Dopamine Sequestration Research Articles

Pathogenesis of parkinson's disease: dopamine, vesicles and α-synuclein

Parkinson's disease is a devastating neurological condition that affects at least four million people. A striking feature of this disorder is the preferential loss of dopamine-producing neurons in the midbrain. Several aetiological triggers have been linked to Parkinson's disease, including genetic mutations and environmental toxins, but the pathway that leads to cell death is unknown. Recent developments have shed light on the pathogenic mechanisms that underlie the degeneration of these cells. We propose that defective sequestration of dopamine into vesicles, leading to the generation of reactive oxygen species in the cytoplasm, is a key event in the demise of dopaminergic neurons in Parkinson's disease, and might represent a common pathway that underlies both genetic and sporadic forms of the disorder.

L-DOPA Does Not Cause Neurotoxicity in VMAT2 Heterozygote Knockout Mice

One of the most useful treatments of Parkinson’s disease (PD) is dihydroxyphenylalanine ( l-DOPA) administration. However, l-DOPA has been suggested to be toxic to dopamine (DA) neurons and perhaps contribute to the progression of the disease. Sequestration of DA and dopaminergic neurotoxins into vesicles by the vesicular monoamine transporter 2 (VMAT2) is a key factor in preventing cellular damage. Mice with reduced expression of VMAT2 (VMAT2 heterozygote knockout mice; VMAT2 (+/−)) are more sensitive to the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and methamphetamine. In this study, we subjected VMAT2 (+/−) mice to subchronic administration of l-DOPA to determine if it was toxic in this model. VMAT2 wild-type (VMAT2 (+/+)) and VMAT2 (+/−) mice were given i.p. injections of l-DOPA:carbidopa (50:5 mg/kg) three times a day for 28 days. Biochemical analysis revealed a significant increase in striatal DA levels in both groups of mice treated with l-DOPA. l-DOPA treatment significantly decreased DAT levels in VMAT2 (+/+) mice, but not in VMAT2 (+/−) mice. VMAT2 protein levels, an index of terminal integrity and the number of tyrosine hydroxylase (TH)-positive nigral cells remained unchanged after l-DOPA treatment. These data indicate that in an animal model that displays increased susceptibility to dopaminergic injury, a subchronic administration of l-DOPA does not induce toxicity.