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1.
Exp Neurol ; 225(2): 384-90, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20655910

ABSTRACT

Parkinson's Disease (PD) and Extrapyramidal Syndrome (EPS) are movement disorders that result from degeneration of the dopaminergic input to the striatum and chronic inhibition of striatal dopamine D(2) receptors by antipsychotics, respectively. Adenosine A(2A) receptors are selectively localized in the basal ganglia, primarily in the striatopallidal ("indirect") pathway, where they appear to operate in concert with D(2) receptors and have been suggested to drive striatopallidal output balance. In cases of dopaminergic hypofunction, A(2A) receptor activation contributes to the overdrive of the indirect pathway. A(2A) receptor antagonists, therefore, have the potential to restore this inhibitor imbalance. Consequently, A(2A) receptor antagonists have therapeutic potential in diseases of dopaminergic hypofunction such as PD and EPS. Targeting the A(2A) receptor may also be a way to avoid the issues associated with direct dopamine agonists. Recently, preladenant was identified as a potent and highly selective A(2A) receptor antagonist, and has produced a significant improvement in motor function in rodent models of PD. Here we investigate the effects of preladenant in two primate movement disorder models. In MPTP-treated cynomolgus monkeys, preladenant (1 or 3 mg/kg; PO) improved motor ability and did not evoke any dopaminergic-mediated dyskinetic or motor complications. In Cebus apella monkeys with a history of chronic haloperidol treatment, preladenant (0.3-3.0 mg/kg; PO) delayed the onset of EPS symptoms evoked by an acute haloperidol challenge. Collectively, these data support the use of preladenant for the treatment of PD and antipsychotic-induced movement disorders.


Subject(s)
Basal Ganglia Diseases/drug therapy , Basal Ganglia/metabolism , Motor Activity/drug effects , Pyrimidines/therapeutic use , Receptor, Adenosine A2A/metabolism , Triazoles/therapeutic use , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , Adenosine A2 Receptor Antagonists , Analysis of Variance , Animals , Area Under Curve , Basal Ganglia Diseases/chemically induced , Basal Ganglia Diseases/metabolism , Cebus , Disease Models, Animal , Female , Macaca fascicularis , Male
2.
Parkinsonism Relat Disord ; 15(6): 445-52, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19196540

ABSTRACT

Dyskinesia is an important complication of treatment in Parkinson's disease (PD). Sarizotan, a 5-HT(1A) agonist with high affinity for D3 and D4 receptors was investigated on L-Dopa-induced dyskinesia (LID) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model of PD. Five MPTP female cynomolgus monkeys (Macaca fascicularis) with a moderate to severe parkinsonian syndrome and LID were used. Sarizotan 0.2, 1, and 2 mg/kg administered alone did not worsen parkinsonian symptoms; there were no effect on locomotor counts or on normal behavior of the monkeys. Sarizotan 0.2, 1, and 2 mg/kg administered 30 min before a fixed dose of L-Dopa (25-30 mg/kg s.c.) + benserazide (50 mg) did not affect the antiparkinsonian response to L-Dopa. However, mean dyskinetic scores were significantly reduced with sarizotan 1 and 2 mg/kg but not at 0.2 mg/kg. Higher doses of sarizotan (4 and 8 mg/kg, administered immediately before L-Dopa) reduced L-Dopa-induced locomotor response in all monkeys. A pharmacokinetic investigation in these monkeys showed a dose-dependent increase in mean plasma sarizotan concentrations with similar mean plasma concentrations for sarizotan 1 mg/kg alone or with L-Dopa, indicating a lack of sarizotan/L-Dopa interaction. The time course of plasma sarizotan concentrations was associated with time of maximal reduction of dyskinesias. When administered daily for two weeks in combination with L-Dopa in the same MPTP monkeys, sarizotan 1 mg/kg had a sustained antidyskinetic effect while maintaining the antiparkinsonian and locomotor effect of L-Dopa. This detailed sarizotan investigation in MPTP monkeys supports the antidyskinetic activity of this drug and for 5-HT(1A) agonists.


