Enantio-selective effects of clenbuterol in cultured neurons and astrocytes, and in a mouse model of cerebral ischemia

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• 作者：Carsten Culmsee ; Vera Junker ; Serge Thal ; Wolfram Kremers ; S ; ra Maier ; Harald Jö ; rn Schneider ; Nikolaus Plesnila ; Josef Krieglstein
• 关键词：Clenbuterol ; Adrenoceptor agonist ; Cerebral ischemia ; Neuroprotection ; Glutamate ; Staurosporine
• 刊名：European Journal of Pharmacology
• 出版年：2007
• 期刊代码：24_00142999
• 类别：neu
• 出版时间：1 December 2007
• 卷：575
• 期：1-3
• 页码：57-65
• 文件大小：809 K

摘要

Neuroprotective effects of the lipophilic β₂-adrenoceptor agonist clenbuterol have been established in neuronal cultures and in various rodent models of stroke. In previous studies, however, clenbuterol was always applied as a racemate, while it has not been established whether the enantiomers differ in their neuroprotective activities. Here, we demonstrate that R,S-clenbuterol and S(+)-clenbuterol, but not the R(−)-enantiomer protect cultured neurons against glutamate-mediated excitotoxicity and staurosporine-induced apoptosis. Similar to previous findings with clenbuterol racemate, the neuroprotective effect of S(+)-clenbuterol correlated well with morphological changes of astrocytes which transformed into dense stellate cells with dendritic processes indicating β₂-adrenoceptor-mediated activation. Most importantly, the S(+)-enantiomer but not R(−)-clenbuterol reduced ischemic brain damage similar to the effect of the racemate. The selective β₂-adrenoceptor antagonist butoxamine blocked this neuroprotective effect of S(+)-clenbuterol. In addition, S(+)-clenbuterol significantly reduced blood pressure, enhanced blood glucose levels and increased glucocorticoid levels compared to vehicle-or R(−)-clenbuterol-treated controls. These results clearly demonstrate that S(+)-clenbuterol is the eutomer that mediates neuroprotective effects of the β₂-adrenoceptor agonist but also according changes of physiological parameters.