ergoline and Parkinsonian-Disorders

Although 6-hydroxydopamine-induced (6-OHDA-induced) rats are a well-known Parkinson's disease model, the effects of dopamine D2 agonists in mice with 6-OHDA-induced lesions are not completely understood. We produced mice with 6-OHDA-induced lesions and measured their total locomotion counts following administration of several dopamine D2 agonists (pramipexole, ropinirole, cabergoline, rotigotine, apomorphine, talipexole, and quinelorane). Cabergoline showed the longest duration of drug action, which was in agreement with its long-lived anti-Parkinson effects in rats and humans. In contrast, pramipexole and ropinirole had notably short durations of drug action. We demonstrated that mice with 6-OHDA-induced lesions accompanied with significant lesions in the striatum may be reasonable models to predict the action duration of anti-Parkinson drug candidates in humans.

Topics: Animals; Antiparkinson Agents; Apomorphine; Azepines; Benzothiazoles; Cabergoline; Corpus Striatum; Disease Models, Animal; Dopamine Agonists; Ergolines; Indoles; Injections, Intraventricular; Male; Mice; Motor Activity; Oxidopamine; Parkinsonian Disorders; Pramipexole; Quinolines; Receptors, Dopamine D2; Tetrahydronaphthalenes; Thiophenes

The orbitofrontal cortex and the dopaminergic system are structures involved in managing impulsivity and sensibility to reinforcements, and both are typically impaired in Parkinson's disease (PD). Also, l-DOPA treatment can contribute to the development of the 'Dopamine Dysregulation Syndrome', a syndrome that can influence the patients' personality and lead to risk-taking behaviors. In this study, we describe the case of a 42-year-old woman (LT) affected by juvenile PD, treated with both l-DOPA and dopamine agonists, who showed a sudden onset of pathological gambling (PG), as the only neuropsychiatric symptom. We assessed LT with a full neuropsychological battery and the Iowa Gambling Task (IGT), in order to describe her specific failure in decision making. LT's performance on the IGT is compared with that of 15 non-demented PD patients under therapy with dopamine agonists and no behavioral dysregulations and with that of 16 age- and education-matched healthy subjects. Results showed fully preserved memory, executive functions, and reasoning abilities for LT, but a remarkable and stable impairment in the IGT. Performance of LT on the IGT is significantly lower than that of both control groups. This case shows, for the first time, that high cognitive functioning and preserved executive functions are no guarantee for advantageous decision making, and that the onset of PG is consistent with selective orbitofrontal disruption and side-effects of dopamine agonist therapy. It is also showed that the IGT is a useful neuropsychological device to detect specific risk-taking behaviors, which compromise functioning in real life.

Topics: Adult; Antiparkinson Agents; Benzothiazoles; Cabergoline; Case-Control Studies; Compulsive Behavior; Decision Making; Dopamine Agonists; Drug Therapy, Combination; Ergolines; Female; Gambling; Humans; Levodopa; Matched-Pair Analysis; Neuropsychological Tests; Parkinsonian Disorders; Pramipexole; Reference Values

Levodopa-induced dyskinesias (LIDs) are abnormal involuntary movements induced by the chronic use of levodopa (l-Dopa) limiting the quality of life of Parkinson's disease (PD) patients. We evaluated changes of the serotonin 5-HT(2A) receptors in control monkeys, in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys and in l-Dopa-treated MPTP monkeys, without or with adjunct treatments to inhibit the expression of LID: CI-1041, a selective NR1A/2B subunit antagonist of glutamate N-methyl-d-aspartic acid (NMDA) receptor, or Cabergoline, a long-acting dopamine D(2) receptor agonist. All treatments were administered for 1 month and animals were killed 24 h after the last dose of l-Dopa. Striatal concentrations of serotonin were decreased in all MPTP monkeys investigated, as measured by high-performance liquid chromatography. [(3) H]Ketanserin-specific binding to 5-HT(2A) receptors was measured by autoradiography. l-Dopa treatment that induced dyskinesias increased 5-HT(2A) receptor-specific binding in the caudate nucleus and the anterior cingulate gyrus (AcgG) compared with control monkeys. Moreover, [(3) H]Ketanserin-specific binding was increased in the dorsomedial caudate nucleus in l-Dopa-treated MPTP monkeys compared with saline-treated MPTP monkeys. Nondyskinetic monkeys treated with CI-1041 or Cabergoline showed low 5-HT(2A) -specific binding in the posterior dorsomedial caudate nucleus and the anterior AcgG compared with dyskinetic monkeys. No significant difference in 5-HT(2A) receptor binding was observed in any brain regions examined in saline-treated MPTP monkeys compared with control monkeys. These results confirm the involvement of serotonergic pathways and the glutamate/serotonin interactions in LID. They also support targeting 5-HT(2A) receptors as a potential treatment for LID.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antiparkinson Agents; Behavior, Animal; Biogenic Amines; Brain; Cabergoline; Dopamine Agents; Dyskinesia, Drug-Induced; Ergolines; Female; Humans; Ketanserin; Levodopa; Macaca; Parkinsonian Disorders; Receptor, Serotonin, 5-HT2A

