Neurodegenerative diseases pose a substantial socioeconomic burden on society. Unfortunately, the aging world population and lack of effective cures foreshadow a negative outlook. Although a large amount of research has been dedicated to elucidating the pathologies of neurodegenerative diseases, their principal causes remain elusive. Metal ion dyshomeostasis, proteopathy, oxidative stress, and neurotransmitter deficiencies are pathological features shared across multiple neurodegenerative disorders. In addition, these factors are proposed to be interrelated upon disease progression. Thus, the development of multifunctional compounds capable of simultaneously interacting with several pathological components has been suggested as a solution to undertake the complex pathologies of neurodegenerative diseases. In this review, we outline and discuss possible therapeutic targets in Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis and molecules, previously designed or discovered as pote...

Development of Multifunctional Molecules as Potential Therapeutic Candidates for Alzheimer’s Disease, Parkinson’s Disease, and Amyotrophic Lateral Sclerosis in the Last Decade

Background: Observations in animal models suggest that A2A antagonists confer benefit by modulating dopaminergic effects on the striatal dysfunction associated with motor disability. This double-blind, placebo-controlled, proof-of-principle study evaluated the pathogenic contribution and therapeutic potential of adenosine A2A receptor–mediated mechanisms in Parkinson disease (PD) and levodopa-induced motor complications. Methods: Fifteen patients with moderate to advanced PD consented to participate. All were randomized to either the selective A2A antagonist KW-6002 or matching placebo capsules in a 6-week dose-rising design (40 and 80 mg/day). Motor function was rated on the Unified PD Rating Scale. Results: KW-6002 alone or in combination with a steady-state IV infusion of each patient’s optimal levodopa dose had no effect on parkinsonian severity. At a low dose of levodopa, however, KW-6002 (80 mg) potentiated the antiparkinsonian response by 36% (p Conclusions: The results support the hypothesis that A2A receptor mechanisms contribute to symptom production in PD and that drugs able to selectively block these receptors may help palliate symptoms in levodopa-treated patients with this disorder.

Adenosine A2A receptor antagonist treatment of Parkinson’s disease

Enormous progress has been made in the treatment of Parkinson’s disease (PD). As a result of advances in experimental therapeutics, many promising therapies for PD are emerging. Levodopa remains the most potent drug for controlling PD symptoms, yet is associated with significant complications such as the “wearing off” effect, levodopa-induced dyskinesias and other motor complications. Catechol-o-methyl-transferase inhibitors, dopamine agonists and nondopaminergic therapy are alternative modalities in the management of PD and may be used concomitantly with levodopa or one another. The neurosurgical treatment, focusing on deep brain stimulation, is reviewed briefly. Although this review has attempted to highlight the most recent advances in the treatment of PD, it is important to note that new treatments are not necessarily better than the established conventional therapy and that the treatment options must be individualized and tailored to the needs of each individual patient.

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Current approaches to the treatment of Parkinson’s disease

Objective: To delineate the frequency and nature of dystonia in multiple system atrophy (MSA). Methods: a cohort of 24 patients with clinically probable MSA over the past 10 years were prospectively followed up. Motor features were either dominated by parkinsonism (MSA-P subtype, n=18) or cerebellar ataxia (MSA-C, n=6). Classification of dystonic features and their changes with time was based on clinical observation during 6–12 monthly follow up visits. Parkinsonian features and complications of drug therapy were assessed. Most patients (22/24) died during the observation period. Neuropathological examination was confirmatory in all of the five necropsied patients. Results: At first neurological visit dystonia was present in 11 (46%) patients all of whom had been levodopa naive at this time point. Six patients (25%) exhibited cervical dystonia (antecollis) (MSA-P n=4, MSA-C n=2), five patients (21%) showed unilateral limb dystonia (MSA-P n=4; MSA-C n=1). A definite initial response to levodopa treatment was seen in 15/18 patients with MSA-P, but in none of the six patients with MSA-C. A subgroup of 12 patients with MSA-P developed levodopa induced dyskinesias 2.3 years (range 0.5–4) after initiation of levodopa therapy. Most patients had peak dose craniocervical dystonia; however, some patients experienced limb or generalised dystonia. Isolated peak dose limb chorea occurred in only one patient. Conclusion: The prospective clinical study suggests that dystonia is common in untreated MSA-P. This finding may reflect younger age at disease onset and putaminal pathology in MSA-P. Levodopa induced dyskinesias were almost exclusively dystonic affecting predominantly craniocervical musculature. Future studies are required to elucidate the underlying pathophysiology of dystonia in MSA.

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Dystonia in multiple system atrophy

Despite clinical experience with levodopa for more than three decades, the role of this agent in the treatment of Parkinson's disease (PD) has not been well defined. Clearly the most effective antiparkinsonian drug, levodopa, is associated with emergence of motor complications, particularly fluctuations and dyskinesias, as well as other side effects. In addition to these limitations, there is an ongoing debate about the potential neurotoxic effects of levodopa, suggested by some in vitro studies. However, there is no support for levodopa-induced neurotoxicity from in vivo studies. This review discusses possible mechanisms of levodopa-related complications and therapeutic strategies for their prevention and management.

Levodopa strengths and weaknesses

A new approach in the treatment of Parkinson's disease is the inhibition of catechol-O-methyl-transferase (COMT) with new generation COMT inhibitors, entacapone and tolcapone. Entacapone acts mainly peripherally whereas tolcapone acts both peripherally and centrally. They induce a dose-dependent inhibition of COMT activity in erythrocytes and a significant decrease in the plasma levels of 3-O-methyl-dopa, indicating their effectiveness as COMT inhibitors. Consequently, they increase the elimination half-life of levodopa and thus prolong the availability of levodopa to the brain without significantly affecting the C max or t max of levodopa. Clinically, the improved levodopa availability is seen as prolonged motor response to levodopa/DDC inhibitor and also as prolonged duration of dyskinesias in Parkinson's disease patients with end-of-dose fluctuations. The dyskinesias are managed by decreasing the daily levodopa dose in Parkinson's disease patients with end-of-dose fluctuations. Both pharmacokinetically and clinically the 200-mg dose of entacapone is the most effective dose compared with placebo. For tolcapone 100 and 200 mg have most often proved to be the optimal - doses. Based on the duration of COMT inhibition entacapone is administered with each levodopa/DDC inhibitor dose whereas tolcapone is given three times daily. Both entacapone and tolcapone are well-tolerated. However, there seems to be a trend for tolcapone to induce more often diarrhoea and increase in liver e transaminases compared with entacapone. Thus, COMT inhibitors are clinically significant and beneficial adjunct to levodopa therapy in Parkinson's disease patients with end-of-dose fluctuations. Their effects and significance also in the treatment of de novo patients need to be clarified.

H. M. Ruottinen

Papers

COMT inhibition in the treatment of Parkinson's disease