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.
Reveron
Maria E
ME
Savelieva
Katerina V
KV
Tillerson
Jennifer L
JL
McCormack
Alison L
AL
Di Monte
Donato A
DA
Miller
Gary W
GW
D000818:Animals; D000978:Antiparkinson Agents / Q000633:toxicity*; D002452:Cell Count; D050483:Dopamine Plasma Membrane Transport Proteins; D005260:Female; D006579:Heterozygote; D007150:Immunohistochemistry; D007980:Levodopa / Q000633:toxicity*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D020258:Neurotoxicity Syndromes / Q000235:genetics / Q000378:metabolism*; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins
D000978:Antiparkinson Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; C493453:Slc18a2 protein, mouse; C493215:Slc6a3 protein, mouse; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D007980:Levodopa; D014446:Tyrosine 3-Monooxygenase