Aim: Traumatic brain injury (TBI) is a leading cause of mortality/morbidity and is associated with chronic neuroinflammation. Melanocortin receptor agonists including adrenocorticotropic hormone (ACTH) ameliorate inflammation and provide a novel therapeutic approach. We examined the effect of long-acting cosyntropin (CoSyn), a synthetic ACTH analog, on the early inflammatory response and functional outcome following experimental TBI.

Methods: The controlled cortical impact model was used to induce TBI in mice. Mice were assigned to injury and treatment protocols resulting in four experimental groups including sham + saline, sham + CoSyn, TBI + saline, and TBI + CoSyn. Treatment was administered subcutaneously 3 h post-injury and daily injections were given for up to 7 days post-injury. The early inflammatory response was evaluated at 3 days post-injury through the evaluation of cytokine expression (IL1β and TNFα) and immune cell response. Quantification of immune cell response included cell counts of microglia/macrophages (Iba1+ cells) and neutrophils (MPO+ cells) in the cortex and hippocampus. Behavioral testing (n = 10–14 animals/group) included open field (OF) and novel object recognition (NOR) during the first week following injury and Morris water maze (MWM) at 10–15 days post-injury.

Results: Immune cell quantification showed decreased accumulation of Iba1+ cells in the perilesional cortex and CA1 region of the hippocampus for CoSyn-treated TBI animals compared to saline-treated. Reduced numbers of MPO+ cells were also found in the perilesional cortex and hippocampus in CoSyn treated TBI mice compared to their saline-treated counterparts. Furthermore, CoSyn treatment reduced IL1β expression in the cortex of TBI mice. Behavioral testing showed a treatment effect of CoSyn for NOR with CoSyn increasing the discrimination ratio in both TBI and Sham groups, indicating increased memory performance. CoSyn also decreased latency to find platform during the early training period of the MWM when comparing CoSyn to saline-treated TBI mice suggesting moderate improvements in spatial memory following CoSyn treatment.

Conclusion: Reduced microglia/macrophage accumulation and neutrophil infiltration in conjunction with moderate improvements in spatial learning in our CoSyn treated TBI mice suggests a beneficial anti-inflammatory effect of CoSyn following TBI.

目标：颅脑外伤（TBI）是导致死亡/发病的主要原因，并与慢性神经炎症相关。包括促肾上腺皮质激素（ACTH）的黑皮质素受体激动剂可减轻炎症，并提供一种新颖的治疗方法。我们检查了长效促合成素（CoSyn）（一种合成的ACTH类似物）对实验性TBI后早期炎症反应和功能结局的影响。

方法：使用受控的皮质撞击模型在小鼠中诱导TBI。将小鼠分配至损伤和治疗方案，产生四个实验组，包括假手术+盐水，假手术+ CoSyn，TBI +盐水和TBI + CoSyn。损伤后3 h进行皮下治疗，损伤后7天每天注射。通过评估细胞因子的表达（IL1β和TNFα）和免疫细胞反应来评估损伤后3天的早期炎症反应。免疫细胞反应的量化包括皮层和海马中的小胶质细胞/巨噬细胞（Iba1 +细胞）和中性粒细胞（MPO +细胞）的细胞计数。行为测试（ñ = 10–14只动物/组）包括受伤后第一周的开阔地带（OF）和新物体识别（NOR），以及受伤后10–15天的莫里斯水迷宫（MWM）。

结果：免疫细胞定量显示，与盐水处理相比，CoSyn处理的TBI动物的Iba1 +细胞在海马周围皮层和CA1区的积累减少。与经盐水处理的同龄小鼠相比，在接受CoSyn处理的TBI小鼠的病灶周围皮层和海马中还发现MPO +细胞数量减少。此外，CoSyn处理可降低TBI小鼠皮质中IL1β的表达。行为测试显示CoSyn对NOR的治疗效果，CoSyn增加了TBI和Sham组的辨别率，表明内存性能提高。当将CoSyn与盐水处理的TBI小鼠进行比较时，CoSyn还减少了MWM早期训练期间发现平台的潜伏期，表明在CoSyn治疗后空间记忆得到了适度的改善。

结论：在我们的CoSyn治疗的TBI小鼠中，小胶质细胞/巨噬细胞积累和中性粒细胞浸润的减少以及空间学习的适度改善，提示TBI后CoSyn具有有益的抗炎作用。