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
1. Laboratory of Functional Neurochemistry, Center for Research In Neurodegenerative Diseases C. Mondino National Neurological Institute, Pavia, Italy;2. Pharmaceutical Institute, Pharmaceutical Chemistry I, Pharma Center Bonn, University of Bonn, Bonn, Germany;3. Department of Chemistry, Faculty of Science, Sultan Qaboos University, Muscat, Oman;4. School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Camerino, Italy;5. Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy;6. National Research Council of Italy, Neuroscience Institute, Cagliari, Italy
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.
