title: Glycogen synthase kinase-3 inhibitors as potent therapeutic agents for the treatment of Parkinson disease.
abstract: Parkinson's disease (PD) is a devastating neurodegenerative disorder characterized by degeneration of the nigrostriatal dopaminergic pathway. Because the current therapies only lead to temporary, limited improvement and have severe side effects, new approaches to treat PD need to be developed. To discover new targets for potential therapeutic intervention, a chemical genetic approach involving the use of small molecules as pharmacological tools has been implemented. First, a screening of an in-house chemical library on a well-established cellular model of PD was done followed by a detailed pharmacological analysis of the hits. Here, we report the results found for the small heterocyclic derivative called SC001, which after different enzymatic assays was revealed to be a new glycogen synthase kinase-3 (GSK-3) inhibitor with IC(50) = 3.38 ± 0.08 μM.  To confirm that GSK-3 could be a good target for PD, the evaluation of a set of structurally diverse GSK-3 inhibitors as neuroprotective agents for PD was performed. Results show that inhibitors of GSK-3 have neuroprotective effects in vitro representing a new pharmacological option for the disease-modifying treatment of PD. Furthermore, we show that SC001 is able to cross the blood-brain barrier, protects dopaminergic neurons, and reduces microglia activation in in vivo models of Parkinson disease, being a good candidate for further drug development.
authors: Instituto de Investigaciones Biomédicas,  CSIC-UAM , Arturo Duperier, 4, and  Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) , 28029-Madrid, Spain.
authors: J A
authors: JA
authors: Morales-García
authors: C
authors: C
authors: Susín
authors: S
authors: S
authors: Alonso-Gil
authors: D I
authors: DI
authors: Pérez
authors: V
authors: V
authors: Palomo
authors: C
authors: C
authors: Pérez
authors: S
authors: S
authors: Conde
authors: A
authors: A
authors: Santos
authors: C
authors: C
authors: Gil
authors: A
authors: A
authors: Martínez
authors: A
authors: A
authors: Pérez-Castillo
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D059290:Dopaminergic Neurons / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006801:Humans; D051379:Mice; D017628:Microglia / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016627:Oxidopamine / Q000494:pharmacology; D010300:Parkinson Disease; D051381:Rats
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; C584016:SC001 compound; D018698:Glutamic Acid; D016627:Oxidopamine; D038362:Glycogen Synthase Kinase 3