Subject(s)
Antiparkinson Agents/adverse effects , Dyskinesia, Drug-Induced/drug therapy , Dyskinesia, Drug-Induced/etiology , Levodopa/adverse effects , Serotonin Receptor Agonists/therapeutic use , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , Animals , Behavior, Animal/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Interactions , Female , Macaca fascicularis , Organic Chemicals/metabolism , Organic Chemicals/pharmacokinetics , Organic Chemicals/therapeutic use , Ovariectomy/methods , Parkinsonian Disorders/chemically induced , Parkinsonian Disorders/drug therapy , Serotonin Receptor Agonists/metabolism , Serotonin Receptor Agonists/pharmacokinetics
3.
Synapse ; 62(2): 101-9, 2008 Feb.
Article in English | MEDLINE | ID: mdl-17992687

ABSTRACT

L-Dopa therapy in Parkinson's disease (PD) is counfounded by the development of involuntary movements such as L-Dopa-induced dyskinesias (LIDs). In this study GABA(A) receptor autoradiography was assessed using [(3)H]flunitrazepam binding to the benzodiazepine site of the GABA(A) receptor and [(35)S]t-butylbicyclophosphorothionate (TBPS) binding to the chloride channel of GABA(A) receptors in the substantia nigra reticulata (SNr) and subthalamic nucleus (STN). L-Dopa-treated parkinsonian monkeys experiencing LIDs were compared to animals in which LIDs was prevented by adjunct treatments with CI-1041, a selective antagonist of the NR1A/2B subtype of NMDA receptor, or low doses of the dopamine D2 receptor agonist, cabergoline. Our results demonstrated a decrease of GABA(A) receptor specific binding in the posterior part of the SNr in dyskinetic monkeys compared to nondyskinetic animals, while no modulation has been observed in the STN. These results provide evidence for the first time that pharmacological treatments preventing LIDs in nonhuman primate model of PD are associated with normalization of GABA(A) receptor-mediated signalling in the SNr.


Subject(s)
Antiparkinson Agents/adverse effects , Benzoxazoles/therapeutic use , Dyskinesia, Drug-Induced/pathology , Dyskinesia, Drug-Induced/prevention & control , Levodopa/adverse effects , Piperidines/therapeutic use , Receptors, GABA/metabolism , Substantia Nigra/drug effects , Analysis of Variance , Animals , Autoradiography/methods , Behavior, Animal , Benzoxazoles/pharmacology , Binding, Competitive/drug effects , Bridged Bicyclo Compounds, Heterocyclic/metabolism , Convulsants/metabolism , Disease Models, Animal , Female , Flunitrazepam/metabolism , GABA Modulators/metabolism , Isotopes/metabolism , Macaca fascicularis , Ovariectomy/methods , Parkinsonian Disorders/drug therapy , Piperidines/pharmacology , Protein Binding/drug effects , Radiography , Substantia Nigra/diagnostic imaging , Substantia Nigra/pathology
4.
Neurobiol Aging ; 29(7): 1040-51, 2008 Jul.
Article in English | MEDLINE | ID: mdl-17353071

ABSTRACT

Modulation of excessive glutamatergic transmission within the basal ganglia is considered as an alternative approach to reduce l-Dopa-induced dyskinesias (LIDs) in Parkinson's disease (PD). In this study receptor binding autoradiography of [3H]MPEP, a metabotropic glutamate receptor 5 (mGluR5) selective radioligand, was used to investigate possible changes in mGluR5 in the basal ganglia of l-Dopa-treated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys having developed LIDs compared to animals in which LIDs was prevented by adjunct treatments. LIDs were associated with an increase of mGluR5 specific binding in the posterior putamen and pallidum (+41% and +56%) compared to controls. By contrast, prevention of dyskinesias was associated with an important decrease of mGluR5 specific binding in these areas (-37% and -48%) compared with dyskinetic animals. Moreover, an upregulation (+34%) of mGluR5 receptor binding was seen in the anterior caudate nucleus of saline treated MPTP monkeys. This study is the first to provide evidence that enhanced mGluR5 specific binding in the posterior putamen and pallidum may contribute to the pathogenesis of LIDs in PD.


Subject(s)
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , Basal Ganglia/metabolism , Parkinsonian Disorders/chemically induced , Parkinsonian Disorders/metabolism , Receptors, Metabotropic Glutamate/metabolism , Animals , Basal Ganglia/drug effects , Female , Macaca fascicularis , Ovariectomy , Receptor, Metabotropic Glutamate 5 , Tissue Distribution
5.
Neuropharmacology ; 54(2): 258-68, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18001807

