The mitochondrial ATP-sensitive potassium channel blocker 5-hydroxydecanoate inhibits toxicity of 6-hydroxydopamine on dopaminergic neurons.
The neurotoxin 6-hydroxydopamine is commonly used in models of Parkinson's disease, and a potential factor in the pathogenesis of the disease. However, the mechanisms responsible for 6-hydroxydopamine-induced dopaminergic degeneration have not been totally clarified. Reactive oxygen species (ROS) derived from 6-OHDA uptake and intraneuronal autooxidation, extracellular 6-OHDA autooxidation, and microglial activation have been involved. The mitochondrial implication is controversial. Mitochondrial ATP-sensitive K (mitoK(ATP)) channels may provide a convergent target that could integrate these different mechanisms. We observed that in primary mesencephalic cultures and neuron-enriched cultures, treatment with the mitoK(ATP) channel blocker 5-hydroxydecanoate, inhibits the dopaminergic degeneration induced by low doses of 6-OHDA. Furthermore, 5-hydroxydecanoate blocks the 6-OHDA-induced decrease in mitochondrial inner membrane potential and inhibits 6-OHDA-induced generation of superoxide-derived ROS in dopaminergic neurons. The results suggest that low doses of 6-OHDA may generate low levels of ROS through several mechanisms, which may be insufficient to induce neuron death. However, they could act as a trigger to activate mitoK(ATP) channels, thereby enhancing ROS production and the subsequent dopaminergic degeneration. Furthermore, the present study provides additional data for considering mitoK(ATP) channels as a potential target for neuroprotection.
Rodriguez-Pallares
J
J
Laboratory of Neuroanatomy and Experimental Neurology, Department of Morphological Sciences, Faculty of Medicine, University of Santiago de Compostela, Santiago, 15782, Spain.
Parga
J A
JA
Joglar
B
B
Guerra
M J
MJ
Labandeira-Garcia
J L
JL
D018663:Adrenergic Agents / Q000633:toxicity*; D000704:Analysis of Variance; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001562:Benzimidazoles / Q000378:metabolism; D002232:Carbocyanines / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002478:Cells, Cultured; D003652:Decanoic Acids / Q000494:pharmacology*; D003981:Diazoxide / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004996:Ethidium / Q000031:analogs & derivatives; D005905:Glyburide / Q000494:pharmacology; D006880:Hydroxy Acids / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008636:Mesencephalon / Q000166:cytology; D009474:Neurons / Q000187:drug effects*; D016627:Oxidopamine / Q000633:toxicity*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012235:Rhodamines / Q000378:metabolism; D013997:Time Factors; D014316:Tritium / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
C116572:(((4-chloromethyl)benzoyl)amino)-tetramethylrhodamine; D018663:Adrenergic Agents; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D002232:Carbocyanines; D003652:Decanoic Acids; D006880:Hydroxy Acids; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D017382:Reactive Oxygen Species; D012235:Rhodamines; C117780:mitochondrial K(ATP) channel; D014316:Tritium; C067883:dihydroethidium; C068624:5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine; C052853:5-hydroxydecanoic acid; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D004996:Ethidium; D003981:Diazoxide; D005905:Glyburide; D004298:Dopamine