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

Neuroprotective effects of the lipophilic beta(2)-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 beta(2)-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 beta(2)-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 beta(2)-adrenoceptor agonist but also according changes of physiological parameters.