title: Chronic levodopa is not toxic for remaining dopamine neurons, but instead promotes their recovery, in rats with moderate nigrostriatal lesions.
abstract: Orally administered levodopa remains the most effective symptomatic treatment for Parkinson's disease (PD). The introduction of levodopa therapy is often delayed, however, because of the fear that it might be toxic for the remaining dopaminergic neurons and, thus, accelerate the deterioration of patients. However, in vivo evidence of levodopa toxicity is scarce. We have evaluated the effects of a 6-month oral levodopa treatment on several dopaminergic markers, in rats with moderate or severe 6-hydroxydopamine-induced lesions of mesencephalic dopamine neurons and sham-lesioned animals. Counts of tyrosine hydroxylase (TH)-immunoreactive neurons in the substantia nigra and ventral tegmental area showed no significant difference between levodopa-treated and vehicle-treated rats. In addition, for rats of the sham-lesioned and severely lesioned groups, immunoradiolabeling for TH, the dopamine transporter (DAT), and the vesicular monoamine transporter (VMAT2) at the striatal level was not significantly different between rats treated with levodopa or vehicle. It was unexpected that quantification of immunoautoradiograms showed a partial recovery of all three dopaminergic markers (TH, DAT, and VMAT2) in the denervated territories of the striatum of moderately lesioned rats receiving levodopa. Furthermore, the density of TH-positive fibers observed in moderately lesioned rats was higher in those treated chronically with levodopa than in those receiving vehicle. Last, that chronic levodopa administration reversed the up-regulation of D2 dopamine receptors seen in severely lesioned rats provided evidence that levodopa reached a biologically active concentration at the basal ganglia. Our results demonstrate that a pharmacologically effective 6-month oral levodopa treatment is not toxic for remaining dopamine neurons in a rat model of PD but instead promotes the recovery of striatal innervation in rats with partial lesions.
authors.affiliation: INSERM U289, Hôpital de la Salpêtrière, Paris, France.
authors.forename: M G
authors.initials: MG
authors.lastname: Murer
authors.forename: G
authors.initials: G
authors.lastname: Dziewczapolski
authors.forename: L B
authors.initials: LB
authors.lastname: Menalled
authors.forename: M C
authors.initials: MC
authors.lastname: García
authors.forename: Y
authors.initials: Y
authors.lastname: Agid
authors.forename: O
authors.initials: O
authors.lastname: Gershanik
authors.forename: R
authors.initials: R
authors.lastname: Raisman-Vozari
mesh_terms: D000661:Amphetamine; D000818:Animals; D000978:Antiparkinson Agents / Q000633:toxicity*; D001058:Apomorphine; D001522:Behavior, Animal / Q000187:drug effects; D002352:Carrier Proteins / Q000032:analysis; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists; D018492:Dopamine Antagonists / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D005260:Female; D007457:Iodine Radioisotopes; D007980:Levodopa / Q000633:toxicity*; D008562:Membrane Glycoproteins / Q000032:analysis; D026901:Membrane Transport Proteins; D009412:Nerve Fibers / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology; D009419:Nerve Tissue Proteins / Q000032:analysis; D009479:Neuropeptides; D018377:Neurotransmitter Agents / Q000032:analysis; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D016548:Prosencephalon / Q000737:chemistry / Q000166:cytology; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000737:chemistry / Q000166:cytology*; D013469:Sulpiride / Q000494:pharmacology; D013565:Sympatholytics; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis; D017557:Ventral Tegmental Area / Q000737:chemistry / Q000166:cytology; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins
chemical_list: D000978:Antiparkinson Agents; D002352:Carrier Proteins; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D007457:Iodine Radioisotopes; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D018377:Neurotransmitter Agents; C493454:Slc18a2 protein, rat; C493216:Slc6a3 protein, rat; D013565:Sympatholytics; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D007980:Levodopa; D013469:Sulpiride; D016627:Oxidopamine; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase; D001058:Apomorphine; D004298:Dopamine