Modulation of of l‐Aromatic Amino Acid Decarboxylase by 3, 4‐dihydroxyphenylalanine in the MPTP mouse model.

Abstract

Parkinson's disease (PD) is a neurological disorder resulting from a deficiency of dopamine (DA) in the neostriatum due to degeneration of dopaminergic neurons in the substantia nigra. The major therapeutic drug for PD is L‐3,4‐dihydroxyphenylalanine (L‐DOPA), which is the precursor of DA. However, long‐term treatment of L‐DOPA induces side effects including dyskinesias, wearing‐off and on‐off phenomenon. Previous studies in our lab led to investigation of the metabolic events of L‐DOPA treatment, including the role of L‐dopa on L‐aromatic amino acid decarboxylase (LAAD), the enzyme that catalyzes the formation of DA from L‐DOPA. In this project we prepare 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) PD disease mouse model and treat them with L‐dopa at 100 mg/kg. We studied the locomotor activity of the mice and performed Western blot assay for LAAD. The results showed that the sub‐chronic administration of L‐DOPA decreased LAAD expression in the striatum of the MPTP‐PD mouse model, but increased it in the cortex. L‐DOPA generates high amounts of DA, therefore, the data suggest that DA causes a feedback or allosteric downregulation of striatal LAAD. This down‐regulation of LAAD may contribute to the wearing‐off phenomenon and may show that the key side effects of L‐dopa may be due to the disturbance of the homeostasis of the catecholamine enzymes by the overload of L‐DOPA.