title: GSK3β inhibition is involved in the neuroprotective effects of cyclin-dependent kinase inhibitors in neurons.
abstract: In the present study, we evaluated the effects of roscovitine (Rosco) and flavopiridol (Flavo), both of which are classified as cyclin-dependent kinase (CDK) inhibitors, on apoptosis induced by the inhibition of PI3K/AKT pathway in cerebellar granule neurons (CGNs). Our results demonstrate that both CDK inhibitors prevented apoptosis induced by LY294002 (LY), as also occurs with SB415286 (SB4), a selective GSK3β inhibitor. Our findings also indicate that these CDK inhibitors inhibit GSK3β, representing a potential pharmacological mechanism involved in their neuroprotective properties. Thus, the increased activity of GSK3β induced by LY294002 and detected by dephosphorylation at Ser9 was prevented by both compounds. Likewise, GSK3β activity was measured by a radioactivity assay, revealing that CDK inhibitors and SB415286 prevented the increase in GSK3β activity induced by PI3K inhibition. In addition, we analysed c-Jun, which is also a mediator of PI3K inhibition-induced apoptosis. However, neither of the CDK inhibitors nor SB415286 prevented the increase in c-Jun phosphorylation induced by PI3K inhibition. Therefore, our data identify GSK3β as a crucial mediator of CGN apoptosis induced by PI3K inhibition and indicate that the antiapoptotic effects of CDKs are mediated by the inhibition of this pharmacological target.
authors.affiliation: Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Centros de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Institut de Biomedicina (IBUB), Universitat de Barcelona, Nucli Universitari de Pedralbes, 08028 Barcelona, Spain.
authors.forename: Aurelio Vazquez
authors.initials: AV
authors.lastname: de la Torre
authors.forename: Felix
authors.initials: F
authors.lastname: Junyent
authors.forename: Jaume
authors.initials: J
authors.lastname: Folch
authors.forename: Carme
authors.initials: C
authors.lastname: Pelegrí
authors.forename: Jordi
authors.initials: J
authors.lastname: Vilaplana
authors.forename: Carme
authors.initials: C
authors.lastname: Auladell
authors.forename: Carlos
authors.initials: C
authors.lastname: Beas-Zarate
authors.forename: Mercè
authors.initials: M
authors.lastname: Pallàs
authors.forename: Ester
authors.initials: E
authors.lastname: Verdaguer
authors.forename: Antoni
authors.initials: A
authors.lastname: Camins
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011687:Purines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077546:Roscovitine; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D005419:Flavonoids; D018696:Neuroprotective Agents; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D011687:Purines; D000077546:Roscovitine; C077990:alvocidib; D058539:Phosphatidylinositol 3-Kinase; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D018844:Cyclin-Dependent Kinases; D038362:Glycogen Synthase Kinase 3