L-Dopa treatment, the gold standard therapy for Parkinson's disease, is hampered by motor complications such as dyskinesias. Recently, impairment of striatal Akt/GSK3 signaling was proposed to play a role in the mechanisms implicated in development of L-Dopa-induced dyskinesias in a rodent model of Parkinson's disease. The present experiment investigated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys, the effects on Akt/GSK3 of chronic L-Dopa treatment inducing dyskinesias compared to L-Dopa with CI-1041 (NMDA receptor antagonist) or a low dose of cabergoline (dopamine D2 receptor agonist) preventing dyskinesias. The extensive dopamine denervation induced by MPTP was associated with a decrease by about half of phosphorylated Akt(Ser473) levels in posterior caudate nucleus, anterior and posterior putamen; smaller changes were observed for phosphorylated Akt(Thr308) levels that did not reach statistical significance. Dopamine depletion reduced phosphorylated GSK3beta(Ser9) levels, mainly in posterior putamen whereas pGSK3beta(Tyr216) and pGSK3alpha(Ser21) were unchanged. In posterior caudate nucleus, anterior and posterior putamen of dyskinetic L-Dopa-treated MPTP monkeys, pAkt(Ser473) and pGSK3beta(Ser9) were elevated whereas L-Dopa+cabergoline treated MPTP monkeys without dyskinesias had lower values in posterior striatum as vehicle-treated MPTP monkeys. In non-dyskinetic MPTP monkeys treated with L-Dopa+CI-1041, putamen pAkt(Ser473) and pGSK3beta(Ser9) levels remained elevated as in dyskinetic monkeys while in posterior caudate nucleus, these levels were low as vehicle-treated and lower than L-Dopa treated MPTP monkeys. Extent of phosphorylation of Akt and GSK3beta in putamen correlated positively with dyskinesias scores of MPTP monkeys; these correlations were higher with dopaminergic drugs (L-Dopa, cabergoline) suggesting implication of additional mechanisms and/or signaling molecules in the NMDA antagonist antidyskinetic effect. In conclusion, our results showed that in MPTP monkeys, loss of striatal dopamine decreased Akt/GSK3 signaling and that increased phosphorylation of Akt and GSK3beta was associated with L-Dopa-induced dyskinesias.

Topics: Animals; Antiparkinson Agents; Benzoxazoles; Cabergoline; Corpus Striatum; Disease Models, Animal; Drug Interactions; Dyskinesia, Drug-Induced; Enzyme Inhibitors; Ergolines; Female; Glycogen Synthase Kinase 3; Levodopa; Macaca fascicularis; Oncogene Protein v-akt; Parkinsonian Disorders; Phosphorylation; Piperidines; Serine; Signal Transduction; Statistics as Topic

Both genetic and environmental factors are thought to be involved in the aetiology of Parkinson's disease (PD). Oxidative damage, mitochondrial and proteasomal dysfunction, and inflammatory change are considered to participate in PD pathogenesis. Dopamine agonists are used in the symptomatic treatment of PD but attention has recently also been focussed on their potential for use in slowing disease progression. We have studied the protective actions of the D2 dopamine agonist cabergoline in toxin (paraquat) and genetic (wild-type and mutant [A53T] alpha-synuclein) models of PD using SHSY-5Y cells. Cabergoline increased glutathione content, reduced free radical production and caspase-3 activation, increased mitochondrial membrane potential and ameliorated cell death in SHSY-5Y cells exposed to paraquat and this action was inhibited in part by D2 receptor blockade. Cabergoline also reduced the toxicity of wild-type and mutant alpha-synuclein expression following paraquat exposure by similar mechanisms. These results confirm the protective action of cabergoline in reducing cell death in two separate genetic and environmental model systems of PD.

