Molecular Neuropharmacology Laboratory, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, SAS Nagar, Sector-67, Punjab 160062, India.
Behav Brain Res. 2011 Jan 20;216(2):606-12. doi: 10.1016/j.bbr.2010.09.001. Epub 2010 Sep 15.
Transient global cerebral ischemia results in acute neurodegeneration in selective brain areas. Global cerebral ischemic-reperfusion (IR) injury induced selective hippocampal damage results into various neurobehavioral deficits including spatial memory and learning deficiencies. In this study, we have investigated the protective effects of a nonthiazolidinedione PPARγ agonist, N-(2-benzoylphenyl)-O-[2-(methyl-2-pyridinylamino)ethyl]-l-tyrosine (GW1929), against global cerebral IR injury induced neurobehavioral deficits and brain damage in gerbils. Bilateral carotid artery occlusion induced global cerebral ischemia in gerbils resulted in neurological deficits, hyperlocomotion, reduced response latency in passive avoidance test and hippocampal damage. Hippocampal neurodegeneration after cerebral IR injury was also associated with significant increase in iNOS and MMP-9 immunoreactivity along with TNFα and IL-6 levels. Massive apoptotic DNA fragmentation as evident from increased TUNEL (terminal deoxynucleotidyl transferase mediated dUTP nick end labelling)-positive cells was also observed in the CA1 hippocampal region of IR challenged gerbils. GW1929 treatment significantly ameliorated cerebral IR induced neurological symptoms, hyperlocomotion, cognitive deficits and hippocampal neuronal damage in CA1 hippocampus region in gerbils. Significant reduction in IR injury induced iNOS and MMP-9 immunoreactivity, TNFα and IL-6 levels and apoptotic DNA fragmentation was also observed with GW1929 treatment. Pioglitazone, thiazolidinedione PPARγ agonist also exhibited similar effects on inflammatory parameters after global cerebral IR injury. In summary, this study demonstrates neuroprotective effects of GW1929 in global cerebral IR injury induced neurobehavioral deficits and brain pathology which may be attributed to reduced inflammation and apoptotic DNA fragmentation, suggesting therapeutic potential of PPARγ agonists in cerebral IR injury.
短暂性全脑缺血导致选择性脑区的急性神经退行性变。全脑缺血再灌注（IR）损伤诱导的选择性海马损伤导致各种神经行为缺陷，包括空间记忆和学习缺陷。在这项研究中，我们研究了非噻唑烷二酮 PPARγ激动剂 N-(2-苯甲酰基苯基）-O-[2-(甲基-2-吡啶基氨基）乙基]-L-酪氨酸（GW1929）对沙土鼠全脑 IR 损伤诱导的神经行为缺陷和脑损伤的保护作用。双侧颈总动脉闭塞诱导沙土鼠全脑缺血导致神经功能缺损、过度活跃、被动回避试验反应潜伏期缩短和海马损伤。脑 IR 损伤后的海马神经退行性变也与 iNOS 和 MMP-9 免疫反应性的显著增加以及 TNFα 和 IL-6 水平相关。在 IR 挑战的沙土鼠 CA1 海马区还观察到大量凋亡 DNA 片段，表现为 TUNEL（末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记）阳性细胞增加。GW1929 治疗显著改善了沙土鼠全脑 IR 诱导的神经症状、过度活跃、认知缺陷和 CA1 海马区的海马神经元损伤。GW1929 治疗还观察到 IR 损伤诱导的 iNOS 和 MMP-9 免疫反应性、TNFα 和 IL-6 水平以及凋亡 DNA 片段的显著减少。噻唑烷二酮 PPARγ激动剂吡格列酮在全脑 IR 损伤后也表现出类似的抗炎参数作用。总之，这项研究表明 GW1929 在全脑 IR 损伤诱导的神经行为缺陷和脑病理中具有神经保护作用，这可能归因于炎症和凋亡 DNA 片段的减少，表明 PPARγ 激动剂在脑 IR 损伤中的治疗潜力。
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