Neuroprotection by pramipexole against dopamine- and levodopa-induced cytotoxicity.
Pramipexole, a novel non-ergoline dopamine (DA) agonist, has been applied successfully for treatment of Parkinson's disease (PD). We report here that pramipexole can protect dopaminergic cell line Mes23.5 against dopamine- and levodopa-induced cytotoxicity possibly through a mechanism related to antioxidant activity. In the MES 23.5 cultures, DA and L-DOPA induce a dose- and time-dependent cytotoxicity, as determined by tetrazolium salt and trypan blue assays. Furthermore, an in situ terminal deoxynucleotidyl transferase assay demonstrates that DA-induced cell death is apoptotic. Pretreatment with pramipexole in a concentration range (4-100 microM) significantly attenuates DA- or L-DOPA-induced cytotoxicity and apoptosis, an action which is not blocked by D3 antagonist U-99194 A or D2 antagonist raclopride. Pramipexole also protects MES 23.5 cells from hydrogen peroxide-induced cytotoxicity in a dose-dependent manner. In cell-free system, pramipexole can effectively inhibit the formation of melanin, an end product resulting from DA or L-DOPA oxidation. These results indicate that pramipexole exerts its neuroprotective effect possibly through a mechanism, which is independent of DA receptors but related to antioxidation or scavenging of free radicals (e.g. hydrogen peroxide). As a direct DA agonist and potentially neuroprotective agent, pramipexole remains attractive in the treatment of PD.
Zou
L
L
Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA.
Jankovic
J
J
Rowe
D B
DB
Xie
W
W
Appel
S H
SH
Le
W
W
D000818:Animals; D052160:Benzothiazoles; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004298:Dopamine / Q000633:toxicity*; D018491:Dopamine Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005910:Glioma; D006822:Hybrid Cells; D007700:Kinetics; D007980:Levodopa / Q000633:toxicity*; D009447:Neuroblastoma; D018696:Neuroprotective Agents / Q000494:pharmacology*; D000077487:Pramipexole; D013844:Thiazoles / Q000494:pharmacology*
D052160:Benzothiazoles; D018491:Dopamine Agonists; D018696:Neuroprotective Agents; D013844:Thiazoles; D007980:Levodopa; D000077487:Pramipexole; D004298:Dopamine