Novel Therapeutic Effects of the Anti-Convulsant, Zonisamide, on Parkinson's Disease

Author: Murata, M.1

Source: Current Pharmaceutical Design, Volume 10, Number 6, February 2004, pp. 687-693(7)


Abstract:
We found that zonisamide (ZNS) has beneficial effects on Parkinson's disease (PD). ZNS is originally synthesized in Japan and has been used for over 10 years to treat intractable epilepsy. We administered 300 mg of ZNS to a patient with PD who incidentally had convulsive attacks. The attacks disappeared and, surprisingly, the parkinsonian symptoms improved dramatically.

An open trial of ZNS (given in addition to their anti-PD drugs) in advanced PD patients clearly showed the lessening of symptoms, especially wearing-off.

Although the effects gradually decreased after 1.5 years, more than 30% improvement of UPDRS total score was maintained up to 3 years.

Nation-wide double-blind controlled study confirmed that the small dose (50mg / day) of ZNS improved all the cardinal symptoms of PD. As for its mechanism, we showed that ZNS increases dopamine contents in the striatum by activating dopamine synthesis and the level of mRNA of tyrosine hydroxylase (TH) prior to that of TH protein.

ZNS moderately inhibits monoamine oxydase (MAO) B. It has no effects on dopamine receptors, dopamine transporter or dopamine release. ZNS has no direct effects on glutamate receptors, adenosine receptors, or serotonergic system, which have been suggested to be effective points of anti-PD drug other than dopamine system.

Therefore, it is suggested that the activation of dopamine synthesis and the moderate level of MAOB inhibition are main mechanisms of ZNS effects on PD. ZNS has significant effects on T-type Ca++ channels and oxidative stress. They may also affect the beneficial action of ZNS on PD.

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The therapy of wearing-off
Nippon Rinsho. 2004 Sep;62(9):1716-9.

* Murata M.

Department of Neurology, Musashi Hospital, National Center of Neurology and Psychiatry.

Wearing-off, predictable end of dose deterioration, is one of the major problems of long-term levodopa treatment for Parkinson's disease. The mechanisms of wearing-off are (1) loss of striatal dopamine storage, (2) change in the peripheral pharmacokinetics of levodopa and (3) modification of dopamine receptors. The main therapeutic strategy for wearing-off is continuous stimulation of dopamine system.

For this purpose, we increase frequency of levodopa doses and use long half-life dopamine agonist(continuous stimulation of dopamine receptors), COMT inhibitor and MAOB inhibitor (prolongation of the half-life of levodopa and dopamine), and zonisamide (long-term increase of dopamine synthesis).

PMID: 15462390 [PubMed - indexed for MEDLINE]