ABSTRACT

L-Dopa-induced dyskinesias (LIDs), the disabling abnormal involuntary movements induced by chronic use of L-Dopa, limit the quality of life in Parkinson's disease (PD) patients. Modulation of group II metabotropic glutamate receptors (mGluR2/3) in the basal ganglia, a brain region critically involved in motor control, is considered as an alternative approach in therapy of PD. In this study, receptor binding autoradiography of [3H]LY341495, a mGluR2/3 selective radioligand, was used to investigate possible changes in mGluR2/3 in the basal ganglia of L-Dopa-treated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys having developed LIDs compared to animals in which LIDs were prevented by adjunct treatments with CI-1041, a selective antagonist of the NR1A/2B subtype of NMDA receptor, or low doses of the dopamine D2 receptor agonist, cabergoline. Our study is the first to provide evidence of: (1) the similar localization of [3H]LY341495 specific binding to mGluR2/3 in the primate basal ganglia as compared to receptor distribution measured by immunohistochemistry in human and rat as well as this ligand binding in intact rat brain; (2) no change of [3H]LY341495 specific binding in basal ganglia after nigrostriatal denervation by MPTP; and (3) a widespread reduction of [(3)H]LY341495 specific binding to mGluR2/3 in the caudate nucleus (-17% to -31%), putamen (-12% to -45%) and globus pallidus (-56 to -59%) of non-dyskinetic animals treated with L-Dopa+cabergoline as compared to controls, MPTP monkeys treated with saline, L-Dopa alone (dyskinetic) or L-Dopa+CI-1041 (non-dyskinetic). This study is the first to propose a close interaction between mGluR2/3 and dopamine D2 receptors activation in the basal ganglia.


Subject(s)
Antiparkinson Agents/adverse effects , Antiparkinson Agents/metabolism , Basal Ganglia/metabolism , Dyskinesia, Drug-Induced/metabolism , Levodopa/adverse effects , Levodopa/metabolism , Receptors, Metabotropic Glutamate/metabolism , Amino Acids/pharmacology , Animals , Autoradiography , Behavior, Animal/drug effects , Cabergoline , Caudate Nucleus/drug effects , Caudate Nucleus/metabolism , Data Interpretation, Statistical , Ergolines/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Female , Macaca fascicularis , Ovariectomy , Putamen/drug effects , Putamen/metabolism , Receptors, Metabotropic Glutamate/drug effects , Xanthenes/pharmacology
6.
Behav Brain Res ; 186(2): 161-7, 2008 Jan 25.
Article in English | MEDLINE | ID: mdl-17868931

ABSTRACT

Increased glutamatergic activity is believed to play a significant role in the development of levodopa-induced dyskinesias (LID). LID may therefore be attenuated by a reduction in glutamatergic function. This was tested pharmacologically in MPTP monkeys by increasing the formation of kynurenic acid (KYNA), a tryptophan metabolite that inhibits glutamate release and also blocks NMDA receptors directly. KYNA synthesis was stimulated by prolonged systemic administration of the kynurenine 3-hydroxylase inhibitor Ro 61-8048. Four MPTP cynomolgus monkeys received l-dopa (LD; 100mg) with benserazide (25 mg) for one month. Progressively, all these animals developed LID. Four other MPTP monkeys received Ro 61-8048 (50mg/kg) daily 3 h before administration of LD/benserazide for one month. The addition of Ro 61-8048 reduced the development of LID but did not affect the antiparkinsonian efficacy of LD. Moreover, Ro 61-8048 administration caused sustained increases in serum kynurenine and KYNA concentrations, which reverted to basal values 24 h after the last treatment. This effect of Ro 61-8048 was less pronounced in the CSF. These results demonstrate that long-lasting elevation of KYNA levels caused by prolonged inhibition of kynurenine 3-hydroxylase is associated with a significant reduction in LID but does not compromise the benefits of chronic LD therapy.


Subject(s)
Antiparkinson Agents/adverse effects , Dyskinesia, Drug-Induced/enzymology , Dyskinesia, Drug-Induced/etiology , Kynurenine 3-Monooxygenase/metabolism , Levodopa/adverse effects , Animals , Behavior, Animal/drug effects , Disease Models, Animal , Drug Interactions , Dyskinesia, Drug-Induced/prevention & control , Enzyme Inhibitors/therapeutic use , Female , Kynurenic Acid/blood , Kynurenine/blood , Kynurenine 3-Monooxygenase/antagonists & inhibitors , Macaca fascicularis , Motor Activity/drug effects , Parkinsonian Disorders/drug therapy , Quinolinic Acid/blood , Quinolinic Acid/cerebrospinal fluid , Sulfonamides/therapeutic use , Thiazoles/therapeutic use , Time Factors
8.
Trends Pharmacol Sci ; 27(10): 512-7, 2006 Oct.
Article in English | MEDLINE | ID: mdl-16908075

