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

Marie Therese Fuzzati-Armentero, Silvia Cerri, Giovanna Levandis, Giulia Ambrosi, Elena Montepeloso, Gianfilippo Antoninetti, Fabio Blandini, Younis Baqi, Christa E. Müller, Rosaria Volpini, Giulia Costa, Nicola Simola, Annalisa Pinna

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15 Citations (Scopus)

Abstract

The glutamate metabotropic receptor 5 (mGluR5) and the adenosine A2A receptor (A2AR) 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 A2AR 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 A2AR 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 A2AR 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.

Original languageEnglish
Pages (from-to)740-747
Number of pages8
JournalJournal of Neurochemistry
Volume134
Issue number4
DOIs
Publication statusPublished - Aug 1 2015

Keywords

  • 6-OHDA
  • adenosine A<inf>2A</inf> receptor
  • antagonist
  • metabotropic glutamate receptor
  • neurodegeneration
  • neuroprotection

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience
  • Medicine(all)

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    Fuzzati-Armentero, M. T., Cerri, S., Levandis, G., Ambrosi, G., Montepeloso, E., Antoninetti, G., Blandini, F., Baqi, Y., Müller, C. E., Volpini, R., Costa, G., Simola, N., & Pinna, A. (2015). 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. Journal of Neurochemistry, 134(4), 740-747. https://doi.org/10.1111/jnc.13162