Vautier Sarah, Milane Aline, Fernandez Christine, Chacun Helene, Lacomblez Lucette, Farinotti Robert
Department of Clinical Pharmacy EA 2706, University Paris Sud XI, Chatenay-Malabry, France.
J Pharm Pharm Sci. 2009;12(2):199-208. doi: 10.18433/j3b596.
MPTP-induced dopaminergic degeneration is an experimental model commonly used to explore Parkinson's disease. Cerebral drug transport by ABC transporters in MPTP models has never been reported.
We have investigated the transport of bromocriptine through the blood-brain barrier (BBB) in a MPTP model to understand the influence of the dopaminergic degeneration on ABCB1 and ABCG2.
We have shown that in MPTP treated mice, bromocriptine is widely distributed to brain (2.3-fold versus control, p less than 0.001) suggesting either disruption of BBB or alteration of active efflux of the drug. In situ brain perfusion of [14C]- sucrose and [3H]-inulin did not evidenced a BBB disruption. Studies of ABCB1 and ABCG2 activity showed that MPTP intoxication did not alter their functionality. Conversely, ABCG2 expression studied on brain capillaries from MPTP-treated mice was decreased (1.3-fold, p less than 0.05) and ABCB1 expression increased (1.43-fold, p less than 0.05) as an off-setting of brain transport.
These data demonstrate that MPTP intoxication does not alter the BBB permeability. However, bromocriptine brain distribution is increased in MPTP animals. Hence, MPTP may interact with another transport mechanism such as uptake and/or other efflux transporters. Inflammation and Parkinson's-like lesions induced by MPTP intoxication could lead to modification of drug pharmacokinetics and have clinical consequences, such as neurotoxicity.
MPTP诱导的多巴胺能神经元变性是常用于探索帕金森病的实验模型。MPTP模型中ABC转运蛋白介导的脑内药物转运从未有过报道。
我们研究了在MPTP模型中溴隐亭通过血脑屏障（BBB）的转运情况，以了解多巴胺能神经元变性对ABCB1和ABCG2的影响。
我们发现，在MPTP处理的小鼠中，溴隐亭广泛分布于脑内（与对照组相比增加2.3倍，p<0.001），这表明要么是血脑屏障被破坏，要么是药物的主动外排发生改变。[14C] - 蔗糖和[3H] - 菊粉的原位脑灌注并未证明血脑屏障被破坏。对ABCB1和ABCG2活性的研究表明，MPTP中毒并未改变它们的功能。相反，在MPTP处理小鼠的脑毛细血管上研究发现，ABCG2的表达降低（1.3倍，p<0.05），而ABCB1的表达增加（1.43倍，p<0.05），作为对脑内转运的一种补偿。
这些数据表明，MPTP中毒不会改变血脑屏障的通透性。然而，在MPTP处理的动物中溴隐亭在脑内的分布增加。因此，MPTP可能与另一种转运机制相互作用，如摄取和/或其他外排转运蛋白。MPTP中毒诱导的炎症和帕金森样病变可能导致药物药代动力学的改变，并产生临床后果，如神经毒性。
