Therapeutic Strategies in Parkinson's Disease
TREATMENT UPDATE
Editor's Note--The Decade of the Brain, now two-thirds through its course, has brought great progress in understanding, ameliorating, and even specifically treating a variety of neurological disorders. Your editor provides as a trial the following short, informative resume by Drs. Feigin and Eidelberg of new understandings and treatments of Parkinson's disease. Please advise us of your response to the idea. If you dislike the idea, please say so. If you appreciate it, please recommend the topics we should review and the length of these mini-reviews. Our goal is to educate and to please.
The clinical manifestations of Parkinson's Disease (PD) result from a progressive loss of dopaminergic neurons projecting from the substantia nigra to the striatum. Traditional pharmacotherapy of PD is aimed at improving dopaminergic neurotransmission. While several new medications being developed for PD also act by improving dopaminergic neurotransmission, others act by novel mechanisms. In addition, as knowledge of the underlying pathophysiology of the neurodegenerative process improves, new therapeutic strategies aimed at slowing the progression of PD are being sought. The introduction of several new surgical approaches has yielded promising clinical results for the treatment of advanced PD.
Currently available medications for PD include levodopa, the dopamine agonists pergolide and bromocriptine, anticholinergics such as trihexyphenidyl and benztropine, the monoamine oxidase B inhibitor deprenyl, and amantadine. Levodopa remains the most effective symptomatic therapy for PD, but combining levodopa with other medications may help to reduce response fluctuations and improve "on" time.
Experimental medications for PD that act by improving dopaminergic neurotransmission include new dopamine agonists and inhibitors of catechol-O-methyl transferase (COMT), a major mediator of dopamine breakdown. Examples of dopamine agonists under development include ropinerole, cabergoline, and pramipexole. These drugs are more specific for the dopamine D2 receptor and therefore may have more potent antiparkinsonian effects than pergolide or bromocriptine, as well as fewer side effects. COMT inhibitors that may be useful in increasing "on" time for PD patients taking levodopa include tolcapone and entecapone.
Excitotoxicity and abnormalities of mitochondrial electron transport have been implicated in the pathogenesis of PD. Therefore, agents that interfere with glutamate-mediated excitotoxicity or that bolster cellular energy production may be useful in the treatment of PD. In addition, antagonists of the glutamate N-methyl-d-aspartate (NMDA) receptor might relieve the symptoms of PD by reducing the stimulatory effect of the subthalamic nucleus (STN) on the internal globus pallidus (GPi). Antiglutamatergic drugs that appear to be well-tolerated in human beings, and therefore may be candidates for clinical trials in PD, include remacemide, riluzole, and lamotrigine. Examples of agents that might bolster cellular energy production include coenzyme Q and NADH. Finally, restorative therapy with nerve growth factors such as ciliary neurotrophic factor, brain-derived neurotrophic factor, and glial-derived neurotrophic factor may be feasible in PD. None of these new therapeutic strategies have been demonstrated to be beneficial for patients with PD, and controlled clinical trials are needed to evaluate the safety and efficacy of these therapies.
Several new surgical approaches have been developed to reduce the functional overactivity of the STN and GPi, and hence improve the symptoms of PD. Stereotactic ablation of posteroventral GPi resulted in significant improvements in "off" state bradykinesia as well as levodopa induced dyskinesias. The mechanism of therapeutic response with pallidotomy has been elucidated by functional imaging studies of brain metabolism. To date, more than 120 pallidotomies have been performed at major medical centers. A sustained improvement has been noted in some patients followed for up to four years following surgery. Promising results have also been achieved through high-frequency electrical stimulation of either GPi or STN. The outcomes of these interventions as well as embryonic dopamine cell engraphment are the focus of several ongoing clinical investigations.
In summary, a number of new therapeutic strategies for PD are showing promise in preliminary investigations. Several new pharmacotherapeutic agents are likely to become available in the near future. Additionally, as more stereotactic surgical interventions are performed, more objective information will become available to assess their role in patient management. --Andrew Feigin, MD, Assistant Attending Neurologist, New York Hospital, and David Eidelberg, MD, Director, Movement Disorders Program, New York Hospital.
Suggested Reading
1. Baron MS, et al. Treatment of advanced Parkinson's disease by internal globus pallidotomy: One-year results of a pilot study. Ann Neurol 1996;40:355-366.
2. Benabid AL, et al. Acute and long-term effects of subthalamic nucleus stimulation in Parkinson's disease. Stereotact Funct Neurosurg 1994;62:76-84.
3. Klockgether T, et al. New medical and surgical treatments for Parkinson's disease. Curr Opin Neurol 1994;7:346-352.
4. Palmer GC, et al. Neuroprotective properties of the uncompetitive NMDA receptor antagonist remacemide hydrochloride. Ann NY Acad Sci 1995;765:236-347.
5. Thomas RJ. Excitatory amino acids in health and disease. J Am Geriatr Soc 1995;43:1279-1289.
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