延迟性神经元丢失；然而，这种神经保护作用不能仅归因于缺血期间细胞外谷氨酸浓度的降低。
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