Protection against paraquat and A53T alpha-synuclein toxicity by cabergoline is partially mediated by dopamine receptors.
Both genetic and environmental factors are thought to be involved in the aetiology of Parkinson's disease (PD). Oxidative damage, mitochondrial and proteasomal dysfunction, and inflammatory change are considered to participate in PD pathogenesis. Dopamine agonists are used in the symptomatic treatment of PD but attention has recently also been focussed on their potential for use in slowing disease progression. We have studied the protective actions of the D2 dopamine agonist cabergoline in toxin (paraquat) and genetic (wild-type and mutant [A53T] alpha-synuclein) models of PD using SHSY-5Y cells. Cabergoline increased glutathione content, reduced free radical production and caspase-3 activation, increased mitochondrial membrane potential and ameliorated cell death in SHSY-5Y cells exposed to paraquat and this action was inhibited in part by D2 receptor blockade. Cabergoline also reduced the toxicity of wild-type and mutant alpha-synuclein expression following paraquat exposure by similar mechanisms. These results confirm the protective action of cabergoline in reducing cell death in two separate genetic and environmental model systems of PD.
Chau
Kai-Yin
KY
University Department of Clinical Neurosciences, Institute of Neurology (Royal Free Campus), University College London, Rowland Hill Street, London NW3 2PF, UK.
Korlipara
L V Prasad
LV
Cooper
J Mark
JM
Schapira
Anthony H V
AH
D000704:Analysis of Variance; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D000077465:Cabergoline; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D004789:Enzyme Activation; D004873:Ergolines / Q000627:therapeutic use*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D045022:Lactate Dehydrogenases / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D010269:Paraquat / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000633:toxicity
D004873:Ergolines; D017382:Reactive Oxygen Species; D017448:Receptors, Dopamine D2; D051844:alpha-Synuclein; D045022:Lactate Dehydrogenases; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3; D005978:Glutathione; D000077465:Cabergoline; D010269:Paraquat