title: Enantio-selective effects of clenbuterol in cultured neurons and astrocytes, and in a mouse model of cerebral ischemia.
abstract: 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.
authors.affiliation: Institut für Pharmakologie und Toxikologie, Philipps-Universität Marburg, Germany. ccuph@cup.uni-muenchen.de
authors.forename: Carsten
authors.initials: C
authors.lastname: Culmsee
authors.forename: Vera
authors.initials: V
authors.lastname: Junker
authors.forename: Serge
authors.initials: S
authors.lastname: Thal
authors.forename: Wolfram
authors.initials: W
authors.lastname: Kremers
authors.forename: Sandra
authors.initials: S
authors.lastname: Maier
authors.forename: Harald Jörn
authors.initials: HJ
authors.lastname: Schneider
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Plesnila
authors.forename: Josef
authors.initials: J
authors.lastname: Krieglstein
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D002478:Cells, Cultured; D002976:Clenbuterol / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D005938:Glucocorticoids / Q000378:metabolism; D018698:Glutamic Acid / Q000494:pharmacology; D007150:Immunohistochemistry; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D013237:Stereoisomerism; D013997:Time Factors
chemical_list: D000318:Adrenergic beta-Agonists; D001786:Blood Glucose; D005938:Glucocorticoids; D018696:Neuroprotective Agents; D018343:Receptors, Adrenergic, beta-2; D018698:Glutamic Acid; D002976:Clenbuterol