ABSTRACT

The long-term treatment of Parkinson's disease with L-dopa is often associated with the appearance of involuntary movements called L-dopa-induced dyskinesias. These debilitating side-effects are thought to result from an aberrant form of plasticity triggered by a combination of factors related to dopamine denervation and repeated L-dopa administration. In animal models of Parkinson's disease, dopamine denervation and repeated L-dopa administration are associated with an enhancement of opioid transmission in the basal ganglia. The exact role of this increased opioid activity is still under debate. It has been proposed that some of the changes in opioid transmission are directly involved in the genesis of L-dopa-induced dyskinesias. In this article, we suggest that changes in opioid transmission in the basal ganglia in response to denervation and repeated L-dopa therapy are, instead, part of compensatory mechanisms to prevent motor complications. Initially, these compensatory mechanisms might be sufficient to attenuate the parkinsonian syndrome and delay the appearance of involuntary movements. But with the progression of the disease and repeated exposure to L-dopa, these mechanisms eventually fail. These new insights could contribute to better understanding of the motor complications in Parkinson's disease and lead to the development or improvement of pharmacological strategies to prevent or reduce L-dopa-induced dyskinesias.


Subject(s)
Antiparkinson Agents/adverse effects , Dyskinesia, Drug-Induced/etiology , Levodopa/adverse effects , Parkinson Disease/drug therapy , Receptors, Opioid/metabolism , Antiparkinson Agents/therapeutic use , Dyskinesia, Drug-Induced/metabolism , Humans , Levodopa/therapeutic use , Parkinson Disease/metabolism
9.
Synapse ; 60(3): 239-50, 2006 Sep 01.
Article in English | MEDLINE | ID: mdl-16739115

ABSTRACT

Adenosine A(2A) receptors (A(2A)R) have received increasing attention for the treatment of L-DOPA-induced dyskinesias in Parkinson disease. In the present study, A(2A)R messenger RNA (mRNA) and receptor-specific binding in the brain of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys were studied after treatment with L-DOPA and a selective NR1A/2B NMDA receptor antagonist, CI-1041. Four MPTP monkeys received L-DOPA/benserazide and all developed dyskinesias, whereas among the four MPTP monkeys who additionally received CI-1041, only one developed mild dyskinesias. Four normal monkeys and four MPTP-treated monkeys were also studied. All MPTP monkeys had similar striatal dopamine (DA) denervation. A(2A)R mRNA levels, measured by in situ hybridization, were increased in the rostral lateral caudate and putamen of saline-treated MPTP monkeys as well as in the caudal lateral and medial putamen when compared with those of controls. A(2A)R mRNA levels remained elevated in the rostral caudate and putamen of L-DOPA-treated MPTP monkeys when compared with those of controls. A(2A)R mRNA levels of L-DOPA + CI-1041-treated monkeys were at control levels and decreased in the lateral rostral caudate and caudal putamen when compared with those of L-DOPA-treated and saline-treated MPTP monkeys respectively. No change was measured in the caudal medial putamen and caudate nucleus. A(2A)Rs labeled by autoradiography with [(3)H]SCH-58261 had lower level in the L-DOPA + CI-1041-treated MPTP monkeys compared with saline- or L-DOPA-treated MPTP and control monkeys in the rostral lateral and medial caudate and the putamen. No effect of lesion or L-DOPA treatment was measured on [(3)H]SCH-58261-specific binding. These findings suggest that blockade of NMDA receptors could prevent the development of dyskinesias by altering A(2A)Rs.


Subject(s)
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , Anti-Dyskinesia Agents , Benzoxazoles/pharmacology , Dopamine Agents , Dyskinesia, Drug-Induced/prevention & control , Parkinson Disease, Secondary/chemically induced , Parkinson Disease, Secondary/prevention & control , Piperidines/pharmacology , Receptor, Adenosine A2A/drug effects , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Animals , Antiparkinson Agents/therapeutic use , Denervation , Dopamine/metabolism , Excitatory Amino Acid Antagonists/pharmacology , Female , Image Processing, Computer-Assisted , In Situ Hybridization , Levodopa/therapeutic use , Macaca fascicularis , Motor Activity/drug effects , Neuroprotective Agents/pharmacokinetics , Neuroprotective Agents/pharmacology , Oligonucleotide Probes , Ovariectomy , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Triazoles/pharmacokinetics , Triazoles/pharmacology
10.
Ann Neurol ; 59(2): 282-8, 2006 Feb.
Article in English | MEDLINE | ID: mdl-16437566

ABSTRACT

OBJECTIVE: The objective of the present study was to investigate the effect of docosahexaenoic acid (DHA), a polyunsaturated fatty acid (omega-3), on levodopa-induced dyskinesias (LIDs) in parkinsonian 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. METHODS: We explored the effect of DHA in two paradigms. First, a group of MPTP monkeys was primed with levodopa for several months before introducing DHA. A second group of MPTP monkeys (de novo) was exposed to DHA before levodopa therapy. RESULTS: DHA administration reduced LIDs in both paradigms without alteration of the anti-parkinsonian effect of levodopa indicating that DHA can reduce the severity or delay the development of LIDs in a nonhuman primate model of Parkinson's disease. INTERPRETATION: These results suggest that DHA can reduce the severity or delay the development of LIDs in a nonhuman primate model of Parkinson's disease. DHA may represent a new approach to improve the quality of life of Parkinson's disease patients.


