Complement Component 5 (C5) Deficiency Improves Cognitive Outcome After Traumatic Brain Injury and Enhances Treatment Effects of Complement Inhibitors C1-Inh and CR2-Crry in a Mouse Model.
Complement Component 5 (C5) Deficiency Improves Cognitive Outcome After Traumatic Brain Injury and Enhances Treatment Effects of Complement Inhibitors C1-Inh and CR2-Crry in a Mouse Model.
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DOI：
10.1089/neur.2023.0024
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发表时间：
2023
影响因子：
2.4
通讯作者：
Reutens, David
中科院分区：
文献类型：
--
作者：
Chen, Min;Edwards, Stephen R.;Maskey, Dhiraj;Woodruff, Trent M.;Tomlinson, Stephen;Reutens, David
补体系统是先天免疫的有效效应器，对创伤性脑损伤 (TBI) 的病理生理学有显着贡献。本研究调查了补体级联在 TBI 后神经行为结果和神经病理学中的作用。 TBI 后 1 小时施用作用于补体系统不同水平的药物，包括 1) C1 酯酶抑制剂 (C1-Inh)、2) CR2-Crry（作用于 C3 的所有途径的抑制剂）和 3) 选择性 C5aR1 拮抗剂 PMX205。在 C5 充足 (C5+/+) 和 C5 缺乏 (C5–/–) CD1 小鼠中，使用旋转装置对运动功能、使用主动位置回避 (APA) 任务的认知功能以及受控皮质冲击损伤后慢性阶段的脑损伤大小进行了评估。在 TBI 后 C5+/+ 小鼠中，CR2-Crry 改善了转棒性能，CR2-Crry 和 PMX205 改善了 APA 性能，PMX205 减少了脑损伤大小。 TBI 后，与 C5+/+ 小鼠相比，C5–/– 小鼠在 APA 任务中表现更好。 C5 缺乏增强了 C1-Inh 对运动功能和脑损伤的影响，以及 CR2-Crry 对 TBI 后脑损伤的影响。我们的研究结果支持 C3 在运动缺陷中的关键作用、C3/C5/C5aR1 轴在认知缺陷中的关键作用以及 C5aR1 信号在 TBI 后脑损伤中的关键作用。研究结果表明，C5 抑制与 C1-Inh 和 CR2-Crry 相结合可作为 TBI 的潜在治疗策略。
A potent effector of innate immunity, the complement system contributes significantly to the pathophysiology of traumatic brain injury (TBI). This study investigated the role of the complement cascade in neurobehavioral outcomes and neuropathology after TBI. Agents acting at different levels of the complement system, including 1) C1 esterase inhibitor (C1-Inh), 2) CR2-Crry, an inhibitor of all pathways acting at C3, and 3) the selective C5aR1 antagonist, PMX205, were administered at 1 h post-TBI. Their effects were evaluated on motor function using the rotarod apparatus, cognitive function using the active place avoidance (APA) task, and brain lesion size at a chronic stage after controlled cortical impact injury in C5-sufficient (C5+/+) and C5-deficient (C5–/–) CD1 mice. In post-TBI C5+/+ mice, rotarod performance was improved by CR2-Crry, APA performance was improved by CR2-Crry and PMX205, and brain lesion size was reduced by PMX205. After TBI, C5–/– mice performed better in the APA task compared with C5+/+ mice. C5 deficiency enhanced the effect of C1-Inh on motor function and brain damage and the effect of CR2-Crry on brain damage after TBI. Our findings support critical roles for C3 in motor deficits, the C3/C5/C5aR1 axis in cognitive deficits, and C5aR1 signaling in brain damage after TBI. Findings suggest the combination of C5 inhibition with C1-Inh and CR2-Crry as potential therapeutic strategies in TBI.
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影响因子：
4.6
作者：
Mizuno T;Yoshioka K;Mizuno M;Shimizu M;Nagano F;Okuda T;Tsuboi N;Maruyama S;Nagamatsu T;Imai M
通讯作者：
Imai M
补体系统在创伤性脑损伤中的作用：综述。
影响因子：
9.3
作者：
Hammad A;Westacott L;Zaben M
通讯作者：
Zaben M
影响因子：
3.3
作者：
Mantovani, S.;Gordon, R.;Woodruff, T. M.
通讯作者：
Woodruff, T. M.
影响因子：
3.5
作者：
Cernotova D;Stuchlik A;Svoboda J
通讯作者：
Svoboda J
影响因子：
9.3
作者：
Schartz ND;Tenner AJ
通讯作者：
Tenner AJ