Oral administration of metal chelator ameliorates motor dysfunction after a small hemorrhage near the internal capsule in rat
Oral administration of metal chelator ameliorates motor dysfunction after a small hemorrhage near the internal capsule in rat
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DOI：
10.1002/jnr.21089
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发表时间：
2007-01-01
影响因子：
4.2
通讯作者：
Nishino, Hitoo
中科院分区：
文献类型：
--
作者：
Masuda, Tadashi;Hida, Hideki;Nishino, Hitoo
脑出血会导致局部产生游离铁、自由基、细胞因子等。为了研究铁介导的自由基产生的减少是否会影响脑出血后的功能恢复，首先建立了一种改良的脑出血大鼠模型，该模型在内囊（IC）附近有一个小出血，伴有相对严重的运动功能障碍。然后口服氯碘羟喹（CQ），一种减少羟基自由基产生的铁螯合剂。将不同剂量的IV型胶原酶（1.4 μ l 1-200 U/ml）注射到Wistar大鼠的左侧纹状体IC附近，发现注射7.5 U/ml胶原酶导致IC附近的小痔病变，并伴有相对严重的运动功能障碍（IC模型）。将荧光金（FG）注射到脊髓（C3-C4）中，逆行标记感觉运动皮层和皮质脊髓束中的神经元，结果显示，在IC模型中，感觉运动皮层中检测到很少的标记神经元，FG标记的轴突消失，IC中24小时内出现FG-包括艾德-1阳性细胞。在IC模型中口服CQ后的行为评估和组织学分析表明，口服CQ防止FG标记的神经元减少，并导致更好的运动功能恢复。CQ抑制过氧化氢诱导的细胞毒性在体外少突胶质细胞，但不是在神经元。我们的数据表明，CQ改善运动功能障碍后，一个小出血附近的IC的机制，减少链反应性羟基自由基的产生少突胶质细胞。(c)2006 Wiley-Liss，Inc.
Cerebral hemorrhage leads to local production of free iron, radicals, cytokines, etc. To investigate whether a decrease of iron-mediated radical production influences functional recovery after intracerebral hemorrhage (ICH), a modified ICH rat model with a small hemorrhage near the internal capsule (IC) accompanied with relatively severe motor dysfunction was first developed. Then clioquinol (CQ), an iron chelator that reduces hydroxyl radical production, was orally administrated. Injection of different doses of Type IV collagenase (1.4 mu l 1-200 U/ml) into the left striatum near the IC in Wistar rats showed that injection of 7.5 U/ml collagenase resulted in a small hemorrhoidal lesion near the IC with relatively severe motor dysfunction (IC model). Retrograde labeling of neurons in the sensory-motor cortex and axons in the corticospinal tract using Fluoro-gold (FG) injection into the spinal cord (C3-C4) showed that few labeled neurons in the sensory-motor cortex were detected in the IC model, FG-labeled axons disappeared, and FG-including ED-1-positive cells appeared within 24 hr in the IC. Assessments of behavior and histologic analysis after oral administration of CQ in the IC model indicated that oral administration of CQ prevented a decrease of FG-labeled neurons, and resulted in better motor-function recovery. CQ inhibited hydrogen peroxide-induced cell toxicity in oligodendrocytes in vitro, but not in neurons. Our data suggests that CQ ameliorated motor dysfunction after a small hemorrhage near the IC by a mechanism that is related to reduction of chain-reactive hydroxyl radical production in oligodendrocytes. (c) 2006 Wiley-Liss, Inc.