title: Combination of acamprosate and baclofen as a promising therapeutic approach for Parkinson's disease.
abstract: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterised by the loss of dopaminergic nigrostriatal neurons but which involves the loss of additional neurotransmitter pathways. Mono- or polytherapeutic interventions in PD patients have declining efficacy long-term and no influence on disease progression. The systematic analysis of available genetic and functional data as well as the substantial overlap between Alzheimer's disease (AD) and PD features led us to repurpose and explore the effectiveness of a combination therapy (ABC) with two drugs - acamprosate and baclofen - that was already effective in AD animal models, for the treatment of PD. We showed in vitro that ABC strongly and synergistically protected neuronal cells from oxidative stress in the oxygen and glucose deprivation model, as well as dopaminergic neurons from cell death in the 6-hydroxydopamine (6-OHDA) rat model. Furthermore, we showed that ABC normalised altered motor symptoms in vivo in 6-OHDA-treated rats, acting by protecting dopaminergic cell bodies and their striatal terminals. Interestingly, ABC also restored a normal behaviour pattern in lesioned rats suggesting a symptomatic effect, and did not negatively interact with L-dopa. Our results demonstrate the potential value of combining repurposed drugs as a promising new strategy to treat this debilitating disease.
authors.affiliation: Pharnext, 11 rue des Peupliers, 92130 Issy-Les-Moulineaux, France.
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Hajj
authors.affiliation: Pharnext, 11 rue des Peupliers, 92130 Issy-Les-Moulineaux, France.
authors.forename: Aude
authors.initials: A
authors.lastname: Milet
authors.affiliation: Pharnext, 11 rue des Peupliers, 92130 Issy-Les-Moulineaux, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Toulorge
authors.affiliation: Pharnext, 11 rue des Peupliers, 92130 Issy-Les-Moulineaux, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Cholet
authors.affiliation: Pharnext, 11 rue des Peupliers, 92130 Issy-Les-Moulineaux, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Laffaire
authors.affiliation: Pharnext, 11 rue des Peupliers, 92130 Issy-Les-Moulineaux, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Foucquier
authors.affiliation: Syncrosome, 163 avenue de Luminy, 13288 Marseille, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Robelet
authors.affiliation: Syncrosome, 163 avenue de Luminy, 13288 Marseille, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Mitry
authors.affiliation: Pharnext, 11 rue des Peupliers, 92130 Issy-Les-Moulineaux, France.
authors.forename: Mickael
authors.initials: M
authors.lastname: Guedj
authors.affiliation: Pharnext, 11 rue des Peupliers, 92130 Issy-Les-Moulineaux, France.
authors.forename: Serguei
authors.initials: S
authors.lastname: Nabirotchkin
authors.affiliation: Pharnext, 11 rue des Peupliers, 92130 Issy-Les-Moulineaux, France.
authors.forename: Ilya
authors.initials: I
authors.lastname: Chumakov
authors.affiliation: Pharnext, 11 rue des Peupliers, 92130 Issy-Les-Moulineaux, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Cohen
mesh_terms: D000077443:Acamprosate; D000818:Animals; D001418:Baclofen / Q000494:pharmacology*; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D008297:Male; D009410:Nerve Degeneration / Q000188:drug therapy / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D016627:Oxidopamine / Q000378:metabolism; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013654:Taurine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D013654:Taurine; D016627:Oxidopamine; D001418:Baclofen; D000077443:Acamprosate; D004298:Dopamine