Microglial activation induced by brain trauma is suppressed by post-injury treatment with a PARP inhibitor.
Microglial activation induced by brain trauma is suppressed by post-injury treatment with a PARP inhibitor.
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DOI：
10.1186/1742-2094-9-31
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发表时间：
2012-02-15
影响因子：
9.3
通讯作者：
Swanson RA
中科院分区：
文献类型：
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作者：
d'Avila JC;Lam TI;Bingham D;Shi J;Won SJ;Kauppinen TM;Massa S;Liu J;Swanson RA
创伤性脑损伤（TBI）诱导小胶质细胞活化。活化的小胶质细胞反过来会增加继发性损伤并损害恢复。这种先天免疫应答需要数小时至数天才能完全显现，从而为治疗干预提供了临床相关的机会窗口。小胶质细胞活化部分受聚（ADP-核糖）聚合酶-1（PARP-1）调节。抑制PARP-1活性可抑制NF-κ B依赖性基因转录，从而阻断小胶质细胞活化的几个方面。在这里，我们评估了PARP抑制剂INO-1001在大鼠皮质撞击后抑制小胶质细胞活化的功效。对大鼠进行受控的皮质撞击，随后在TBI后20 - 24小时开始用10 mg/kg的INO-1001（或单独的载体）治疗。在几个时间点收获脑，使用小胶质细胞活化（形态学和CD 11b表达）、星形胶质细胞活化（GFAP）和神经元存活（NeuN）的标志物进行炎症和神经元存活的组织学评价。在TBI后8周，还使用测量前肢灵活性来评估大鼠：胶带试验、圆筒试验和粉丝试验。在损伤后5至7天观察到峰值小胶质细胞和星形胶质细胞活化。INO-1001显著降低了病变周围皮质和同侧海马中的小胶质细胞活化。在用INO-1001或媒介物处理12天随后不用药4天的大鼠中未观察到反弹性炎症。炎症的减少与损伤周围皮层神经元存活的增加有关，并且在TBI后8周进行的前肢灵活性测试中表现改善。TBI后用PARP抑制剂治疗12天，在损伤后20小时给予第一剂，可以减少炎症并改善组织学和功能结果。
Traumatic brain injury (TBI) induces activation of microglia. Activated microglia can in turn increase secondary injury and impair recovery. This innate immune response requires hours to days to become fully manifest, thus providing a clinically relevant window of opportunity for therapeutic intervention. Microglial activation is regulated in part by poly(ADP-ribose) polymerase-1 (PARP-1). Inhibition of PARP-1 activity suppresses NF-kB-dependent gene transcription and thereby blocks several aspects of microglial activation. Here we evaluated the efficacy of a PARP inhibitor, INO-1001, in suppressing microglial activation after cortical impact in the rat. Rats were subjected to controlled cortical impact and subsequently treated with 10 mg/kg of INO-1001 (or vehicle alone) beginning 20 - 24 hours after the TBI. Brains were harvested at several time points for histological evaluation of inflammation and neuronal survival, using markers for microglial activation (morphology and CD11b expression), astrocyte activation (GFAP), and neuronal survival (NeuN). Rats were also evaluated at 8 weeks after TBI using measures of forelimb dexterity: the sticky tape test, cylinder test, and vermicelli test. Peak microglial and astrocyte activation was observed 5 to 7 days after this injury. INO-1001 significantly reduced microglial activation in the peri-lesion cortex and ipsilateral hippocampus. No rebound inflammation was observed in rats that were treated with INO-1001 or vehicle for 12 days followed by 4 days without drug. The reduced inflammation was associated with increased neuronal survival in the peri-lesion cortex and improved performance on tests of forelimb dexterity conducted 8 weeks after TBI. Treatment with a PARP inhibitor for 12 days after TBI, with the first dose given as long as 20 hours after injury, can reduce inflammation and improve histological and functional outcomes.