The Role of the Regulatory Enzymes of Catecholamine Synthesis in Parkinson\u27s Disease

The major neuropathology of Parkinson€™s disease (PD) is the degeneration of nigrostriatal dopamine (DA), resulting in a deficiency of DA, and of the enzyme tyrosine hydroxylase (TH), which catalyzes the synthesis of l-dopa. The symptomatic treatment of PD consists of replenishing DA by administering l-dopa, which is enzymatically converted to DA in the striatum. The increase of TH activity by modification of the enzyme leads to an increased synthesis of striatal l-dopa, and thereby replenishes the missing DA more efficiently. The activity of TH is increased by protein kinase-dependent phosphorylation of the enzyme or by inhibition of dephosphorylation with specific phosphatase inhibitors. Thus, modification of TH results in an activated form of the enzyme, which might provide a basis for developing new strategies in the treatment of PD. The extraneuronal enzyme, catechol-O-methyl transferase (COMT), inactivates catecholamines by O-methylation, and its inhibition leads to increased levels of striatal DA. The availability of selective and nontoxic COMT inhibitors makes it possible to assess their therapeutic role in treatment of PD. The intraneuronal enzymes, monoamine oxidase (MAO)-A and MAO-B, inactivate catecholamines and other biogenic amines, such as serotonin, by deamination. Inhibition of these enzyme activities leads to increased levels of striatal DA. The irreversible MAO-B inhibitor selegiline was shown to exert antiparkinsonian activity, especially in the early stages of parkinsonism. Selegiline also prevents the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in MPTP-treated mice and monkeys. Its role in the prevention of the disease is under investigation in several clinical centers

Investigation of electrochemical behaviour of 3-allyl-4-hydroxy-3'-4'- dimethylazobenzene

The reductive voltammetric and polarographic behaviour of the 3-allyl-4-hydroxy-3'-4'-dimethylazobenzene at a hanging mercury drop electrode (HMDE) and static mercury drop electrode (SMDE) has been studied in Britton-Robinson (B-R) buffers in the pH range of 2.0-12.0. The 3-allyl-4-hydroxy-3'-4'-dimethylazobenzene gave one voltammetric and polarographic peak, corresponding to the reduction of the azo group to hydrazo and amine. The reduction process was found to be dependent on the pH of the supporting electrolyte. The reduction of the azo group to amino group in acidic media and hydrazo step in neutral and basic media was observed. From the observation an electrode reaction mechanism has been suggested for the compound. © 2013 by ESG

1-Methyl-4-phenylpyridinium (MPP +) but not 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) selectively destroys dopaminergic neurons in cultures of dissociated rat mesencephalic neurons

Dopaminergic neurons were studied in cultures of dissociated cells from the ventral mesencephalon of fetal rat embryos (gestational day E15–16). After a week of growth, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP +) was added to the growth medium for 24 h. Dopaminergic neurons were then visualized with tyrosine hydroxylase (TH) immunocytochemistry or catecholamine (CA) cytofluorescence. Concentrations of MPTP in the range of 10 to 100 μM obliterated CA fluorescence without affecting the number of TH-positive neurons. At concentrations greater than 100 μM, MPTP decreased the number of TH-positive neurons as well as the number of all other cell types. MPP + (0.1–10.0 μM) produced a decrease in the number of TH-positive neurons without decreasing the total number of all cell types. The findings indicate that MPP + but not MPTP is able to selectively destroy rat dopaminergic neurons in our cultures. The selective toxicity of MPP + for dopaminergic neurons was partially prevented by pretreatment and co-incubation with mazindol (a selective inhibitor of dopamine uptake) but not by desipramine or deprenil, in confirmation of the notion that MPP + enters dopaminergic neurons by the specific uptake mechanism for dopamine