title: Comparable Neuroprotective Effects of Pergolide and Pramipexole on Ferrous Sulfate-Induced Dopaminergic Cell Death in Cell Culture.
abstract: BACKGROUND
  Dopamine agonists are utilized clinically as an initial treatment in younger Parkinson's disease patients to delay the side effects associated with commencement of levodopa medication. These agonists also serveas adjunctive therapeutics with levodopa to lower the incidence of adverse motor symptoms in advanced stages of the disease.
  
  
  OBJECTIVE
  To compare the neuroprotective effects of the dopamine agonists pergolide and pramipexole on ferrous sulfate-induced neurotoxicity in dopaminergic neurons from primary mesencephalic cell culture.
  
  
  METHODS
  Pergolide (0.001-1 μM) and pramipexole (0.01-200 μM) were administered to 8 day primary murine mesencephalic cultures for 24 h. in the presence or absence of desferal, sulpiride or cycloheximide. Ferrous sulfate (450 μM) was then added for 24 hrs. Lactate dehydrogenase was assayed in the supernatant, glutathione concentrations measured in cell lysates and fixed cells were stained for tyrosine hydroxylase.
  
  
  RESULTS
  Ferrous sulphate induced neurotoxity in cultures (p<0.0001) was abolished in the presence of the iron chelator desferal (p<0.008). Both pergolide (p<0.0001) and pramipexole (p<0.0001) significantly protected dopaminergic neurons against ferrous sulfate induced neurotoxicity and pramipexole helped preserve neurite morphology. Pramipexole treatment significantly reduced lactate dehydrogenase release (p<0.0001) as a measure of cellular injury. The dopamine receptor antagonist sulpiride (p<0.0001) and the protein synthesis inhibitor cycloheximide (p<0.0001) reduced the neuroprotective effects of pergolide indicating the involvement receptor stimulation and de novo protein synthesis in pergolide-mediated neuroprotection. Pramipexole also significantly reversed the decrease in cellular glutathione concentrations induced by ferrous sulfate (p<0.001).
  
  
  CONCLUSIONS
  Both pergolide and pramipexole protect dopaminergic neurons against the neurotoxicity of ferrous sulfate. Pergolide specifically protects dopaminergic neurons through activation of dopamine receptors and de novo protein synthesis whereas pramipexole shows an overall effect through an antioxidant mechanism.
authors.forename: Doreen
authors.initials: D
authors.lastname: Reichelt
authors.affiliation: Department of Pathology, Faculty of Veterinary Medicine, Assiut University, Assiut 71526, Egypt. khaledradad@hotmail.com.
authors.forename: Khaled
authors.initials: K
authors.lastname: Radad
authors.forename: Rudolf
authors.initials: R
authors.lastname: Moldzio
authors.forename: Wolf-Dieter
authors.initials: WD
authors.lastname: Rausch
authors.forename: Heinz
authors.initials: H
authors.lastname: Reichmann
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gille
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D003513:Cycloheximide / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D005296:Ferrous Compounds / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008636:Mesencephalon / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010479:Pergolide / Q000494:pharmacology*; D000077487:Pramipexole; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D018709:Statistics, Nonparametric
chemical_list: D052160:Benzothiazoles; D005296:Ferrous Compounds; D018696:Neuroprotective Agents; D011500:Protein Synthesis Inhibitors; D010479:Pergolide; C020748:ferrous sulfate; D000077487:Pramipexole; D003513:Cycloheximide; D007770:L-Lactate Dehydrogenase; D005978:Glutathione