Metabotropic glutamate receptor 5 antagonist protects dopaminergic and noradrenergic neurons from degeneration in MPTP-treated monkeys

Abstract

Degeneration of the dopaminergic nigrostriatal system and of noradrenergic neurons in the locus coeruleus are important pathological features of Parkinson's disease. There is an urgent need to develop therapies that slow down the progression of neurodegeneration in Parkinson's disease. In the present study, we tested whether the highly specific metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, reduces dopaminergic and noradrenergic neuronal loss in monkeys rendered parkinsonian by chronic treatment with low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Weekly intramuscular 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injections (0.2-0.5 mg/kg body weight), in combination with daily administration of 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine or vehicle, were performed until the development of parkinsonian motor symptoms in either of the two experimental groups (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine versus 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle). After 21 weeks of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment, all 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals displayed parkinsonian symptoms, whereas none of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys were significantly affected. These behavioural observations were consistent with in vivo positron emission tomography dopamine transporter imaging data, and with post-mortem stereological counts of midbrain dopaminergic neurons, as well as striatal intensity measurements of dopamine transporter and tyrosine hydroxylase immunoreactivity, which were all significantly higher in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated animals than in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated monkeys. The 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine treatment also had a significant effect on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced loss of norepinephrine neurons in the locus coeruleus and adjoining A5 and A7 noradrenaline cell groups. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals, almost 40% loss of tyrosine hydroxylase-positive norepinephrine neurons was found in locus coeruleus/A5/A7 noradrenaline cell groups, whereas the extent of neuronal loss was lower than 15% of control values in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys. Our data demonstrate that chronic treatment with the metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, significantly reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity towards dopaminergic and noradrenergic cell groups in non-human primates. This suggests that the use of metabotropic glutamate receptor 5 antagonists may be a useful strategy to reduce degeneration of catecholaminergic neuro...

Inflammatory cytokines in depression: Neurobiological mechanisms and therapeutic implications

“…Given that the neurotoxic effects of QUIN may be mediated by excessive glutamate excitotoxicity (Schwarcz and Pellicciari, 2002, Tavares et al, 2002, Tavares et al, 2005), glutamate antagonists may be useful in preventing excitotoxic effects on other neurotransmitter systems. For instance, metabotropic glutamate receptor antagonists that modulate glutamate transmission in the basal ganglia have been successful in reducing dopamine cell loss in an animal model of PD (Masilamoni et al, 2011). Furthermore, inhibition of the NMDA receptor with memantine prevented the onset of DA deficits in the brains of SIV-infected macaques, and effect mediated by increased BDNF (Meisner et al, 2008).…”

Inflammation Effects on Motivation and Motor Activity: Role of Dopamine

“…Given that the neurotoxic effects of QUIN may be mediated by excessive glutamate excitotoxicity (Schwarcz et al, 2002;Tavares et al, 2005;Tavares et al, 2002), glutamate antagonists may be useful in preventing excitotoxic and oxidative effects on the highly sensitive DA neurons. Indeed, metabotropic glutamate receptor antagonists that modulate glutamate transmission in the basal ganglia have been successful in reducing DA cell loss in an animal model of PD (Masilamoni et al, 2011). Antagonism of the NMDA receptor with memantine in monkeys infected with simian immunodeficiency virus (SIV) also reversed the loss of DA in the striatum (Meisner et al, 2008) that occurs during SIV and HIV infection secondary to immune cell activation in the basal ganglia Scheller et al, 2005), in association with increased brain-derived neurotrophic factor (BDNF).…”

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

“…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). In MPTP-treated nonhuman primates, MTEP also protects locus coeruleus noradrenergic neurons from degeneration (Masilamoni et al, 2011).…”

“…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). In MPTP-treated nonhuman primates, MTEP also protects locus coeruleus noradrenergic neurons from degeneration (Masilamoni et al, 2011). The translation of these preclinical studies in animal models to patients with PD must be interpreted with caution.…”