Lee Kyung-Jae, Jang Young-Ho, Lee Hyung, Yoo Ho-Sang, Lee Seong-Ryong
Department of Pharmacology, School of Medicine, Keimyung University, Taegu 700-712, South Korea.
Eur J Neurosci. 2008 Jan;27(2):334-42. doi: 10.1111/j.1460-9568.2007.06007.x.
Previous studies have demonstrated that pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, inhibits ischemia-induced injury in various tissues including neural tissue. Pioglitazone has also been shown to reduce matrix metalloproteinase (MMP) activity. Because MMP is known to play a major role in the pathophysiology of brain ischemia, the present study was undertaken to test whether pioglitazone attenuates ischemic neuronal damage through MMP inhibition. C57BL/6 mice were subjected to global brain ischemia for 20 min. Animals were killed 72 h after ischemia. Oral pioglitazone (40 mg/kg/day, as a suspension in 0.5% carboxymethylcellulose) was administered to mice twice daily for 3 days before ischemia and twice daily after ischemia until the animals were killed. We investigated gelatinase activity by zymography and laminin immunohistochemistry. Histological analysis was also performed to test the protective effect of pioglitazone on neuronal damage. Mice treated with pioglitazone had attenuated gelatinase activity. Gelatin gel and in situ zymography showed up-regulation of gelatinase activity after ischemia. Pioglitazone significantly inhibited ischemia-induced elevation of the active form of MMP-9. Pioglitazone also reduced up-regulation of in situ gelatinase activity and laminin breakdown induced by ischemia in the hippocampus. There was marked neuronal damage in the CA1 and CA2 areas after ischemia. Neuronal damage in mice was significantly decreased by pioglitazone treatment, compared with vehicle-treated mice. Pioglitazone also inhibited TdT-mediated dUTP nick end labeling staining in CA1 and CA2 areas. Pioglitazone, a PPARgamma agonist, reduces delayed neuronal damage induced by global ischemia through inhibition of MMP-9 activity.
先前的研究表明，吡格列酮作为一种过氧化物酶体增殖物激活受体γ（PPARγ）激动剂，可抑制包括神经组织在内的多种组织中的缺血性损伤。吡格列酮还被证明可降低基质金属蛋白酶（MMP）的活性。由于已知MMP在脑缺血的病理生理学中起主要作用，因此进行了本研究以测试吡格列酮是否通过抑制MMP来减轻缺血性神经元损伤。将C57BL / 6小鼠进行全脑缺血20分钟。缺血72小时后处死动物。在缺血前3天每天给小鼠口服吡格列酮（40 mg / kg /天，以0.5％羧甲基纤维素混悬液形式），每天两次，缺血后每天两次，直至处死动物。我们通过酶谱法和层粘连蛋白免疫组织化学研究了明胶酶活性。还进行了组织学分析以测试吡格列酮对神经元损伤的保护作用。用吡格列酮治疗的小鼠的明胶酶活性减弱。明胶凝胶和原位酶谱显示缺血后明胶酶活性上调。吡格列酮可显著抑制缺血诱导的MMP-9活性形式的升高。吡格列酮还减少了海马中缺血诱导的原位明胶酶活性上调和层粘连蛋白分解。缺血后CA1和CA2区域有明显的神经元损伤。与载体处理的小鼠相比，吡格列酮处理可显著减少小鼠的神经元损伤。吡格列酮还抑制了CA1和CA2区域的TdT介导的dUTP缺口末端标记染色。吡格列酮作为一种PPARγ激动剂，通过抑制MMP-9活性减少全脑缺血诱导的迟发性神经元损伤。
