Fleming Jennifer C, Bao Feng, Chen Yuhua, Hamilton Eilis F, Relton Jane K, Weaver Lynne C
Spinal Cord Injury Laboratory, BioTherapeutics Research Group, Robarts Research Institute, The University of Western Ontario, London, Ontario, Canada N6A 5K8.
Exp Neurol. 2008 Dec;214(2):147-59. doi: 10.1016/j.expneurol.2008.04.024. Epub 2008 May 1.
The extent of disability caused by spinal cord injury (SCI) relates to secondary tissue destruction arising partly from an intraspinal influx of neutrophils and monocyte/macrophages after the initial injury. The integrin alpha4beta1, expressed by these leukocytes, is a key to their activation and migration into/within tissue. Therefore, blocking this integrin's functions may afford significant neuroprotection. Rats were treated intravenously with a blocking monoclonal antibody (mAb) to the alpha4 subunit of alpha4beta1 at 2 and 24 h after thoracic clip-compression SCI. Anti-alpha4beta1 treatment significantly decreased neutrophil and monocyte/macrophage influx at 3 d by 47% and 53%, respectively, and decreased neutrophil influx by 61% at 7 d after SCI. Anti-alpha4beta1 treatment also significantly reduced oxidative activity in injured cord homogenates at 3 d. For example, myeloperoxidase activity decreased by 38%, inducible nitric oxide by 44%, dichlorofluorescein (marking free radicals) by 33% and lipid peroxidation (malondialdehyde) by 42%. At 2-8 weeks after SCI, motor function improved by up to 2 points on an open-field locomotor scale. Treated rats supported weight with their hind paws instead of sweeping. At 2-4 weeks after SCI, anti-alpha4beta1 treatment decreased blood pressure responses during autonomic dysreflexia by as much as 43% and, at 2-8 weeks, decreased mechanical allodynia elicited from the trunk and hind paw by up to 54% and 40%, respectively. This improved functional recovery correlated with spared myelin-containing white matter and >10-fold more bulbospinal serotonergic axons below the injury than were in controls. The significant neurological improvement offered by this neuroprotective strategy underscores the potential for an anti-integrin treatment for SCI.
脊髓损伤（SCI）所导致的残疾程度与继发性组织破坏有关，这种破坏部分源于初始损伤后中性粒细胞以及单核细胞/巨噬细胞向脊髓内的涌入。这些白细胞所表达的整合素α4β1是其激活并迁移至组织内/在组织内迁移的关键。因此，阻断这种整合素的功能可能会提供显著的神经保护作用。在大鼠胸段夹闭压迫性脊髓损伤后2小时和24小时，静脉注射针对α4β1α4亚基的阻断性单克隆抗体（mAb）进行治疗。抗α4β1治疗在损伤后3天时分别使中性粒细胞和单核细胞/巨噬细胞的涌入显著减少了47%和53%，在损伤后7天时使中性粒细胞的涌入减少了61%。抗α4β1治疗在损伤后3天时还显著降低了损伤脊髓匀浆中的氧化活性。例如，髓过氧化物酶活性降低了38%，诱导型一氧化氮降低了44%，二氯荧光素（标记自由基）降低了33%，脂质过氧化（丙二醛）降低了42%。在脊髓损伤后2 - 8周，在旷场运动量表上运动功能改善了多达2分。接受治疗的大鼠用后爪支撑体重而非拖行。在脊髓损伤后2 - 4周，抗α4β1治疗使自主神经反射异常期间的血压反应降低了多达43%，在2 - 8周时，分别使来自躯干和后爪的机械性异常性疼痛降低了多达54%和40%。这种功能恢复的改善与保留的含髓鞘白质以及损伤下方延髓脊髓5 - 羟色胺能轴突数量比对照组多10倍以上相关。这种神经保护策略所带来的显著神经功能改善突出了抗整合素治疗脊髓损伤的潜力。
