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α2-Adrenoceptor Antagonists

A New Approach to Parkinson’s Disease?

  • Drug Therapy
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Abstract

Postmortem studies have shown that noradrenergic neurotransmission is impaired in Parkinson’s disease. This abnormality may have functional importance because (α2-adrenoceptor antagonists, which increase central noradrenergic transmission, improve motor behaviour in various animal models of this disease.

Pilot clinical data suggest that (α2-antagonists may indeed have several potential indications in the treatment of Parkinson’s disease: (i) 3 recent placebocontrolled studies reported an improvement in motor scores following short term intravenous or long term oral administration of two different (α2-antagonists (idazoxan and efaroxan), suggesting that both drugs provide symptomatic benefit with regard to motor symptoms, especially rigidity and akinesia; (ii) an acute oral challenge with idazoxan reduced the severity of ‘peak-dose’ levodopa-induced dyskinesia, one of the most disabling complications of long term therapy with that drug, in a placebo-controlled study; (iii) biochemical and pharmacological experiments have suggested that levodopa-resistant parkinsonian symptoms, such as frozen gait, cognitive dysfunction, depressive state and dysautonomia, could be improved by enhancing central noradrenergic function; however, controlled clinical studies are necessary to evaluate the usefulness of (α2-adrenoceptor antagonists in these indications; and (iv) some preliminary experimental data support the hypothesis that noradrenergic mechanisms could be involved in the progression of Parkinson’s disease; thus, there is a rationale for testing the putative neuroprotective effects of (α2-adrenoceptor antagonists in this disorder.

It has yet to be determined whether the antiparkisonian effects of (α2-antagonists are due to a direct effect of noradrenaline (norepinephrine) on motor systems or to an indirect effect, by means of noradrenergic interactions with dopamine or other neurotransmitters controlling motor behaviour or via other mechanisms.

A careful evaluation of (α2-antagonists in the treatment of Parkinson’s disease must also consider their potential adverse effects, because these drugs possess cardiovascular and psychiatric properties which might compromise their risk-benefit ratio.

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Authors and Affiliations

  1. Service de Pharmacologie Médicale et Clinique, INSERM U317-U455, Toulouse, France

    Christine Brefel-Courbon, Jean-Michel Senard, Jean-Louis Montastruc &  Olivier Rascol

  2. Centre d’Investigation Clinique, Toulouse, France

    Claire Thalamas &  Olivier Rascol

  3. Institut de Recherche Pierre Fabre, Boulogne, France

    Hélène Peyro Saint Paul

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  1. Christine Brefel-Courbon
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  2. Claire Thalamas
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  3. Hélène Peyro Saint Paul
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  4. Jean-Michel Senard
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  5. Jean-Louis Montastruc
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  6. Olivier Rascol
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Correspondence to Olivier Rascol.

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Brefel-Courbon, C., Thalamas, C., Peyro Saint Paul, H. et al. α2-Adrenoceptor Antagonists. Mol Diag Ther 10, 189–207 (1998). https://doi.org/10.2165/00023210-199810030-00004

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