ro-25-6981 and Parkinsonian-Disorders

Metabotropic glutamate 5 (mGlu5) receptor antagonists reduce L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias (LID) in Parkinson's disease (PD). The aim of this study was to investigate the long-term effect of the prototypal mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) on glutamate receptors known to be involved in the development of LID in the de novo chronic treatment of monkeys lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP monkeys were treated for one month with L-DOPA and developed dyskinesias while those treated with L-DOPA and MPEP (10 mg/kg) developed significantly less. Normal control and saline-treated MPTP monkeys were also included. All MPTP monkeys were extensively and similarly denervated. The basal ganglia [(3)H]ABP688 specific binding (mGlu5 receptors) was elevated in L-DOPA-treated MPTP monkeys compared to controls but not in those treated with L-DOPA and MPEP; dyskinesia scores of these monkeys correlated positively with their [(3)H]ABP688 specific binding. Striatal density (B(max)) of [(3)H]ABP688 specific binding increased in L-DOPA-treated MPTP monkeys compared to other groups and affinity (Kd) remained unchanged. Striatal mGlu5 receptor mRNA remained unchanged following treatments. Elevated basal ganglia specific binding of [(3)H]Ro 25-6981 (NMDA NR1/NR2B receptors), [(3)H]Ro 48-8587 (AMPA receptors) but not [(3)H]CGP-39653 (NMDA NR1/NR2A receptors) was observed only in L-DOPA-treated MPTP monkeys; dyskinesias scores correlated with binding. By contrast, basal ganglia [(3)H]LY341495 specific binding (mGlu2/3 receptors) decreased in L-DOPA-treated MPTP monkeys compared to controls, saline and L-DOPA + MPEP treated MPTP monkeys; dyskinesias scores correlated negatively with this binding. Hence, chronic MPEP treatment reduces the development of LID and is associated with a normalization of glutamate neurotransmission.

Topics: 2-Amino-5-phosphonovalerate; Amino Acids; Animals; Basal Ganglia; Corpus Striatum; Dyskinesia, Drug-Induced; Female; Imidazoles; Levodopa; Macaca fascicularis; Oximes; Parkinsonian Disorders; Phenols; Piperidines; Pyridines; Quinazolines; Radioligand Assay; Receptor, Metabotropic Glutamate 5; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Tritium; Xanthenes

Parkinson's disease (PD) is characterised by the loss of nigrostriatal dopamine (DA) neurones and glutamate overactivity. There is substantial evidence to suggest that oestrogens prevent or delay the disease. 17β-oestradiol has neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD and modulates brain NMDA receptors. In MPTP-lesioned mice, oestrogen receptor (ER)α and ERβ are important in 17β-oestradiol-induced neuroprotection. To evaluate the role of ERs in the response of NMDA receptors to lesion, we compared wild-type (WT) with ER knockout (KO) C57Bl/6 male mice that received 7, 9 or 11 mg/kg of MPTP. These mice were also treated with MPTP (9 mg/kg) and 17β-oestradiol. [(3) H]Ro 25-6981 specific binding autoradiography was used to label NMDA receptors containing NR2B subunits. In the frontal and cingulate cortex and striatum, vehicle-treated WT mice had higher [(3) H]Ro 25-6981 specific binding compared to ERKO mice. Cortical [(3) H]Ro 25-6981 specific binding decreased with increasing doses of MPTP in WT and ERKOα but not ERKOβ mice, whereas a dose-related decrease was only observed in the striatum of WT mice remaining low in ERKOα and ERKOβ mice. No effect of 17β-oestradiol treatment in intact or MPTP-lesioned mice of all three genotypes was observed in the cortex, whereas it increased striatal specific binding of intact ERKOβ and MPTP-lesioned WT mice. Striatal [(3) H]Ro 25-6981 specific binding positively correlated with striatal DA concentrations only in WT mice. MPTP and 17β-oestradiol treatments had more limited effects in the hippocampus. Only in the CA3 and dentate gyrus did vehicle and 17β-oestradiol-treated ERKOα mice have higher [(3) H]Ro 25-6981 specific binding than WT and ERKOβ mice, whereas MPTP decreased this specific binding only in the CA1, CA2 and CA3 of ERKOα mice. Hence, brain NMDA receptors were affected by the deletion of ERs, which affect the response to MPTP and 17β-oestradiol treatments with brain region specificity.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Brain; CA1 Region, Hippocampal; Dose-Response Relationship, Drug; Estradiol; Gene Expression Regulation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Parkinsonian Disorders; Phenols; Piperidines; Receptors, Estrogen; Receptors, N-Methyl-D-Aspartate

N-methyl-D-aspartate (NMDA) receptor antagonists have antiakinetic and antidyskinetic effects in animals models of Parkinson's disease (PD). However, non-selective inhibition of NMDA receptors throughout the central nervous system may result in undesired effects such as ataxia and psychosis. We therefore studied Ro 25-6981, an activity-dependent antagonist of NMDA receptors containing the NR2B subunit which are predominantly expressed in the striatum. Ro 25-6981 induced contraversive rotations in 6-hydroxydopamine (6-OHDA)-lesioned rats without stimulating locomotion in normal rats and reversed parkinsonian symptoms in 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP)-treated common marmosets. Due to the small number of marmosets, there were no significant differences between Ro 25-6981 and vehicle though there was a significant trend toward differences, as shown by the Page test. Furthermore, Ro 25-6981 potentiated the action of levodopa in both species and attenuated the maximal levodopa response in 6-OHDA-lesioned rats chronically treated with levodopa without reducing the overall response. Ro 25-6981 also potentiated the action of the dopamine receptor agonists apomorphine, A68930 and quinpirole in 6-OHDA-lesioned rats. The present observations suggest a therapeutic potential of NR2B-selective NMDA receptor antagonists in the management of PD.

Topics: Animals; Antiparkinson Agents; Apomorphine; Callithrix; Disease Models, Animal; Dopamine Agonists; Dose-Response Relationship, Drug; Drug Synergism; Levodopa; Male; Motor Activity; Oxidopamine; Parkinsonian Disorders; Phenols; Piperidines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate