Enhancing aromatic L-amino acid decarboxylase activity: implications for L-DOPA treatment in Parkinson's disease.
Aromatic L-amino acid decarboxylase (AAAD) is an essential enzyme for the formation of catecholamines, indolamines, and trace amines. Moreover, it is a required enzyme for converting L-DOPA to dopamine when treating patients with Parkinson's disease (PD). There is now substantial evidence that the activity of AAAD in striatum is regulated by activation and induction, and second messengers play a role. Enzyme activity can be modulated by drugs acting on a number of neurotransmitter receptors including dopamine (D1-4), glutamate (NMDA), serotonin (5-HT(1A), 5-HT(2A)) and nicotinic acetylcholine receptors. Generally, antagonists enhance AAAD activity; while, agonists may diminish it. Enhancement of AAAD activity is functional, as the formation of dopamine from exogenous L-DOPA mirrors activity. Following a lesion of nigrostriatal dopaminergic neurons, AAAD in striatum responds more robustly to pharmacological manipulations, and this is true for the decarboxylation of exogenous L-DOPA as well. We review the evidence for parallel modulation of AAAD activity and L-DOPA decarboxylation and propose that this knowledge can be exploited to optimize the formation of dopamine from exogenous L-DOPA. This information can be used as a blue print for the design of novel L-DOPA treatment adjuvants to benefit patients with PD.
Hadjiconstantinou
Maria
M
Division of Molecular Neuropsychopharmacology, Department of Psychiatry, College of Medicine, Ohio State University, Columbus, OH 43210, USA.
Neff
Norton H
NH
D000818:Animals; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000378:metabolism*; D003342:Corpus Striatum / Q000201:enzymology; D003653:Decarboxylation; D006801:Humans; D007980:Levodopa / Q000378:metabolism / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000201:enzymology; D011954:Receptors, Dopamine / Q000187:drug effects
D011954:Receptors, Dopamine; D007980:Levodopa; D001142:Aromatic-L-Amino-Acid Decarboxylases