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. (4th June 2015)

• Record Type: Journal Article
• Authors: Fuzzati‐Armentero, Marie‐Therese; Cerri, Silvia; Levandis, Giovanna; Ambrosi, Giulia; Montepeloso, Elena; Antoninetti, Gianfilippo; Blandini, Fabio; Baqi, Younis; Müller, Christa E.; Volpini, Rosaria; Costa, Giulia; Simola, Nicola; Pinna, Annalisa
• Is Part Of: Journal of neurochemistry. Volume 134:Number 4(2015:Aug.)
• Page Start: 740
• Page End: 747
• Publication Date: 2015-06-04
• Subjects: Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.13162
• Languages: English
• ISSNs: 0022-3042

Abstract

<abstract abstract-type="main" id="jnc13162-abs-0001"> <title>Abstract</title> <p>The glutamate metabotropic receptor 5 (mGluR5) and the adenosine A<sub>2A</sub> receptor (A<sub>2A</sub>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 A<sub>2A</sub>R antagonists, (<italic>E</italic>)‐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 <sc>l</sc>‐DOPA‐induced turning behavior. Combination of either A<sub>2A</sub>R antagonists with MPEP synergistically increased L‐DOPA‐induced turning. This effect was dose‐dependent and required subthreshold drug concentration, which <italic>per se</italic> had no motor stimulating effect. Our findings suggest that co‐treatment with A<sub>2A</sub>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. <boxed-text content-type="graphic" id="jnc13162-blkfxd-1001" position="anchor" orientation="portrait"><graphic position="anchor" mimetype="image" xlink:href="ark:/27927/pgj253nxz7b" orientation="portrait" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /></boxed-text></p> <p>Combined treatment with low concentrations of known adenosine A<sub>2A</sub> receptor (A<sub>2A</sub>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.</p> </abstract>