Subject(s)
Antiparkinson Agents/adverse effects , Docosahexaenoic Acids/therapeutic use , Dyskinesias/etiology , Levodopa/adverse effects , Analysis of Variance , Animals , Behavior, Animal , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Interactions , Dyskinesias/drug therapy , Dyskinesias/physiopathology , Female , MPTP Poisoning/chemically induced , MPTP Poisoning/drug therapy , MPTP Poisoning/physiopathology , Macaca fascicularis , Motor Activity/drug effects , Ovariectomy/methods , Severity of Illness Index , Time Factors
11.
Neurochem Int ; 48(5): 404-14, 2006 Apr.
Article in English | MEDLINE | ID: mdl-16442670

ABSTRACT

Fatty acids play a critical role in brain function but their specific role in the pathophysiology of Parkinson disease (PD) and levodopa-induced motor complications is still unknown. From a therapeutic standpoint, it is important to determine the relation between brain fatty acids and PD because the brain fatty acid content depends on nutritional intake, a readily manipulable environmental factor. Here, we report a postmortem analysis of fatty acid profile by gas chromatography in the brain cortex of human patients (12 PD patients and nine Controls) as well as in the brain cortex of monkeys (four controls, five drug-naive MPTP monkeys and seven levodopa-treated MPTP monkeys). Brain fatty acid profile of cerebral cortex tissue was similar between PD patients and Controls and was not correlated with age of death, delay to autopsy or brain pH. Levodopa administration in MPTP monkeys increased arachidonic acid content (+7%; P < 0 .05) but decreased docosahexaenoic acid concentration (-15%; P < 0.05) and total n-3:n-6 polyunsaturated fatty acids ratio (-27%; P < 0.01) compared to drug-naive MPTP animals. Interestingly, PD patients who experienced motor complications to levodopa had higher arachidonic acid concentrations in the cortex compared to Controls (+13.6%; P < 0.05) and to levodopa-treated PD patients devoid of motor complications (+14.4%; P < 0.05). Furthermore, PD patients who took an above-median cumulative dose of levodopa had a higher relative amount of saturated fatty acids but lower monounsaturated fatty acids in their brain cortex (P < 0.01). These results suggest that changes in brain fatty acid relative concentrations are associated with levodopa treatment in PD patients and in a non-human primate model of parkinsonism.


Subject(s)
Cerebral Cortex/metabolism , Fatty Acids/metabolism , Levodopa/pharmacology , Lipid Metabolism/physiology , Parkinson Disease/metabolism , Parkinsonian Disorders/metabolism , Aged , Aged, 80 and over , Animals , Arachidonic Acid/metabolism , Cerebral Cortex/drug effects , Cerebral Cortex/physiopathology , Chromatography, Gas , Dietary Fats/metabolism , Disease Models, Animal , Docosahexaenoic Acids/metabolism , Dopamine Agents/pharmacology , Dyskinesia, Drug-Induced/metabolism , Dyskinesia, Drug-Induced/physiopathology , Fatty Acids, Unsaturated/metabolism , Female , Humans , Lipid Metabolism/drug effects , Macaca fascicularis , Male , Neurons/drug effects , Neurons/metabolism , Parkinson Disease/physiopathology , Parkinsonian Disorders/physiopathology , Postmortem Changes , Species Specificity
12.
Mov Disord ; 21(1): 9-17, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16127720

ABSTRACT

Enkephalin is reported to play an important role in the pathophysiology of levodopa (LD) -induced dyskinesias. The present study investigated the effect of chronic treatment with a selective NR1A/2B N-methyl-D-aspartate (NMDA) receptor antagonist, CI-1041, on the expression of preproenkephalin-A (PPE-A) in brains of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) -treated monkeys in relation to the development of LD-induced dyskinesias. Four MPTP-monkeys received LD/benserazide alone; they all developed dyskinesias. Four other MPTP-monkeys received LD/benserazide plus CI-1041; only one of them developed mild dyskinesias at the end of the fourth week of treatment. Four normal monkeys and four saline-treated MPTP monkeys were also included. MPTP-treated monkeys had extensive and similar striatal dopamine denervation. An increase of PPE-A mRNA levels assayed by in situ hybridization was observed in the lateral putamen (rostral and caudal) and caudate nucleus (rostral) of saline-treated MPTP monkeys compared to controls, whereas no change or a small increase was observed in their medial parts. Striatal PPE-A mRNA levels remained elevated in LD-treated MPTP monkeys, whereas cotreatment with CI-1041 brought them back to control values. These findings suggest that chronic blockade of striatal NR1A/2B NMDA receptors with CI-1041 normalizes PPE-A mRNA expression and prevents the development of LD-induced dyskinesias in an animal model of Parkinson disease.


