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Cellular localization of the organic cation transporters, OCT1 and OCT2, in brain microvessel endothelial cells and its implication for MPTP-induced dopaminergic toxicity
organic cation transporters (OCTs),MPTP,amantadine,
|Publication Year :||2010|
|Abstract:||攝入1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) 會增加其具毒性之代謝物1-methyl-4- phenylpyridinium (MPP+) 於大腦的量，並進而選擇性的對多巴胺神經產生毒性，使得腦中多巴胺濃度降低，造成類似巴金森氏症的症狀。Amantadine在臨床上可用於治療巴金森氏症，但其機制尚未完全清楚。已知amantadine為有機陽離子轉運蛋白 (organic cation transporters，OCTs) 的受質。本研究目的於探討amantadine對於MPTP在血腦屏障穿透與MPTP引發之多巴胺毒性的影響，同時，本研究也探討腦血管內皮細胞上OCTs的表現和分布位置，以及OCTs在腦血管內皮細胞攝取MPTP扮演中的角色。
Exposure to the chemical 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) can lead to the presence of its toxic metabolite, 1-methyl-4-phenylpyridinium (MPP+), in the brain, which induces a selective destruction of dopaminergic nigrostriatal neurons and the occurance of Parkinson’s disease. Amantadine is used in the treatment of Parkinson’s disease. However, its mechanism is not fully understood. Amantadine is known to be as substrate of organic cation transporters (OCTs). The purpose of this study was to evaluate the effects of amantadine on blood-brain barrier (BBB) transport of MPTP, and on MPTP-induced dopaminergic toxicity. Also, the expression and cellular localization of OCTs were investigated. The role of OCTs on MPTP uptake was studied in brain microvessel endothelial cells (BMECs).
The results of in vivo brain microdialysis showed that amantadine significantly reduced the area under the time-concentration curves of MPTP and MPP+ in brain extracellular fluid in rats and mice. Likewise, amantadine increased the level of dopamine and dopamine metabolites in brain striatum of mice, compared with mice recieving MPTP only. PET scan showed amantadine ameliorated MPTP-induced dopaminergic toxicity in the brain of mice. The confocal and Western blot analyses showed that OCT1 and OCT2 were mainly expressed on the luminal side of BMECs and adult rat brain endothelial cells (ARBECs). Cellular uptake of MPTP was decreased with OCT1/OCT2 silencing in BMECs and ARBECs.
In conclusion, amantadine reduces the BBB transfer of MPTP and MPTP-induced dopaminergic toxicity in rodents, and OCT1 and OCT2 are important for MPTP transfer across the BBB.
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