Departement of Neuroscience, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14620, USA; Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854, USA.
Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854, USA.
Exp Neurol. 2024 Nov;381:114930. doi: 10.1016/j.expneurol.2024.114930. Epub 2024 Aug 21.
Traumatic brain injury (TBI) presents a significant public health challenge, necessitating innovative interventions for effective treatment. Recent studies have challenged conventional perspectives on neurogenesis, unveiling endogenous repair mechanisms within the adult brain following injury. However, the intricate mechanisms governing post-TBI neurogenesis remain unclear. The microenvironment of an injured brain, characterized by astrogliosis, neuroinflammation, and excessive cell death, significantly influences the fate of newly generated neurons. Adenosine kinase (ADK), the key metabolic regulator of adenosine, emerges as a crucial factor in brain development and cell proliferation after TBI. This study investigates the hypothesis that targeting ADK could enhance brain repair, promote neuronal survival, and facilitate differentiation. In a TBI model induced by controlled cortical impact, C57BL/6 male mice received intraperitoneal injections of the small molecule ADK inhibitor 5-iodotubercidin (ITU) for three days following TBI. To trace the fate of TBI-associated proliferative cells, animals received intraperitoneal injections of BrdU for seven days, beginning immediately after TBI. Our results show that ADK inhibition by ITU improved brain repair 14 days after injury as evidenced by a diminished injury size. Additionally, the number of mature neurons generated after TBI was increased in ITU-treated mice. Remarkably, the TBI-associated pathological events including astrogliosis, neuroinflammation, and cell death were arrested in ITU-treated mice. Finally, ADK inhibition modulated cell death by regulating the PERK signaling pathway. Together, these findings demonstrate a novel therapeutic approach to target multiple pathological mechanisms involved in TBI. This research contributes valuable insights into the intricate molecular mechanisms underlying neurogenesis and gliosis after TBT.
创伤性脑损伤 (TBI) 是一个重大的公共健康挑战，需要创新的干预措施来进行有效的治疗。最近的研究挑战了神经发生的传统观点，揭示了成年大脑在受伤后的内源性修复机制。然而，TBI 后神经发生的复杂机制仍不清楚。受伤大脑的微环境，以星形胶质细胞增生、神经炎症和过度细胞死亡为特征，极大地影响了新生成神经元的命运。腺苷激酶 (ADK) 是腺苷的关键代谢调节剂，在 TBI 后大脑发育和细胞增殖中是一个关键因素。本研究假设靶向 ADK 可以增强大脑修复、促进神经元存活并促进分化。在由皮质冲击控制诱导的 TBI 模型中，C57BL/6 雄性小鼠在 TBI 后三天接受腹腔注射小分子 ADK 抑制剂 5-碘尿苷 (ITU)。为了追踪 TBI 相关增殖细胞的命运，动物在 TBI 后立即开始连续七天腹腔注射 BrdU。我们的研究结果表明，ITU 通过 ADK 抑制在损伤后 14 天改善了大脑修复，表现为损伤体积减小。此外，在 ITU 处理的小鼠中，TBI 后生成的成熟神经元数量增加。值得注意的是，在 ITU 处理的小鼠中，TBI 相关的病理事件，包括星形胶质细胞增生、神经炎症和细胞死亡，被阻止了。最后，ADK 抑制通过调节 PERK 信号通路调节细胞死亡。总之，这些发现展示了一种针对 TBI 涉及的多种病理机制的新治疗方法。这项研究为 TBT 后神经发生和神经胶质增生的复杂分子机制提供了有价值的见解。