Subject(s)
Antiparkinson Agents/toxicity , Benzoxazoles/pharmacology , Dyskinesia, Drug-Induced/physiopathology , Enkephalins/physiology , Levodopa/toxicity , Parkinsonian Disorders/physiopathology , Piperidines/pharmacology , Protein Precursors/physiology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Animals , Benserazide/toxicity , Corpus Striatum/drug effects , Corpus Striatum/pathology , Corpus Striatum/physiopathology , Dopamine/metabolism , Drug Therapy, Combination , Dyskinesia, Drug-Induced/pathology , Enkephalins/genetics , Female , Gene Expression/drug effects , Macaca fascicularis , Parkinsonian Disorders/pathology , Protein Precursors/genetics , RNA, Messenger/genetics
13.
Neurobiol Aging ; 27(11): 1684-93, 2006 Nov.
Article in English | MEDLINE | ID: mdl-16253392

ABSTRACT

The steroid dehydroepiandrosterone (DHEA) is abundant in men and women and decreases rapidly during aging. Parkinson's disease (PD) is the second most common neurodegenerative disorder just behind Alzheimer. l-3,4-Dihydroxyphenylalanine (l-Dopa) therapy remains the most effective treatment but many patients develop motor complications. This study investigated the acute effect of DHEA alone and with l-Dopa in 12 females monkeys lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to model PD. DHEA administration alone improved the mean parkinsonian score at 1, 5 and 15mg/kg in moderately and severely impaired MPTP monkeys and increased blood DHEA concentrations. DHEA with a low dose of l-Dopa increased the l-Dopa effect in moderately and severely impaired MPTP monkeys. DHEA lengthened duration of the effect of the low dose of l-Dopa by 15-45min. DHEA at 1, 5 and 15mg/kg combined with a high dose of l-Dopa did not increase dyskinesias. DHEA could act by reducing inhibitory GABAergic activity in the striatal output pathways. DHEA could also be metabolized into estradiol in the brain and increase acutely dopamine activity.


Subject(s)
Antiparkinson Agents/pharmacology , Dehydroepiandrosterone/pharmacology , Dyskinesia, Drug-Induced/drug therapy , Parkinsonian Disorders/drug therapy , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , Animals , Antiparkinson Agents/administration & dosage , Antiparkinson Agents/blood , Antiparkinson Agents/pharmacokinetics , Dehydroepiandrosterone/administration & dosage , Dehydroepiandrosterone/blood , Dehydroepiandrosterone/pharmacokinetics , Dyskinesia, Drug-Induced/psychology , Female , Levodopa/administration & dosage , Levodopa/pharmacokinetics , Levodopa/pharmacology , Macaca fascicularis , Motor Activity , Parkinsonian Disorders/chemically induced , Parkinsonian Disorders/physiopathology , Parkinsonian Disorders/psychology , Severity of Illness Index
14.
Neuropharmacology ; 49(2): 165-73, 2005 Aug.
Article in English | MEDLINE | ID: mdl-15996565

ABSTRACT

Nigrostriatal dopaminergic denervation and levodopa therapy in animal models and in parkinsonian patients are associated with an enhanced opioid transmission in the striatum. The functional role of this increase has always been a subject of debate. In this study two groups of drug-naïve macaque monkeys with MPTP-induced parkinsonism were treated daily, during four weeks, with l-Dopa alone or l-Dopa plus naltrexone, a non-selective opioid receptor antagonist. The improvement of parkinsonism in all animals treated with l-Dopa alone was clearly displayed from the first day of treatment. By contrast, naltrexone co-treatment blocked the antiparkinsonian action of l-Dopa for 7-14 days. As soon as the therapeutical action of l-Dopa appeared in naltrexone-treated monkeys, the magnitude and duration of the antiparkinsonian response were similar in both groups. Furthermore, in animals treated with l-Dopa plus naltrexone the beginning of the therapeutical effect of l-Dopa was accompanied by the appearance of dyskinesias. In this group, the severity of dyskinesias during the third and fourth weeks of treatment was significantly higher than the group treated with l-Dopa alone. The results of the present study demonstrate that in de novo MPTP parkinsonian monkeys antagonizing the action of opioid receptors worsens the motor response to l-Dopa.


