Methyl-beta-carbolinium analogs of MPP+ cause nigrostriatal toxicity after substantia nigra injections in rats.
Methyl-beta-carbolinium analogs of MPP+ cause nigrostriatal toxicity after substantia nigra injections in rats.
复制标题
MPP 的甲基-β-碳啉类似物在大鼠黑质注射后引起黑质纹状体毒性。
DOI：
10.1016/0006-8993(95)00082-2
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发表时间：
1995
期刊：
影响因子：
2.9
通讯作者：
Collins,MA
中科院分区：
文献类型：
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作者：
Neafsey,EJ;Albores,R;Gearhart,D;Kindel,G;Raikoff,K;Tamayo,F;Collins,MA
将 11 种 β-碳化合物 (βC+s) 和 MPP+ 立体定向注射（5 μl 载体中的 40-200 nmol）单侧注射到麻醉的成年雄性 Sprague-Dawley 大鼠的黑质中。三周后处死大鼠。使用 HPLC 分析同侧纹状体的多巴胺和 DOPAC 水平。固定脑干注射部位并进行冠状切割。使用 NIH IMAGE 测量每只动物的最大病变面积。三种 βC+ 产生的损伤的平均面积几乎与 MPP+ 产生的损伤一样大（定义为 100%）：2,9-Me2-harman (94%)、2-Me-harmol (74%) 和 2,9-Me2-norhaman (57%)。其他三种化合物产生的损伤稍小：2-Me-骆驼蓬碱 (34%)、6-MeO-2-Meharman (29%) 和 2-Me-骆驼蓬碱 (25%)。其余化合物无效（⩽ 12%）：去甲哈曼、2-Me-去甲哈曼、2-Me-哈曼、去氢骆驼蓬碱和 2-Me-6-MeO-哈马兰。 40 nmol 剂量的 MPP+ 将同侧纹状体多巴胺降低至对照的 0.6%。没有一个 βC+ 达到这一水平，尽管有几个在 40 nmol（2,9-Me2-harman (37%)、2,9-Me2-norharman (42%) 和 2-Me-harman (63%)）或 200 nmol（2-Me-harmaline (23%)、norharman (63%) 和 200 nmol）剂量下确实显着降低了纹状体多巴胺。 2-Me-诺哈曼 (64%))。病变大小和多巴胺水平之间存在中度负相关（r = -0.65）。 βC+黑质病变区域或纹状体多巴胺水平效力与其之前描述的抑制线粒体呼吸的 IC50 值或其对培养的 PC12 细胞的毒性之间也存在中等强度的相关性 (r = 0.39−0.78)。有趣的是，我们的相关分析揭示了 βC+KiMAO-A 值与其对 PC12 LDH 释放 (r = -0.84) 或 PC12 蛋白损失 (r = 0.79) 的毒性之间存在非常强的相关性。尽管 βC+ 似乎是不如 MPP+ 特异性的毒素，但它们在人体黑质中的水平比皮质中高 8-20 倍，这使得它们在帕金森病中作为相对选择性的黑质毒素的作用是合理的。
Eleven β-carbolinium compounds (βC+s) and MPP+were stereotaxically injected (40–200 nmol in 5 μl of vehicle) unilaterally into the substantia nigra of anesthetized adult male Sprague-Dawley rats. The rats were sacrificed after three weeks. The ipsilateral striatum was analyzed for dopamine and DOPAC levels with HPLC. The brainstem injection site was fixed and cut coronally. The largest lesion area in each animal was measured using NIH IMAGE. Three βC+s produced lesions whose mean areas were nearly as large as that produced by MPP+(defined as 100%): 2,9-Me2-harman (94%), 2-Me-harmol (74%), and 2,9-Me2-norhaman (57%). Three other compounds produced somewhat smaller lesions: 2-Me-harmaline (34%), 6-MeO-2-Meharman (29%), and 2-Me-harmine (25%). The remaining compounds were ineffective (⩽ 12%): norharman, 2-Me-norharman, 2-Me-harman, harmine, and 2-Me-6-MeO-harmalan. A 40 nmol dose of MPP+reduced ipsilateral striatal dopamine to 0.6% of control. None of the βC+s approached this, although several did significantly reduced striatal dopamine at doses of either 40 nmol (2,9-Me2-harman (37%), 2,9-Me2-norharman (42%), and 2-Me-harman (63%)) or 200 nmol (2-Me-harmaline (23%), norharman (63%), and 2-Me-norharman (64%)). There was a moderate negative correlation between lesion size and dopamine level (r = −0.65). There were also moderately strong correlations (r = 0.39−0.78) between the βC+nigral lesion area or striatal dopamine level potencies and their previously described IC50 values for inhibiting mitochondrial respiration or their toxicity to PC12 cells in culture. Interestingly, our correlation analysis revealed a remarkably strong correlation between βC+KiMAO-A values and their toxicity to PC12 LDH release (r = −0.84) or PC12 protein loss (r = 0.79). Although βC+s appear to be less specific toxins than MPP+, their levels in human substantia nigra are 8–20-fold higher than in cortex, making their role as relatively selective nigral toxins in Parkinson's disease plausible.