6-methyl-2-(phenylethynyl)pyridine and Parkinson-Disease--Secondary

L-DOPA-induced dyskinesias (LID) appear in the majority of Parkinson's disease (PD) patients. Nicotinic acetylcholine (nACh) receptor-mediated signaling has been implicated in PD and LID and modulation of brain α7 nACh receptors might be a potential therapeutic target for PD. This study used [(125)I]α-Bungarotoxin autoradiography to investigate α7 nACh receptors in LID in post-mortem brains from PD patients (n=14) and control subjects (n=11), and from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys treated with saline (n=5), L-DOPA (n=4) or L-DOPA+2-methyl-6-(phenylethynyl)pyridine (MPEP) (n=5), and control monkeys (n=4). MPEP is the prototypal metabotropic glutamate 5 (mGlu5) receptor antagonist; it reduced the development of LID in these monkeys. [(125)I]α-Bungarotoxin specific binding to striatal and pallidal α7 nACh receptors were only increased in L-DOPA-treated dyskinetic MPTP monkeys as compared to controls, saline and L-DOPA+MPEP MPTP monkeys; dyskinesia scores correlated positively with this binding. The total group of Parkinsonian patients had higher [(125)I]α-Bungarotoxin specific binding compared to controls in the caudate nucleus but not in the putamen. PD patients without motor complications had higher [(125)I]α-Bungarotoxin specific binding compared to controls only in the caudate nucleus. PD patients with LID only had higher [(125)I]α-Bungarotoxin specific binding compared to controls in the caudate nucleus and compared to those without motor complications and controls in the putamen. PD patients with wearing-off only, had [(125)I]α-Bungarotoxin specific binding at control values in the caudate nucleus and lower in the putamen. Reduced motor complications were associated with normal striatal α7 nACh receptors, suggesting the potential of this receptor to manage motor complications in PD.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Aged; Aged, 80 and over; alpha7 Nicotinic Acetylcholine Receptor; Animals; Antiparkinson Agents; Bungarotoxins; Case-Control Studies; Caudate Nucleus; Corpus Striatum; Dyskinesia, Drug-Induced; Excitatory Amino Acid Antagonists; Female; Gene Expression; Humans; Iodine Radioisotopes; Levodopa; Macaca fascicularis; Male; Organ Specificity; Ovariectomy; Parkinson Disease; Parkinson Disease, Secondary; Putamen; Pyridines; Signal Transduction

It has been suggested that Group I metabotropic glutamate receptor antagonists could have potential therapeutic value in the treatment of Parkinson's disease. There is evidence that when given systemically, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a metabotropic glutamate receptor type 5 (mGluR5) antagonist, produces anti-parkinsonian effects in animal models, but the site of action has not been directly established. In the present study, we examined whether the subthalamic nucleus (STN) and its output structures may mediate such an effect using a unilateral rat model of Parkinson's disease. A battery of simple behavioral tests, reliably sensitive to dopamine depletion, was applied consecutively: (i) prior to surgery; (ii) 3 weeks following a unilateral 6-hydroxydopamine lesion of the substantia nigra pars compacta; (iii) at 1 h, 24 h and 4 days following a microinjection of MPEP, via an indwelling cannula, into the STN, entopeduncular nucleus (EP) or substantia nigra zona reticulata. Unilaterally dopamine-depleted animals typically had severe motor and sensorimotor asymmetries 3 weeks following surgery. Microinjection of 25 nmol MPEP into the STN of these animals significantly attenuated these asymmetries relative to vehicle. Further microinjections of lower doses (5 and 10 nmol) revealed a dose-response effect. Microinjection of MPEP into either the EP or substantia nigra zona reticulata was without effect. These data suggest that MPEP may act at the level of the STN to reduce glutamatergic overactivity and thereby induce anti-parkinsonian effects.

Topics: Animals; Behavior, Animal; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Drug Interactions; Excitatory Amino Acid Antagonists; Functional Laterality; Male; Motor Activity; Oxidopamine; Parkinson Disease; Parkinson Disease, Secondary; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Subthalamic Nucleus; Sympatholytics; Time Factors

Recent evidence suggest that antagonism of adenosine A2A receptors represent an alternative therapeutic approach to Parkinson's disease (PD). Coactivation of A2A and the glutamate subtype 5 metabotropic receptors (mGlu5) 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, A2A and mGlu5 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 A2A and mGlu5 receptor potentiate their beneficial effects supporting this pharmacological strategy as a promising anti-Parkinsonian therapy.

Topics: Adenosine A2 Receptor Antagonists; Animals; Brain; Caffeine; Conditioning, Operant; Dopamine; Dopamine and cAMP-Regulated Phosphoprotein 32; Gene Expression Regulation; Genes, fos; Male; Nerve Tissue Proteins; Oxidopamine; Parkinson Disease, Secondary; Phosphoproteins; Phosphorylation; Psychomotor Performance; Pyridines; Rats; Reaction Time; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Sympatholytics