Effects of an alpha2 antagonist ina 20-year-old Java monkey with MPTP-induced parkinsonian signs

Colpaert, Françis C.; Degryse, Anne‐Dominique; Craenendonck, Hansfried Van

doi:10.1016/0361-9230(91)90106-t

Cited by 26 publications

(12 citation statements)

References 29 publications

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“…For one, α 2 -adrenoceptors may influence the mechanisms underlying PD signs in our model as idazoxan administered with the vehicle was capable of reversing the parkinsonian features in half of the animals. This finding supports other studies in MPTP monkeys which have similarly reported a beneficial symptomatic effect in a limited number of animals (n = 1-2) using idazoxan (Bezard et al 1997) and the α 2 -adrenoceptor antagonist R47243 (Clopaert et al 1991). The present results also indicate that idazoxan has a facilitatory influence on DA-mediated locomotor activity in MPTP-exposed cynomolgus monkeys as it can potentiate L-dopa-induced increase in locomotor activity after repeated administrations.…”

Section: Discussionsupporting

confidence: 93%

Noradrenoceptor antagonism with idazoxan improves l-dopa-induced dyskinesias in MPTP monkeys

Grondin

Tahar

Doan

et al. 2000

Naunyn-Schmiedeberg's Arch Pharmacol

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Treatment of Parkinson's disease with L-dopa is plagued in a majority of patients by dyskinesias. Noradrenaline/dopamine interactions are proposed on behavioral, biochemical, physiological and anatomical grounds. The aim of the study was to test the potential antidyskinetic effect of the alpha2-adrenoceptor antagonist, idazoxan, in a primate model of Parkinson's disease. Six female cynomolgus monkeys previously rendered parkinsonian by the toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and presenting an unchanged syndrome for several months were used. All responded readily to L-dopa but had developed dyskinesias which were manifested with each dose. In the first part of the study, seven doses of idazoxan (ranging from 0.25 mg/kg to 10 mg/kg, p.o.) were administered together with the vehicle or in combination with a fixed dose of L-dopa/benserazide (100/25 mg, p.o.). In the second part of the study, a fixed dose of idazoxan (7.5 mg/kg) was administered daily for 10 days and L-dopa was added to idazoxan on days 1, 4, 7 and 10. Vehicle (empty capsule) was used as control. Idazoxan, by itself (ranging from 5 mg/kg to 10 mg/kg), increased locomotor activity and improved the disability score with virtually no dyskinesias in three animals. In combination with L-dopa, idazoxan did not impair the antiparkinsonian response but significantly reduced dyskinesias in all six animals up to 65% at doses of 7.5 mg/kg and 10 mg/kg and delayed their onset, so that the "ON" state without dyskinesias was prolonged. The antidyskinetic effect of idazoxan was maintained when repeatedly administered for 10 days. On day 10, the locomotor response to L-dopa was significantly potentiated by chronic administration of idazoxan. Our results indicate that idazoxan has some antiparkinsonian effect of its own and may constitute a useful adjunct to L-dopa as it can reduce dyskinesias without impairing the relief of symptoms, this effect being maintained over time in this model.

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Section: Discussionsupporting

confidence: 93%

Noradrenoceptor antagonism with idazoxan improves l-dopa-induced dyskinesias in MPTP monkeys

Grondin

Tahar

Doan

et al. 2000

Naunyn-Schmiedeberg's Arch Pharmacol

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“…Pharmacological manipulations of the noradrenergic system by alpha 2 antagonists and agonists have been used in treating the symptoms of Parkinson's patients and suppress development of symptoms in PD animal models (Cash et al . 1984; Colpaert 1987, 1991; Fornai et al . 1995; Grondin et al .…”

Section: Discussionmentioning

confidence: 99%

Reduced MPTP toxicity in noradrenaline transporter knockout mice

Rommelfanger

Weinshenker

Miller

2004

Journal of Neurochemistry

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The noradrenergic neurons of the locus coeruleus (LC) are damaged in Parkinson's disease (PD). Neurotoxin ablation of the LC noradrenergic neurons has been shown to exacerbate the dopaminergic toxicity of MPTP, suggesting that the noradrenergic system protects dopamine neurons. We utilized mice that exhibit elevated synaptic noradrenaline (NA) by genetically deleting the noradrenaline transporter (NET), a key regulator of the noradrenergic system (NET KO mice). NET KO and wild-type littermates were administered MPTP and striatal dopamine terminal integrity was assessed by HPLC of monoamines, immmunoblotting for dopaminergic markers and tyrosine hydroxylase (TH) immunohistochemistry. MPTP significantly reduced striatal dopamine in wild-type mice, but not in the NET KO mice. To confirm that the protection observed in the NET KO mice was due to the lack of NET, we treated wild-type mice with the specific NET inhibitor, nisoxetine, and then challenged them with MPTP. Nisoxetine conferred protection to the dopaminergic system. These data indicate that NA can modulate MPTP toxicity and suggest that manipulation of the noradrenergic system may have therapeutic value in PD.

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“…Antagonists of α 2 -adrenoceptors are a prime example. These compounds elicit little improvement in parkinsonian symptoms if given alone 135,136 , but they exert anti-dyskinetic actions when given in combination with levodopa in rat, monkey and humans [137][138][139] . The fact that α 2 -adrenergic antagonists can markedly reduce dyskinesia elicited by levodopa, but not by dopamine agonists 140 , indicates that our understanding of treatmentrelated dyskinesia in PD is far from complete.…”

Section: R E V I E W Smentioning

confidence: 99%

Pathophysiology of levodopa-induced dyskinesia: Potential for new therapies

2001

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Involuntary movements--or dyskinesias--are a debilitating complication of levodopa therapy for Parkinson's disease, and is experienced in most patients. Despite the importance of this problem, little was known about the cause of dyskinesia until recently; however, this situation has changed significantly in the past few years. Our increased understanding of levodopa-induced dyskinesia is not only valuable for improving patient care, but also in providing us with new insights into the functional organization of the basal ganglia and motor systems.

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Effects of an alpha2 antagonist ina 20-year-old Java monkey with MPTP-induced parkinsonian signs

Cited by 26 publications

References 29 publications

Noradrenoceptor antagonism with idazoxan improves l-dopa-induced dyskinesias in MPTP monkeys

Noradrenoceptor antagonism with idazoxan improves l-dopa-induced dyskinesias in MPTP monkeys

Reduced MPTP toxicity in noradrenaline transporter knockout mice

Pathophysiology of levodopa-induced dyskinesia: Potential for new therapies

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