Wessex Neurological Centre, University Hospital Southampton, Southampton, UK.
School of Nursing, University of Pittsburgh, Pittsburgh, PA, USA.
Nat Rev Neurol. 2018 Jul;14(7):416-432. doi: 10.1038/s41582-018-0020-0.
Haemoglobin is released into the CNS during the breakdown of red blood cells after intracranial bleeding. Extracellular free haemoglobin is directly neurotoxic. Haemoglobin scavenging mechanisms clear haemoglobin and reduce toxicity; these mechanisms include erythrophagocytosis, haptoglobin binding of haemoglobin, haemopexin binding of haem and haem oxygenase breakdown of haem. However, the capacity of these mechanisms is limited in the CNS, and they easily become overwhelmed. Targeting of haemoglobin toxicity and scavenging is, therefore, a rational therapeutic strategy. In this Review, we summarize the neurotoxic mechanisms of extracellular haemoglobin and the peculiarities of haemoglobin scavenging pathways in the brain. Evidence for a role of haemoglobin toxicity in neurological disorders is discussed, with a focus on subarachnoid haemorrhage and intracerebral haemorrhage, and emerging treatment strategies based on the molecular pathways involved are considered. By focusing on a fundamental biological commonality between diverse neurological conditions, we aim to encourage the application of knowledge of haemoglobin toxicity and scavenging across various conditions. We also hope that the principles highlighted will stimulate research to explore the potential of the pathways discussed. Finally, we present a consensus opinion on the research priorities that will help to bring about clinical benefits.
血红蛋白在颅内出血后红细胞破裂时释放到中枢神经系统中。细胞外游离血红蛋白具有直接的神经毒性。血红蛋白清除机制可清除血红蛋白并降低其毒性；这些机制包括红细胞吞噬作用、血红蛋白与触珠蛋白结合、血红素与血红素结合蛋白结合以及血红素氧合酶分解血红素。然而，这些机制在中枢神经系统中的能力有限，很容易被血红蛋白淹没。因此，针对血红蛋白毒性和清除的靶向治疗是一种合理的治疗策略。在这篇综述中，我们总结了细胞外血红蛋白的神经毒性机制以及大脑中血红蛋白清除途径的特点。讨论了血红蛋白毒性在神经疾病中的作用的证据，重点是蛛网膜下腔出血和脑出血，并考虑了基于相关分子途径的新兴治疗策略。通过关注各种神经疾病之间的基本生物学共性，我们旨在鼓励将血红蛋白毒性和清除的知识应用于各种疾病。我们还希望所强调的原则将激发研究，以探索所讨论途径的潜力。最后，我们提出了一个共识意见，即确定有助于带来临床效益的研究重点。
