Haupt Matteo, Bähr Mathias, Doeppner Thorsten R
University Medical Center Göttingen, Department of Neurology, Göttingen, Germany.
Neural Regen Res. 2021 Dec;16(12):2383-2387. doi: 10.4103/1673-5374.313015.
Lithium has been used in the treatment of bipolar disorders for decades, but the exact mechanisms of action remain elusive to this day. Recent evidence suggests that lithium is critically involved in a variety of signaling pathways affecting apoptosis, inflammation, and neurogenesis, all of which contributing to the complex pathophysiology of various neurological diseases. As a matter of fact, preclinical work reports both acute and long-term neuroprotection in distinct neurological disease models such as Parkinson's disease, traumatic brain injury, Alzheimer's disease, and ischemic stroke. Lithium treatment reduces cell injury, decreases α synuclein aggregation and Tau protein phosphorylation, modulates inflammation and even stimulates neuroregeneration under experimental conditions of Parkinson's disease, traumatic brain injury, and Alzheimer's disease. The therapeutic impact of lithium under conditions of ischemic stroke was also studied in numerous preclinical in vitro and in vivo studies, giving rise to a randomized double-blind clinical stroke trial. The preclinic data revealed a lithium-induced upregulation of anti-apoptotic proteins such as B-cell lymphoma 2, heat shock protein 70, and activated protein 1, resulting in decreased neuronal cell loss. Lithium, however, does not only yield postischemic neuroprotection but also enhances endogenous neuroregeneration by stimulating neural stem cell proliferation and by regulating distinct signaling pathways such as the RE1-silencing transcription factor. In line with this, lithium treatment has been shown to modulate postischemic cytokine secretion patterns, diminishing microglial activation and stabilizing blood-brain barrier integrity yielding reduced levels of neuroinflammation. The aforementioned observations culminated in a first clinical trial, which revealed an improved motor recovery in patients with cortical stroke after lithium treatment. Beside its well-known psychiatric indications, lithium is thus a promising neuroprotective candidate for the aforementioned neurological diseases. A detailed understanding of the lithium-induced mechanisms, however, is important for prospective clinical trials which may pave the way for a successful bench-to-bedside translation in the future. In this review, we will give an overview of lithium-induced neuroprotective mechanisms under various pathological conditions, with special emphasis on ischemic stroke.
几十年来，锂一直被用于治疗双相情感障碍，但确切的作用机制至今仍不清楚。最近的证据表明，锂在影响细胞凋亡、炎症和神经发生的各种信号通路中起着关键作用，所有这些都与各种神经系统疾病复杂的病理生理学有关。事实上，临床前研究报告了锂在帕金森病、创伤性脑损伤、阿尔茨海默病和缺血性中风等不同神经系统疾病模型中的急性和长期神经保护作用。在帕金森病、创伤性脑损伤和阿尔茨海默病的实验条件下，锂治疗可减少细胞损伤，减少α-突触核蛋白聚集和tau蛋白磷酸化，调节炎症，甚至刺激神经再生。在众多临床前体外和体内研究中也对锂在缺血性中风条件下的治疗作用进行了研究，从而开展了一项随机双盲临床中风试验。临床前数据显示，锂可诱导抗凋亡蛋白如B细胞淋巴瘤2、热休克蛋白70和活化蛋白1的上调，从而减少神经元细胞损失。然而，锂不仅能产生缺血后神经保护作用，还能通过刺激神经干细胞增殖和调节不同的信号通路如RE1沉默转录因子来增强内源性神经再生。与此一致的是，锂治疗已被证明可调节缺血后细胞因子分泌模式，减少小胶质细胞活化并稳定血脑屏障完整性，从而降低神经炎症水平。上述观察结果促成了第一项临床试验，该试验显示锂治疗后皮质中风患者的运动恢复有所改善。因此，除了其众所周知的精神科适应症外，锂是上述神经系统疾病的一个有前景的神经保护候选药物。然而，详细了解锂诱导的机制对于未来的临床试验很重要，这可能为未来成功的从 bench 到 bedside 的转化铺平道路。在这篇综述中，我们将概述锂在各种病理条件下诱导的神经保护机制，特别强调缺血性中风。
