Lesional RhoA+ cell numbers are suppressed by anti-inflammatory, cyclooxygenase-inhibiting treatment following subacute spinal cord injury
Lesional RhoA+ cell numbers are suppressed by anti-inflammatory, cyclooxygenase-inhibiting treatment following subacute spinal cord injury
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DOI：
10.1002/glia.20031
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发表时间：
2004-09-01
期刊：
影响因子：
6.2
通讯作者：
Schluesener, HJ
中科院分区：
文献类型：
--
作者：
Schwab, JM;Conrad, S;Schluesener, HJ
抑制小GT酶RhoA或其下游靶点Rho相关卷曲激酶（ROCK）已被证明可促进成年大鼠脊髓损伤（SCI）后轴突再生并改善功能恢复。RhoA还涉及延迟的继发性损伤病理生理学，如自由基形成和内皮完整性丧失导致水肿形成。在本报告中，我们分析了中枢神经系统（CNS）允许的，脓毒神经保护的，抗炎的环氧合酶-1/-2（考克斯-1/-2）抑制剂吲哚美辛在中枢神经系统有效剂量（2 mg/kg/d）对亚急性脊髓损伤后病变RhoA表达的影响。在仅接受载体的对照大鼠中，RhoA（+）细胞在病变部位积聚（Th 8）。在SCI后第3天，RhoA（+）细胞成分主要由小胶质细胞/巨噬细胞和多单核粒细胞组成，但很少有反应性星形胶质细胞。与此相反，在Verum组中，RhoA细胞的损伤数量被吲哚美辛治疗减少超过60%（P < 0.0001）。炎症依赖性RhoA表达可通过环氧合酶抑制提出免疫相关机制。我们的研究结果确定了考克斯阻滞剂作为一个安全的，协同的，辅助治疗的选择与细胞特异性的方法相结合，以Rho失活，有效地减少池RhoA（+）细胞在损伤部位后SCI的候选人。(C)2004 Wiley-Liss，Inc.
Inhibition of the small GTPase RhoA or its downstream target Rho-associated coiled kinase (ROCK) has been shown to promote axon regeneration and to improve functional recovery following spinal cord injury (SCI) in the adult rat. RhoA has also been implicated in delayed secondary injury pathophysiology, such as free radical formation and loss of endothelial integrity leading to edema formation. In the present report, we have analyzed the effect of the central nervous system (CNS) permissive, putatively neuroprotective, anti-inflammatory cyclooxygenase-1/-2 (COX-1/-2) inhibitor indomethacin in CNS effective dosage (2 mg/kg/day) on lesional RhoA expression following subacute spinal cord injury. In control rats receiving vehicle alone, RhoA(+) cells accumulate at the lesion site (Th8). At day 3 following SCI, the RhoA(+) cellular composition is composed prevailingly of microglia/macrophages and polymononuclear granulocytes, but few reactive astrocytes. In contrast, in the Verum group, lesional numbers of RhoA cells were reduced by indomethacin treatment by more than 60% (P < 0.0001). Inflammation-dependent RhoA expression accessible by cyclooxygenase inhibition proposes an immune-related mechanism. Our results identify COX blockers as candidates for a safe, synergistic, adjuvant treatment option in combination with cell-specific approaches to Rho inactivation, effectively minimizing the pool of RhoA(+) cells at the lesion site following SCI. (C) 2004 Wiley-Liss, Inc.