Clinical Implications

The Parkinson's-Reversing Breakthrough

Parkinson Disease Cure

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When treating PD patients with exogenous L-DOPA, AAAD becomes the rate limiting step for the formation of dopamine and the potential to modulate the activity of the enzyme by pharmacological means should not be disregarded. We propose that enhancing and stabilizing AAAD activity might be an alternative approach to achieve and maintain optimal dopaminergic transmission with L-DOPA treatment, and AAAD inducers may prove to be useful L-DOPA adjuncts. Drugs that increase AAAD activity in the striatum enhance the formation of dopamine from L-DOPA, and are expected to decrease the dose of L-DOPA, smooth the rise and fall of striatal dopamine following intermittent administration of L-DOPA, and maintain relatively constant levels of intrasynaptic dopamine resulting, thus, to a more physiological receptor stimulation. Hence, L-DOPA decarboxylation enhancers could meet two important tenets for successful L-DOPA therapy: 1) to use the least amount of drug that improves disability and 2) to achieve a relatively continuous stimulation of dopamine receptors [110-112]. High doses of L-DOPA are associated with an increased risk of motor complications [113,114] and continuous dopaminergic stimulation in early PD is believed to reduce this risk [111,112,115].

Clinical studies provide implicit support for the translational inferences we made afore. The L-DOPA adjuvants amantadine, budipine and memantine, increase AAAD activity and L-DOPA decarboxylation in experimental animals (61-63), improve parkinsonian symptoms

[116-121] and reduce motor complications [121,122]. In L-DOPA treated patients, the atypical antipsychotic clozapine moderately improves motor performance [123-130] and reduces motor fluctuations and dyskinesias [122,130-136]; while, in a PD model, it augments AAAD activity and L-DOPA decarboxylation [66]. Finally, the antidepressants mianserin, nefazodone and ritanserin improve parkinsonian symptoms [137-139] and the blockade of 5-HT2A receptors enhances AAAD activity in the striatum of mice [66]. These observations call for further studies to understand the regulation of AAAD and its role in L-DOPA treatment and adjuvant L-DOPA therapies.

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