Topics: alpha-Synuclein; Analysis of Variance; Apoptosis; Blotting, Western; Cabergoline; Caspase 3; Cell Line; Enzyme Activation; Ergolines; Glutathione; Humans; Immunohistochemistry; JNK Mitogen-Activated Protein Kinases; Lactate Dehydrogenases; Membrane Potential, Mitochondrial; Paraquat; Parkinsonian Disorders; Reactive Oxygen Species; Receptors, Dopamine D2

Levodopa-induced dyskinesias are one of the major limiting side effects encountered in the treatment of Parkinson's disease. Dopamine agonists of the D2 family are less prone to induce these abnormal involuntary movements (AIMs), and in some instances it has been proposed that they could counteract them once already established. As differences in the plasma half-life of a given DA agonist could be related with a greater or lesser propensity to induce or to counteract AIMs, we compared the effects of two D2 agonists (cabergoline and pramipexole) with different half-lives, and levodopa, at doses producing similar improvement in purposeful forelimb use, in rats with severe nigrostriatal lesion, previously sensitized to levodopa. The same therapeutic regime was subsequently used in pharmacologically naïve rats. We found that: (i) prior induction of AIMs by levodopa administration primes rats for the occurrence of AIMs during mono-therapy with pramipexole (but not with cabergoline); (ii) an intervening period of D2 agonist mono-therapy does not modify the severity of AIMs induced by subsequent mono-therapy with levodopa; iii. de novo treatment with D2 agonists is associated with a lower risk of AIMs (regardless of the severity of the lesion) and does not modify AIMs during subsequent mono-therapy with levodopa. An unexpected finding was that prior levodopa therapy sensitized rats to the therapeutic effects of D2 agonists given in mono-therapy. In summary, the use of the rat with nigrostriatal lesion to model relevant therapeutic conditions does not support that D2 agonists prevent the development of AIMs during subsequent levodopa mono-therapy or can revert the dysfunction underlying it.

Topics: Amphetamine; Animals; Antiparkinson Agents; Behavior, Animal; Benzothiazoles; Cabergoline; Disease Models, Animal; Dopamine Antagonists; Drug Interactions; Dyskinesia, Drug-Induced; Ergolines; Female; Levodopa; Mesencephalon; Oxidopamine; Parkinsonian Disorders; Pramipexole; Rats; Rats, Wistar; Stereotyped Behavior; Tyrosine 3-Monooxygenase

A 29-year-old woman with two sons developed a rest tremor and motor slowness in her right limbs. She was diagnosed as Parkinson's disease (PD) and was treated with anti-cholinergic drugs. After three years of taking a dopamine agonist (cabergoline, 4 mg per day), she became pregnant. The patient and her husband decided to have an abortion because they worried that the cabergoline might have harmed the fetus. The patient hoped to prepare for future planned birth, so we canceled the cabergoline and gradually increased her carbidopa/levodopa dose. Her motor disability gradually worsened during the pregnancy, and she developed prominent bradykinesia while taking a high dose of carbidopa/levodopa (1,000 mg per day) and a continuous infusion of levodopa. A cesarean section was performed, and the patient gave birth to a healthy baby. After the delivery, she was treated with pramipexole (2 mg per day), and her bradykinesia decreased. The initial anti-PD medication schedule for fertile female PD patients should be carefully considered to lessen the harm to the fetus, especially during organogenesis. Motor disability may worsen during pregnancy, and appropriate childcare support should be prepared.

Topics: Adult; Antiparkinson Agents; Benzothiazoles; Cabergoline; Carbidopa; Contraindications; Dopamine Agents; Dopamine Agonists; Ergolines; Family Planning Services; Female; Humans; Infant, Newborn; Levodopa; Parkinsonian Disorders; Pramipexole; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Thiazoles

Topics: Aminoquinolines; Animals; Behavior, Animal; Benzazepines; Cabergoline; Disease Models, Animal; Dopamine Agonists; Ergolines; Female; Gene Expression; Imidazoles; Infusion Pumps, Implantable; Macaca fascicularis; Motor Activity; Parkinsonian Disorders; Pulse Therapy, Drug; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Dopamine D3; RNA, Messenger

A paucity of studies are available concerning the comparative therapeutic effectiveness of presently available dopamine agonist agents in the control of Parkinson symptoms. To provide a basis for resolving this issue, we measured the circling response in unilaterally nigrotomized (6-OHDA) rats following the administration of ropinirole, pramipexole, pergolide, bromocriptine, and cabergoline. Cabergoline, and to a lesser extent pergolide, produced the most vigorous and longest lasting circling response. This response was sustained with administration of these agents over a nine day period. Bromocriptine, pramipexole and ropinirole were all less effective. These results suggest that dopamine agonists whose effect is primarily on D1 and D2 receptors are more effective than those whose actions do not include D1 activation.

Topics: Animals; Benzothiazoles; Brain; Bromocriptine; Cabergoline; Dopamine Agonists; Drug Administration Schedule; Ergolines; Indoles; Male; Motor Activity; Oxidopamine; Parkinsonian Disorders; Pergolide; Pramipexole; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, Dopamine D1; Receptors, Dopamine D2; Thiazoles