Simultaneous Blockade of Adenosine A2A and Metabotropic Glutamate mGlu5 Receptors Increase their Efficacy in Reversing Parkinsonian Deficits in Rats

Abstract

Recent evidence suggest that antagonism of adenosine A 2A receptors represent an alternative therapeutic approach to Parkinson's disease (PD). Coactivation of A 2A and the glutamate subtype 5 metabotropic receptors (mGlu 5 ) synergistically stimulates DARPP-32 phosphorylation and c-fos expression in the striatum. This study therefore tested the effects of a joint blockade of these receptors to alleviate the motor dysfunction in a rat model of PD. 6-Hydroxydopamine infusions in the striatum produced akinetic deficits in rats trained to release a lever after a stimulus in a reaction time (RT) task. At 2 weeks after the lesion, A 2A and mGlu 5 receptors selective antagonists 8-(3-chlorostyryl)caffeine (CSC) and 2-methyl-6-(phenylethynyl)-pyridine (MPEP) were administered daily for 3 weeks either as a single or joint treatment. Injections of CSC (1.25 mg/kg) and MPEP (1.5 mg/kg) separately or in combination reduced the increase of delayed responses and RTs induced by 6-OHDA lesions, while the same treatment had no effect in controls. Furthermore, coadministration of lower doses of 0.625 mg/kg CSC and 0.375 mg/kg MPEP noneffective as a single treatment promoted a full and immediate recovery of akinesia, which was found to be more efficient than the separate blockade of these receptors. These results demonstrate that the combined inactivation of A 2A and mGlu 5 receptor potentiate their beneficial effects supporting this pharmacological strategy as a promising anti-Parkinsonian therapy.

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

“…The mGluR5 antagonists, MPEP (2-methyl-6-(phenlethenyl)-pyridine) and MTEP (3-(2-methyl-1,3-thiazol-4-yl(ethynyl)pyridine)), are among the potential antiparkinsonian therapeutic agents that have been tested in rodent and nonhuman primate models of PD. Although the antiparkinsonian effects of acute administration of these drugs are modest, behavioral data suggest that chronic exposure to MPEP may be more effective than acute administration in alleviating parkinsonian motor signs in partially dopamine-depleted rats (Breysse et al, 2002(Breysse et al, , 2003Coccurello et al, 2004;Ossowska et al, 2005). In addition, antidyskinetic effects of the mGluR5 antagonist have been seen in both rat and monkey models of PD (Mela et al, 2007;Rylander et al, 2009;DeKundy et al, 2010;Johnston et al, 2010;Gregoire et al, 2011;Marin et al, 2011).…”

“…In addition, antidyskinetic effects of the mGluR5 antagonist have been seen in both rat and monkey models of PD (Mela et al, 2007;Rylander et al, 2009;DeKundy et al, 2010;Johnston et al, 2010;Gregoire et al, 2011;Marin et al, 2011). Interestingly, mGluR5 and A 2A receptor antagonists exert synergistic antiparkinsonian effects in rat models of PD (Coccurello et al, 2004). It is noteworthy that MPEP and MTEP are also neuroprotective toward degeneration of midbrain dopaminergic neurons in mice and monkey models of PD (Flor et al, 2002;Battaglia et al, 2004;Masilamoni et al, 2011).…”

Local Glutamate Level Dictates Adenosine A2AReceptor Regulation of Neuroinflammation and Traumatic Brain Injury

“…Heteromeric complexes contain both A 2A Rs and mGlu5 receptors and functional synergism between the two receptors has been demonstrated in striatal neurons (Ferré et al, 2002;Coccurello et al, 2004;Kachroo et al, 2005;Tebano et al, 2005). Since both mGluR and A 2A Rs are expressed on inflammatory cells (polymorphonuclear neutrophils and microglial cells) (Gill and Pulido, 2001), this cross talk between the A 2A Rs and mGluR5 receptors is one possible molecular basis for the glutamate concentration-mediated regulation of A 2A R function.…”

Metabotropic Glutamate Receptor Subtype 5 Antagonists MPEP and MTEP

“…Over the past several years, MPEP has been used to study the potential role of the mGluR5 subtype in neuroprotection (16,(18)(19)(20)26,35,38,75,105,114,119,154,158), Parkinson's disease (10,20,31,32,50,60,65,74,91,137,140,158,181,201,205,207,210), Huntington's disease (65,164), epilepsy (2,17,65,106,109,112,113,115,116,120,124,178,187,198), Fragile X syndrome (13,211), addiction (107,145,…”

“…MPEP non-competitively inhibits mGluR5 through a novel allosteric site (68,69,141) reducing the efficacy of glutamate-stimulated phosphoinositide (PI) hydrolysis without affecting the Hill coefficient or EC 50 of glutamate (68,163). MPEP completely inhibits quisqualate-stimulated PI hydrolysis (IC 50 = 36 nM) (69) and is without effect on human mGluR6 (£10 ìM), mGluR1b (£30 ìM), or mGlu2, -3, -4a, -7b, or -8a (£100 ìM) (69).…”