Pioglitazone attenuates mitochondrial dysfunction, cognitive impairment, cortical tissue loss, and inflammation following traumatic brain injury.
Pioglitazone attenuates mitochondrial dysfunction, cognitive impairment, cortical tissue loss, and inflammation following traumatic brain injury.
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DOI：
10.1016/j.expneurol.2010.10.003
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发表时间：
2011-01
影响因子：
5.3
通讯作者：
Sullivan, Patrick G.
中科院分区：
文献类型：
--
作者：
Sauerbeck, Andrew;Gao, Jianxin;Readnower, Ryan;Liu, Mei;Pauly, James R.;Bing, Guoying;Sullivan, Patrick G.
关键词：
创伤性脑损伤（TBI）后存在显著的神经病理学，包括线粒体功能障碍、皮质灰质丧失、小胶质细胞激活和认知障碍。先前的证据表明，过氧化物酶体增殖物激活受体（ppar）的激活在颅脑和脊髓损伤后提供神经保护。在目前的研究中，我们假设PPAR配体吡格列酮治疗可以促进大鼠脑外伤控制皮质冲击模型后的神经保护。动物接受单侧1.5mm控制皮质冲击，然后在损伤后15分钟开始以10mg/kg剂量给予吡格列酮，随后每24小时一次，连续5天。损伤后第1天开始，线粒体生物能量功能明显受损，吡格列酮治疗后15分钟和24小时线粒体生物能量功能减弱（p<0.05）。在另一组动物中，使用Morris水迷宫（MWM）评估认知功能，观察到在四天的测试过程中，损伤产生的潜伏期（p<0.05）和到平台的距离（p<0.05）显著增加。用吡格列酮治疗的动物表现与假动物相似，并且在MWM表现中没有表现出任何损害。损伤16天后，通过病变部位的组织切片进行量化，以确定皮质病变的大小。小鼠平均病变大小为5.09±0.73mm3，吡格列酮组病变大小为2.27±0.27mm3，比对照组减少55% （p<0.01）。拮抗剂T0070907与吡格列酮合用阻断了吡格列酮单用的保护作用。损伤后，在靠近损伤部位的皮质区域，激活的小胶质细胞数量显著增加（p<0.05）。吡格列酮治疗阻止了激活的小胶质细胞数量的增加，并且在假手术和吡格列酮治疗的动物之间没有观察到差异。从这些研究中我们得出结论，在创伤性脑损伤后，吡格列酮能够改善神经病理的多个方面。这些研究进一步支持PPAR配体，特别是吡格列酮的神经保护作用。
Following traumatic brain injury (TBI) there is significant neuropathology which includes mitochondrial dysfunction, loss of cortical grey matter, microglial activation, and cognitive impairment. Previous evidence has shown that activation of the peroxisome proliferator-activated receptors (PPARs) provide neuroprotection following traumatic brain and spinal injuries. In the current study we hypothesized that treatment with the PPAR ligand Pioglitazone would promote neuroprotection following a rat controlled cortical impact model of TBI. Animals received a unilateral 1.5mm controlled cortical impact followed by administration of pioglitazone at 10mg/kg beginning 15 minutes after the injury and subsequently every 24hrs for five days. Beginning one day after the injury there was significant impairment in mitochondrial bioenergetic function which was attenuated by treatment with Pioglitazone at 15 minutes and 24 hours (p<0.05). In an additional set of animals, cognitive function was assessed using the Morris Water Maze (MWM) and it was observed that over the course of four days of testing the injury produced a significant increase in both latency (p<0.05) and distance (p<0.05) to the platform. Animals treated with Pioglitazone performed similarly to sham animals and did not exhibit any impairment in MWM performance. Sixteen days after the injury tissue sections through the lesion site were quantified to determine the size of the cortical lesion. Vehicle treated animals had an average lesion size of 5.09±0.73mm3 and treatment with Pioglitazone significantly reduced the lesion size by 55% to 2.27±0.27mm3 (p<0.01). Co-administration of the antagonist T0070907 with Pioglitazone blocked the protective effect seen with administration of Pioglitazone by itself. Following the injury there was a significant increase in the number of activated microglia in the area of the cortex adjacent to the site of the lesion (p<0.05). Treatment with Pioglitazone prevented the increase in the number of activated microglia and no difference was observed between sham and Pioglitazone treated animals. From these studies we conclude that following TBI Pioglitazone is capable ameliorating multiple aspect of neuropathology. These studies provide further support for the use of PPAR ligands, specifically Pioglitazone, for neuroprotection.
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影响因子：
7.4
作者：
Collino, Massimo;Aragno, Manuela;Fantozzi, Roberto
通讯作者：
Fantozzi, Roberto
影响因子：
5.3
作者：
Heneka, MT;Klockgether, T;Feinstein, DL
通讯作者：
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影响因子：
3.3
作者：
Heneka, MT;Feinstein, DL;Klockgether, T
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Klockgether, T
影响因子：
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作者：
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DOI：
10.1124/jpet.108.140368
发表时间：
2008-09-01
影响因子：
3.5
作者：
Chen, Xiao Ru;Besson, Valerie C.;Marchand-Leroux, Catherine
通讯作者：
Marchand-Leroux, Catherine