Subject(s)
Antiparkinson Agents/therapeutic use , Dyskinesias/etiology , Levodopa/therapeutic use , Naltrexone/adverse effects , Narcotic Antagonists/adverse effects , Parkinsonian Disorders/drug therapy , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , Analysis of Variance , Animals , Antiparkinson Agents/adverse effects , Behavior, Animal , Disease Models, Animal , Female , Macaca fascicularis , Motor Activity/drug effects , Ovariectomy/methods , Parkinsonian Disorders/chemically induced , Parkinsonian Disorders/complications , Statistics, Nonparametric , Time Factors
15.
Mov Disord ; 20(7): 792-802, 2005 Jul.
Article in English | MEDLINE | ID: mdl-15954116

ABSTRACT

Homeostatic interactions between dopamine and glutamate are central to the normal physiology of the basal ganglia. This relationship is altered in Parkinsonism and in levodopa-induced dyskinesias (LID), resulting in an upregulation of corticostriatal glutamatergic function. Kynurenic acid (KYNA), a tryptophan metabolite with antagonist activity at ionotropic glutamate receptors and the capability to inhibit glutamate release presynaptically, might therefore be of therapeutic value in LID. To evaluate this hypothesis, we used a pharmacological tool, the kynurenine 3-hydroxylase inhibitor Ro 61-8048, which raises KYNA levels acutely. Ro 61-8048 was tested in MPTP cynomolgus monkeys with a stable parkinsonian syndrome and reproducible dyskinesias after each dose of levodopa. Serum and CSF concentrations of KYNA and its precursor kynurenine increased dose-dependently after Ro 61-8048 administration, alone or in combination with levodopa. Coadministration of Ro 61-8048 with levodopa produced a moderate but significant reduction in the severity of dyskinesias while maintaining the motor benefit. These results suggest that elevation of KYNA levels through inhibition of kynurenine 3-hydroxylase constitutes a promising novel approach for managing LID in Parkinson's disease.


Subject(s)
Antiparkinson Agents/therapeutic use , Dyskinesia, Drug-Induced/drug therapy , Levodopa/therapeutic use , Mixed Function Oxygenases/metabolism , Parkinsonian Disorders/drug therapy , Analysis of Variance , Animals , Behavior, Animal/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Interactions , Female , Kynurenic Acid/metabolism , Kynurenine 3-Monooxygenase , Macaca fascicularis , Mixed Function Oxygenases/antagonists & inhibitors , Mixed Function Oxygenases/blood , Motor Activity/drug effects , Quinolinic Acid/blood , Quinolinic Acid/cerebrospinal fluid , Sulfonamides/blood , Sulfonamides/cerebrospinal fluid , Sulfonamides/pharmacology , Thiazoles/blood , Thiazoles/cerebrospinal fluid , Thiazoles/pharmacology , Time Factors
16.
J Pharmacol Exp Ther ; 314(3): 1248-56, 2005 Sep.
Article in English | MEDLINE | ID: mdl-15980060

ABSTRACT

The purpose of this study is to demonstrate that sumanirole is a novel dopamine receptor agonist with high in vitro and in vivo selectivity for the D(2) receptor subtype. Sumanirole, (R)-5,6-dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (Z)-2-butenedioate (1:1), is unique; it has greater than 200-fold selectivity for the D(2) receptor subtype versus the other dopamine receptor subtypes in radioligand binding assays. In cell-based assays, sumanirole is a fully efficacious agonist, with EC(50) values between 17 and 75 nM. In animals, sumanirole elicits many physiological responses attributed to D(2)-like receptor function. In rats, sumanirole is a full agonist for elevation of striatal acetylcholine levels (ED(50) = 12.1 micromol/kg i.p.). Sumanirole s.c. dose dependently decreased plasma prolactin levels and depressed dopamine neuron firing rates in the substantia nigra pars compacta with an ED(50) of 2.3 micromol/kg i.v. This high selectivity for D(2) receptors translates into excellent locomotor stimulant activity in animal models of Parkinson's disease. In reserpinized, alpha-methyl-para-tyrosine-treated rats, sumanirole caused a significant and sustained increase in horizontal activity at doses > or =12.5 micromol/kg s.c. In unilateral 6-hydroxydopamine-lesioned rats, sumanirole caused profound, sustained rotational behavior and was substantially more efficacious than any other agonist tested. Sumanirole-stimulated rotational behavior was blocked by the dopamine receptor antagonist haloperidol. Sumanirole dose dependently improved disability scores and locomotor activities of two of three 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned monkeys. In summary, sumanirole is the first published selective D(2) receptor agonist. The compound has activity in animal models of dopamine hypofunction and has a high level of efficacy in animal models of Parkinson's disease.


