title: Dual target strategy: combining distinct non-dopaminergic treatments reduces neuronal cell loss and synergistically modulates L-DOPA-induced rotational behavior in a rodent model of Parkinson's disease.
abstract: The glutamate metabotropic receptor 5 (mGluR5) and the adenosine A2A receptor (A2A R) represent major non-dopaminergic therapeutic targets in Parkinson's disease (PD) to improve motor symptoms and slow down/revert disease progression. The 6-hydroxydopamine rat model of PD was used to determine/compare the neuroprotective and behavioral impacts of single and combined administration of one mGluR5 antagonist, 2-methyl-6-(phenylethynyl)pyridine (MPEP), and two A2A R antagonists, (E)-phosphoric acid mono-[3-[8-[2-(3-methoxyphenyl)vinyl]-7-methyl-2,6-dioxo-1-prop-2-ynyl-1,2,6,7-tetrahydropurin-3-yl]propyl] (MSX-3) and 8-ethoxy-9-ethyladenine (ANR 94). Chronic treatment with MPEP or MSX-3 alone, but not with ANR 94, reduced the toxin-induced loss of dopaminergic neurons in the substantia nigra pars compacta. Combining MSX-3 and MPEP further improved the neuroprotective effect of either antagonists. At the behavioral level, ANR 94 and MSX-3 given alone significantly potentiated L-DOPA-induced turning behavior. Combination of either A2A R antagonists with MPEP synergistically increased L-DOPA-induced turning. This effect was dose-dependent and required subthreshold drug concentration, which per se had no motor stimulating effect. Our findings suggest that co-treatment with A2A R and mGluR5 antagonists provides better therapeutic benefits than those produced by either drug alone. Our study sheds some light on the efficacy and advantages of combined non-dopaminergic PD treatment using low drug concentration and establishes the basis for in-depth studies to identify optimal doses at which these drugs reach highest efficacy. Combined treatment with low concentrations of known adenosine A2A receptor (A2A R) and metabotropic glutamate receptor (mGluR5) antagonists results in a therapeutic benefit and provides better results than those produced by either drug given alone, both in terms of motor performance and neuroprotection. Future trials should involve careful optimization of drug combinations and concentrations that may avoid the emergence of debilitating side effects and slow-down/revert disease progression.
authors.affiliation: Laboratory of Functional Neurochemistry, Center for Research In Neurodegenerative Diseases C. Mondino National Neurological Institute, Pavia, Italy.
authors.forename: Marie-Therese
authors.initials: MT
authors.lastname: Fuzzati-Armentero
authors.affiliation: Laboratory of Functional Neurochemistry, Center for Research In Neurodegenerative Diseases C. Mondino National Neurological Institute, Pavia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Cerri
authors.affiliation: Laboratory of Functional Neurochemistry, Center for Research In Neurodegenerative Diseases C. Mondino National Neurological Institute, Pavia, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Levandis
authors.affiliation: Laboratory of Functional Neurochemistry, Center for Research In Neurodegenerative Diseases C. Mondino National Neurological Institute, Pavia, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Ambrosi
authors.affiliation: Laboratory of Functional Neurochemistry, Center for Research In Neurodegenerative Diseases C. Mondino National Neurological Institute, Pavia, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Montepeloso
authors.affiliation: Laboratory of Functional Neurochemistry, Center for Research In Neurodegenerative Diseases C. Mondino National Neurological Institute, Pavia, Italy.
authors.forename: Gianfilippo
authors.initials: G
authors.lastname: Antoninetti
authors.affiliation: Laboratory of Functional Neurochemistry, Center for Research In Neurodegenerative Diseases C. Mondino National Neurological Institute, Pavia, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Blandini
authors.affiliation: Pharmaceutical Institute, Pharmaceutical Chemistry I, Pharma Center Bonn, University of Bonn, Bonn, Germany.|Department of Chemistry, Faculty of Science, Sultan Qaboos University, Muscat, Oman.
authors.forename: Younis
authors.initials: Y
authors.lastname: Baqi
authors.affiliation: Pharmaceutical Institute, Pharmaceutical Chemistry I, Pharma Center Bonn, University of Bonn, Bonn, Germany.
authors.forename: Christa E
authors.initials: CE
authors.lastname: Müller
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Camerino, Italy.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Volpini
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Costa
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Simola
authors.affiliation: National Research Council of Italy, Neuroscience Institute, Cagliari, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pinna
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods; D004357:Drug Synergism; D007980:Levodopa / Q000008:administration & dosage*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000473:pathology / Q000523:psychology; D058915:Purinergic P1 Receptor Antagonists / Q000008:administration & dosage*; D011725:Pyridines / Q000008:administration & dosage; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors*; D012399:Rotation; D016896:Treatment Outcome; D014970:Xanthines / Q000008:administration & dosage
chemical_list: C502530:8-ethoxy- 9-ethyladenine; C578937:Grm5 protein, rat; C113602:MSX 3 compound; D018696:Neuroprotective Agents; D058915:Purinergic P1 Receptor Antagonists; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D014970:Xanthines; D007980:Levodopa; C121465:6-methyl-2-(phenylethynyl)pyridine; D000225:Adenine
keywords: 6-OHDA; adenosine A2A receptor; antagonist; metabotropic glutamate receptor; neurodegeneration; neuroprotection