Pharmacological Treatments Inhibiting Levodopa-Induced Dyskinesias in MPTP-Lesioned Monkeys: Brain Glutamate Biochemical Correlates

Abstract

Anti-glutamatergic drugs can relieve Parkinson’s disease (PD) symptoms and decrease l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesias (LID). This review reports relevant studies investigating glutamate receptor subtypes in relation to motor complications in PD patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys. Antagonists of the ionotropic glutamate receptors, such as N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, display antidyskinetic activity in PD patients and animal models such as the MPTP monkey. Metabotropic glutamate 5 (mGlu5) receptor antagonists were shown to reduce the severity of LID in PD patients as well as in already dyskinetic non-human primates and to prevent the development of LID in de novo treatments in non-human primates. An increase in striatal post-synaptic NMDA, AMPA, and mGlu5 receptors is documented in PD patients and MPTP monkeys with LID. This increase can be prevented in MPTP monkeys with the addition of a specific glutamate receptor antagonist to the l-DOPA treatment and also with drugs of various pharmacological specificities suggesting multiple receptor interactions. This is yet to be well documented for presynaptic mGlu4 and mGlu2/3 and offers additional new promising avenues.

l-DOPA-induced dyskinesia in Parkinson's disease: Are neuroinflammation and astrocytes key elements?

“…The only pharmacological treatment used to deal with L-DOPAinduced dyskinesia in PD patients is the noncompetitive antagonist of the N-methyl-D-aspartate (NMDA)-type glutamate receptor, amantadine (Blanpied, Clarke, & Johnson, 2005;Luginger, Wenning, B€ osch, & Poewe, 2000;Meissner et al, 2011;Metman et al, 1999;Ossola et al, 2011;Wandinger et al, 1999). Increased glutamatergic neurotransmission has been associated with the pathophysiology of L-DOPA-induced dyskinesia (Ahmed et al, 2011;Huot, Johnston, Koprich, Fox, & Brotchie, 2013;Morin & Di Paolo, 2014;Papa, Boldry, Engber, Kask, & Chase, 1995;Rylander et al, 2009;Solís, García-Sanz, Herranz, Asensio, & Moratalla, 2016). Nonetheless, pharmacotherapy with amantadine is limited due to the development of central adverse effects including dizziness, confusion, and hallucinations (Macchio, Ito, & Sahgal, 1993;Shannon, Goetz, Carroll, Tanner, & Klawans, 1987;Thomas et al, 2004;Wolf et al, 2010).…”

Neural substrates and potential treatments for levodopa-induced dyskinesias in Parkinson’s disease

“…Interestingly, in rat models, the effects of NMDA antagonists are dependent on whether dyskinesia is due to impairment in the indirect or direct striatal pathway (Flores et al, 2014). An increase in striatal postsynaptic glutamate-5 receptors (mGlu5) has been noted in PD patients and animal models of PD (Morin and Di Paolo, 2014). Mellone et al (2015) reported an abnormal ratio of GluN2A/GluN2B subunit of NMDA receptors in the striatum of postmortem brain specimens from 16 PD patients, 6-OHDA model of PD in male Sprague-Dawley rats, and MPTP monkey model of PD suffering from LID.…”

Discovery of potential negative allosteric modulators of mGluR5 from natural products using pharmacophore modeling, molecular docking, and molecular dynamics simulation studies

“…mGluR5 is a promising therapeutic target and many preclinical models of disease where efficacy has been observed with mGluR5 NAMs include anxiety 15 , GERD 16 , dyskinesias 17 , migraine 18 , fragile X syndrome (FXS) 19 , and Parkinson's disease levodopa induced dyskinesia (PD-LID) 20 . By analyzing the chemical structures of mGluR5 NAMs, all chemotypes can be divided into two types, which depends on whether there is a disubstituted alkyne or not 21 .…”