α2-adrenoceptor antagonists -: A new approach to Parkinson's disease?

Postmortem studies have shown that noradrenergic neurotransmission is impaired in Parkinson's disease. This abnormality may have functional importance because alpha(2)-adrenoceptor antagonists, which increase central noradrenergic transmission, improve motor behaviour in various animal models of this disease. Pilot clinical data suggest that alpha(2)-antagonists may indeed have several potential indications in the treatment of Parkinson's disease: (i) 3 recent placebo-controlled studies reported an improvement in motor scores following short term intravenous or long term oral administration of two different alpha(2)-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 alpha(2)-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 alpha(2)-adrenoceptor antagonists in this disorder. It has yet to be determined whether the antiparkisonian effects of alpha(2)-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 alpha(2)-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.