2-3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline and Parkinson-Disease--Secondary

Current antiparkinsonian therapies focus on either replacing dopamine via precursor (L-DOPA) administration, or directly stimulating post-synaptic dopamine receptors with dopamine agonists. Unfortunately, this approach is associated with numerous side effects and these drugs lose efficacy with disease progression. This article reviews recent evidence which suggests that negative modulation of glutamatergic neurotransmission has antiparkinsonian effects in a variety of rodent and primate models of parkinsonism. The pronounced synergism between dopaminergic agents and glutamate receptor antagonists may provide a means of using very low doses of the two drug classes in concert to treat Parkinson's disease effectively and minimize dose-related drug side effects.

Topics: Animals; Antiparkinson Agents; Basal Ganglia; Disease Models, Animal; Dizocilpine Maleate; Dopamine; Dopamine Agents; Drug Evaluation, Preclinical; Drug Synergism; Drug Tolerance; Excitatory Amino Acid Antagonists; Glutamates; Glutamic Acid; Haplorhini; Humans; Mice; MPTP Poisoning; Oxidopamine; Parkinson Disease; Parkinson Disease, Secondary; Quinoxalines; Rats; Receptors, Dopamine; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission

Topics: Animals; Dyskinesia, Drug-Induced; Excitatory Amino Acid Antagonists; Levodopa; Male; Parkinson Disease, Secondary; Piperazines; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, Glutamate; Rotation; Stereotyped Behavior; Time Factors

Stimulation of the dopamine (DA) D-2 and D-1 receptors results in behavioural activation (i.e., induction of contralateral rotations) in 6-hydroxydopamine (6-OHDA) substantia nigra lesioned rats. Competitive N-methyl-D-aspartate (NMDA) antagonists as well as alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) antagonists potentiate the stimulatory responses to threshold doses of L-DOPA or the mixed dopamine D-1/D-2 agonist apomorphine in this model, indicating the potential of such combinations for the management of Parkinson's disease. Neuroanatomic and electrophysiologic data indicate a differential distribution of DA D-1 and DA D-2 receptors within motor loops of the basal ganglia. DA D-1 receptors are preferentially located on GABAergic neurones projecting to the substantia nigra compacta (SNc) and to the substantia nigra reticulata (SNr), whereas DA D-2 receptors are preferentially located on neurones that innervate the external pallidum. NMDA receptors are present in high densities within the striatum, whereas AMPA receptors are enriched in the entopeduncular nucleus/internal pallidum and the SNr. To further characterise the functional interaction between DA and glutamate receptors, we tested the competitive NMDA antagonist 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) and the AMPA antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f] quinoxaline (NBQX) following systemic administration in combination with the DA D-2 selective agonist quinpirole or the DAD-1 selective agonist A 68 930 (1R,3S)-1-aminomethyl-5,6-dihydroxy-3-phenylisochroman) in rats with chronic 6-OHDA lesions of the SNc. CPP potentiated quinpirole-induced rotations and did not affect those induced by the D-1 agonist A 68930. By contrast, NBQX had no effect on quinpirole-induced rotations, whereas synergism was seen with A 68930. These results suggest that rotations induced by combined treatment with glutamate antagonists and DA agonists are mediated by different pathways within the basal ganglia, depending on which subtype of receptor is involved. AMPA antagonists could act preferentially by activating the direct motor pathway, whereas NMDA antagonists could modulate the indirect loop.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Apomorphine; Dopamine Agonists; Drug Interactions; Excitatory Amino Acid Antagonists; Male; Oxidopamine; Parkinson Disease, Secondary; Quinoxalines; Rats; Rats, Wistar; Receptors, AMPA; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, N-Methyl-D-Aspartate; Rotation; Stereotyped Behavior

It was shown in the present study that three antagonists of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) glutamate receptor, including 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX), 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466) and 6-(1H-imidazole-1-yl)-7-nitro-2,3-(1H, 4H)-quinoxalinedione (YM90K), caused marked reversal of akinesia when administered into the entopeduncular nucleus of rats rendered parkinsonian by bilateral substantia nigra pars compacta lesion. These data suggest that centrally active AMPA antagonists may have therapeutic utility in the treatment of idiopathic Parkinson's disease.