Subject(s)
Benzimidazoles/pharmacology , Dopamine Agonists/pharmacology , Parkinson Disease, Secondary/drug therapy , Receptors, Dopamine D2/agonists , Animals , CHO Cells , Cricetinae , Dose-Response Relationship, Drug , Female , MPTP Poisoning/drug therapy , Macaca fascicularis , Male , Motor Activity/drug effects , Parkinson Disease, Secondary/psychology , Rats , Rats, Long-Evans
17.
Neurobiol Dis ; 19(1-2): 266-72, 2005.
Article in English | MEDLINE | ID: mdl-15837582

ABSTRACT

Storage of motor memory involves the basal ganglia and more precisely the striatum, which receives afferents from all regions of the cerebral cortex. In Parkinsonian (MPTP) monkeys, we observed an increase in the dyskinetic response to dopaminergic agents when combined with opioid antagonists (naloxone or naltrexone) while morphine, attenuated the dyskinetic response. An interesting phenomenon observed after several acute co-administrations of naltrexone with dopaminergic agents was the manifestation of dyskinesias even after the injection of saline or naltrexone alone. However, this phenomenon was not observed when morphine was used in the same conditions. These unexpected observations concerning the acquisition of dyskinesias with saline or naltrexone alone, reported for the first time, might suggest the implication of a learning phenomenon in the induction of levodopa-induced dyskinesias.


Subject(s)
Dopamine Agents/toxicity , Dyskinesia, Drug-Induced , Naltrexone/toxicity , Parkinsonian Disorders/chemically induced , Sodium Chloride/toxicity , Animals , Dopamine Agents/administration & dosage , Dose-Response Relationship, Drug , Drug Combinations , Dyskinesia, Drug-Induced/physiopathology , Female , Macaca fascicularis , Naltrexone/administration & dosage , Parkinsonian Disorders/physiopathology , Sodium Chloride/administration & dosage
19.
Parkinsonism Relat Disord ; 10(5): 297-304, 2004 Jul.
Article in English | MEDLINE | ID: mdl-15196509

ABSTRACT

For nearly 20 years, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate model has allowed great strides to be made in our understanding of the maladaptive changes underlying the levodopa-related motor response complications occurring in most parkinsonian patients. Studies indicate that sustained dopamine D2 receptor occupancy can prevent and reverse existing dyskinesias. Recent experiments in levodopa-treated MPTP animals, co-administered either a threshold dose of cabergoline or a glutamate NMDA NR2B-selective antagonist (CI-1041), have afforded protection against dyskinesia, perhaps through presynaptic inhibition of glutamate release and blockade of supersensitive postsynaptic NMDA receptors in the striatum, respectively. Some of the biochemical events that have correlated with dyskinesias, namely upregulated GABA(A) receptors in the internal pallidum, rise in pre-proenkephalin-A gene expression in the striatum, and upregulated striatal glutamate ionotropic receptors and adenosine A(2a) receptors, may be counteracted by these preventive strategies.


Subject(s)
Disease Models, Animal , Dyskinesias/metabolism , Parkinsonian Disorders/metabolism , Animals , Dyskinesias/prevention & control , Haplorhini , Humans , Parkinsonian Disorders/prevention & control
20.
Neurobiol Dis ; 16(1): 246-53, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15207281

ABSTRACT

In parkinsonian patients as well as in primate models with levodopa-induced dyskinesias (LID), an increase in the expression of preproenkephalin in the striatal output pathways has been demonstrated. Does this increase contribute to the development of LID, or does it rather act as a protection mechanism? To clarify this question, we have investigated the effect of different doses of morphine on the dyskinetic response to L-DOPA, a D2 agonist, and a D1 agonist. We have used MPTP-treated cynomolgus monkeys with a stable parkinsonian syndrome and reproducible dyskinesias to L-DOPA. Co-administration of morphine with dopaminergic agents produces a significant reduction in the severity of dyskinesias, while it does not affect the anti-parkinsonian efficacy of the treatment. This study suggests that the increased production of opioids in the striatal projection neurons might have a protective role to compensate the changes in synaptic transmissions that are responsible for dyskinesias, rather than be the cause of dyskinesias.


Subject(s)
Dopamine Agents/adverse effects , Dyskinesia, Drug-Induced/drug therapy , Morphine/therapeutic use , Parkinsonian Disorders/drug therapy , Receptors, Opioid/agonists , Analgesics, Opioid/therapeutic use , Animals , Dopamine Agents/therapeutic use , Dose-Response Relationship, Drug , Dyskinesia, Drug-Induced/physiopathology , Female , Macaca fascicularis , Parkinsonian Disorders/physiopathology , Receptors, Opioid/physiology
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