Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
Departments of Neurosurgery, Pediatrics, and Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT, USA.
Expert Opin Ther Targets. 2020 Jun;24(6):525-533. doi: 10.1080/14728222.2020.1752182. Epub 2020 Apr 17.
Recent data have implicated inflammation of the cerebrospinal fluid spaces after subarachnoid, intraventricular, and intracerebral hemorrhage to be a critical driver of multiple secondary brain injuries such as hydrocephalus, cerebral edema, and vasospasm. While TLR4-dependent reparative inflammation is an important protective response that can eliminate physical irritants and damaged cells, sustained or inappropriately triggered inflammation can initiate or propagate disease.: We review recent advances in our understanding of how TLR4, including its upstream damage-associated molecular patterns and its downstream MyD88-dependent and independent signaling pathways, contributes to hemorrhage-induced inflammation in numerous brain diseases. We discuss prospects for the pharmacotherapeutic targeting of TLR4 in these disorders, including the use of repurposed FDA-approved agents.: TLR4 inhibitors with good blood-brain-barrier (BBB) penetration could be useful adjuncts in post-hemorrhagic hydrocephalus and multiple other diseases associated with brain hemorrhage and inflammation.
最近的数据表明，蛛网膜下腔、脑室和脑内出血后脑脊液空间的炎症是多种继发性脑损伤（如脑积水、脑水肿和血管痉挛）的关键驱动因素。虽然 TLR4 依赖性修复性炎症是一种重要的保护反应，可以消除物理刺激物和受损细胞，但持续或不适当触发的炎症可能会引发或传播疾病。我们回顾了最近在理解 TLR4 方面的进展，包括其上游损伤相关分子模式及其下游 MyD88 依赖性和非依赖性信号通路，这些都有助于多种脑部疾病中由出血引起的炎症。我们讨论了在这些疾病中靶向 TLR4 的药物治疗前景，包括重新利用已获 FDA 批准的药物。具有良好血脑屏障（BBB）通透性的 TLR4 抑制剂可能是出血后脑积水和其他多种与脑出血和炎症相关疾病的有用辅助药物。