Topics: Animals; Anti-Anxiety Agents; Benzodiazepines; Excitatory Amino Acid Antagonists; Male; Mesencephalon; Microinjections; Motor Activity; Oxidopamine; Parkinson Disease, Secondary; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Substantia Nigra

Degeneration of dopaminergic nigrostriatal neurons in primate models of Parkinson's disease (PD) leads to an overactivity of excitatory glutamatergic projections from the subthalamic nucleus (STN) to the output nuclei of the basal ganglia resulting in rigidity and akinesia. The selective alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) antagonist 6-nitro-sulfamoyl-benzo-quinoxaline-dione (NBQX) and the competitive N-methyl-D-aspartate (NMDA) antagonist 3-carboxy-piperazin-propyl phosphonic acid (CPP) ameliorate parkinsonian symptomatology when co-administered with threshold doses of L-DOPA in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets and induce rotations in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra (SN). Here we report that in the 6-OHDA-lesioned rat NBQX and CPP induce contralateral rotations when combined with threshold doses of the direct dopamine agonists lisuride or apomorphine. AMPA antagonists and competitive NMDA antagonists may therefore be suitable as adjuvants for the treatment of PD.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Amphetamine; Animals; Apomorphine; Dopamine Agents; Drug Synergism; Ibotenic Acid; Lisuride; Male; Neurons; Oxidopamine; Parkinson Disease, Secondary; Piperazines; Quinoxalines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Stereotyped Behavior; Substantia Nigra; Sympathectomy, Chemical

Advance in understanding of the anatomy, physiology and pharmacology of basal ganglia organisation over the past decade revealed a functional relation between excitatory glutamatergic and the degenerated dopaminergic nigrostriatal transmitter systems which could serve as targets for pharmacological interventions in Parkinson's disease. The selective AMPA-antagonist NBQX is not effective in animal models of Parkinson's disease when given alone but ameliorates parkinsonian symptomatology and enhances the locomotor response of a threshold dose of L-DOPA. These synergistic effects are seen in the MPTP-treated (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) common marmoset and the rat with unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra. Here we report that, in the latter model, such synergism of NBQX is also seen with the direct dopamine agonists lisuride and apomorphine, indicating the potential usefulness of AMPA antagonists for the symptomatic treatment of Parkinson's disease.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Apomorphine; Drug Synergism; Lisuride; Male; Motor Activity; Oxidopamine; Parkinson Disease, Secondary; Quinoxalines; Rats; Rats, Wistar; Stereotaxic Techniques; Substantia Nigra

Abnormally increased subthalamic nucleus output to the internal pallidal segment and the reticular part of the substantia nigra plays a critical pathophysiological role in the development of parkinsonism. Because synaptic transmission of subthalamic output is glutamatergic and mediated, in part, by the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) subtype of glutamate receptor, AMPA receptor antagonists may possess antiparkinsonian properties. We report that in monoamine-depleted rats, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX) (Novo-Nordisk, Copenhagen, Denmark)--a selective antagonist of the AMPA subtype of glutamate receptor--suppressed muscular rigidity but had no effect on akinesia. NBQX microinjected into the subthalamic nucleus, internal pallidal segment, and reticular part of the substantia nigra, but not into the laterodorsal neostriatum of the rats, stimulated locomotor activity and reduced muscular rigidity. In aged Rhesus monkeys with bilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism, intramuscular NBQX produced clinically apparent improvement in akinesia, tremor, posture, and gross motor skills. NBQX also potentiated the antiparkinsonian effects of L-3,4-dihydroxyphenylalanine in both rats and monkeys. Blockade of excitatory synaptic transmission by AMPA receptor antagonists may provide a new therapeutic strategy for Parkinson's disease (PD).

Topics: Animals; Dopamine; Female; Globus Pallidus; Levodopa; Macaca mulatta; MPTP Poisoning; Parkinson Disease, Secondary; Quinoxalines; Rats; Receptors, AMPA; Receptors, Neurotransmitter; Synaptic Transmission

Degeneration of dopaminergic nigrostriatal neurons in Parkinson's disease results in an overactivity of excitatory glutamatergic projections from the subthalamic nucleus to the output nuclei of the basal ganglia resulting in rigidity and akinesia. In theory pharmacological blockade of these overactive systems should improve parkinsonian symptomatology. The selective AMPA-antagonist NBQX and the competitive NMDA-antagonist CPP are not effective in animal models of Parkinson's disease when given alone but ameliorate parkinsonian symptomatology and stimulate locomotor activity when co-administered with a threshold dose of L-Dopa. These synergistic effects are seen in the MPTP-treated (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) common marmoset and the rat with unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra. Therefore competitive NMDA and non-NMDA antagonists may offer a new therapeutic strategy for the treatment of Parkinson's disease.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Analysis of Variance; Animals; Callithrix; Disease Models, Animal; Drug Synergism; Ibotenic Acid; Levodopa; Male; Motor Activity; Oxidopamine; Parkinson Disease, Secondary; Piperazines; Quinoxalines; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Substantia Nigra