Traumatic brain injury (TBI) is a common pathological condition that presently lacks a specific pharmacological treatment. Adenosine levels rise following TBI, which is thought to be neuroprotective against secondary brain injury. Evidence from stroke and inflammatory disease models suggests that adenosine signaling through the G protein-coupled A3 adenosine receptor (A3AR) can provide antiinflammatory and neuroprotective effects. However, the role of A3AR in TBI has not been investigated. Using the selective A3AR agonist, MRS5980, we evaluated the effects of A3AR activation on the pathological outcomes and cognitive function in CD1 male mouse models of TBI. When measured 24 h after controlled cortical impact (CCI) TBI, male mice treated with intraperitoneal injections of MRS5980 (1 mg/kg) had reduced secondary tissue injury and brain infarction than vehicle-treated mice with TBI. These effects were associated with attenuated neuroinflammation marked by reduced activation of nuclear factor of kappa light polypeptide gene enhancer in B cells (NFκB) and MAPK (p38 and extracellular signal-regulated kinase (ERK)) pathways and downstream NOD-like receptor pyrin domain-containing 3 inflammasome activation. MRS5980 also attenuated TBI-induced CD4+ and CD8+ T cell influx. Moreover, when measured 4–5 weeks after closed head weight-drop TBI, male mice treated with MRS5980 (1 mg/kg) performed significantly better in novel object-placement retention tests (NOPRT) and T maze trials than untreated mice with TBI without altered locomotor activity or increased anxiety. Our results provide support for the beneficial effects of small molecule A3AR agonists to mitigate secondary tissue injury and cognitive impairment following TBI.

中文翻译：

---

腺苷 A3 受体作为一种新的治疗靶点，可减少创伤性脑损伤后的继发性事件并改善神经认知功能

创伤性脑损伤 (TBI) 是一种常见的病理状况，目前缺乏特定的药物治疗。TBI 后腺苷水平升高，这被认为对继发性脑损伤具有神经保护作用。来自中风和炎症疾病模型的证据表明，通过 G 蛋白偶联的 A3 腺苷受体 (A3AR) 的腺苷信号传导可以提供抗炎和神经保护作用。然而，A3AR 在 TBI 中的作用尚未得到研究。使用选择性 A3AR 激动剂 MRS5980，我们评估了 A3AR 激活对 TBI 的 CD1 雄性小鼠模型的病理结果和认知功能的影响。在受控皮质撞击 (CCI) TBI 后 24 小时测量时，与载体治疗的 TBI 小鼠相比，用 MRS5980 (1 mg/kg) 腹腔注射治疗的雄性小鼠的继发性组织损伤和脑梗塞减少。这些作用与减弱的神经炎症有关，其特征是 B 细胞 (NFκB) 和 MAPK（p38 和细胞外信号调节激酶 (ERK)）通路和下游 NOD 样受体 pyrin 结构域中 kappa 轻多肽基因增强子的核因子的活化减少。含 3 个炎性体激活。MRS5980 还减弱了 TBI 诱导的 CD4+ 和 CD8+ T 细胞流入。此外，在闭合头部减重 TBI 后 4-5 周测量时，用 MRS5980 (1 mg/kg) 治疗的雄性小鼠在新的物体放置保留测试 (NOPRT) 和 T 迷宫试验中表现明显优于未治疗的 TBI 小鼠改变运动活动或增加焦虑。