Pharmacological approaches to counter the toxicity of Dopa.
Dopa and related catecholamines and their degradation products have been demonstrated to have neurotoxic potential in a number of cellular and in vivo experiments. Several mechanisms have been hypothesized to be involved including generation of prooxidant products that subsequently oxidize membrane lipids and exposed macromolecules. We have utilized a neuronal culture of cerebellar granule cells to study the toxicity of Dopa and the ability of various neuroprotective and antiparkinsonian compounds to offer protection therefrom. This model is apparently based on the ability of Dopa to non-enzymatically induce an oxidative injury to the neuronal cultures. Evidence for this arises from the equal neurotoxic potency of L- and D-Dopa in these cells and the ability of catalase, superoxide dismutase and glutathione to protect the neurons from this toxicity. Further, we found that the neuroprotective antioxidant, PNU-101033 is more effective and potent than vitamin E and deprenyl in this regard. Similarly the D2/D3 agonist, pramipexole is also capable of blocking Dopa toxicity in this model and this effect is independent of dopamine receptor affinity as both enantiomers are equally potent in this assay but disparate in receptor affinity. Also the protection by pramipexole is accompanied by the preservation of reduced glutathione. Thus, this activity seems to be a function of the oxidation potential of pramipexole and it's consequent antioxidant property. Potent antioxidants are effective blockers of Dopa toxicity. If the mechanisms involved in this toxicity have relevance to the progression of Parkinson's pathology in Dopa treated (or untreated) patients, these compounds have the potential to alter the course of the illness.
VonVoigtlander
P F
PF
CNS Diseases Research, Pharmacia & Upjohn, Inc., Kalamazoo, Michigan, USA.
Fici
G J
GJ
Althaus
J S
JS
D000818:Animals; D052160:Benzothiazoles; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects* / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000187:drug effects* / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism / Q000494:pharmacology; D007980:Levodopa / Q000009:adverse effects* / Q000037:antagonists & inhibitors; D018696:Neuroprotective Agents / Q000494:pharmacology*; D000077487:Pramipexole; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012642:Selegiline / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D014810:Vitamin E / Q000494:pharmacology
D052160:Benzothiazoles; D018696:Neuroprotective Agents; C112281:PNU 101033E; D011743:Pyrimidines; D011758:Pyrroles; D013844:Thiazoles; D014810:Vitamin E; D012642:Selegiline; D007980:Levodopa; D000077487:Pramipexole; D005978:Glutathione