Therapeutic advances in idiopathic Parkinsonism

Abstract

Parkinson's disease (PD) is the only neurodegenerative disorder in which pharmacologic intervention has resulted in a marked decrease in morbidity and a significant delay in mortality. The discovery of striatal dopamine deficiency as the neurochemical basis of PD in 1960 was a pivotal event that led to the era of levodopa therapy. Although levodopa produces dramatic improvements in patients' symptoms, it is also associated with adverse effects that can be disabling. Some of these are felt to be related to fluctuating levels of levodopa in the plasma and brain, and as a result, research has focused on drugs that can provide more continuous dopamine receptor stimulation. Dopamine agonists and catechol-O-methyl-transferase (COMT) inhibitors have been valuable adjuncts to levodopa, but until now levodopa has remained the cornerstone of therapy. Recent studies indicate that the newer dopamine agonists may be assuming greater importance in the control of symptoms. Other drugs, such as nicotinic acetylcholine receptor agonists, neurotrophic factors and adenosine receptor antagonists are under investigation. Efforts are being concentrated on understanding the causes and mechanisms involved in the death of dopaminergic neurones in the substantia nigra. Overactivity of the subthalamic nucleus and glutamate-mediated excitotoxicity might play key roles in the genesis of the disease. Therapeutic approaches aimed at correcting these abnormalities may lead to neuroprotective therapy that can inhibit or prevent the relentless progression of nigral neuronal loss. Well- controlled clinical trials using positron emission tomography (PET) and single photon emission computerised tomography (SPECT) will assist in assessing the putative neuroprotective properties attributed to various agents.