Section on Molecular Neurobiology, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA.
J Neurotrauma. 2012 Jan 20;29(2):362-74. doi: 10.1089/neu.2011.1942. Epub 2011 Nov 1.
Although traumatic brain injury (TBI) is recognized as one of the leading causes of death from trauma to the central nervous system (CNS), no known treatment effectively mitigates its effects. Lithium, a primary drug for the treatment of bipolar disorder, has been known to have neuroprotective effects in various neurodegenerative conditions such as stroke. Until this study, however, it has not been investigated as a post-insult treatment for TBI. To evaluate whether lithium could have beneficial effects following TBI, lithium at a dose of 1.5 mEq/kg was administered after injury. Assessed at 3 days and 3 weeks post-injury using hematoxylin and eosin staining, lithium treatment was found to reduce lesion volume. Lithium at doses of 2.0 and 3.0 mEq/kg also significantly reduced lesion volume at 3 days after injury, and the therapeutic window was at least 3 h post-injury. TBI-induced neuronal death, microglial activation, and cyclooxygenase-2 induction were all attenuated by lithium at 3 days after injury. In addition, lithium treatment reduced TBI-induced matrix metalloproteinase-9 expression and preserved the integrity of the blood-brain barrier. As for behavioral outcomes, lithium treatment reduced anxiety-like behavior in an open-field test, and improved short- and long-term motor coordination in rotarod and beam-walk tests. Lithium robustly increased serine phosphorylation of glycogen synthase kinase-3β (GSK-3β), suggesting that the underlying mechanisms responsible for lithium's protective effects are triggered by increasing phosphorylation of this kinase and thereby inhibiting its activity. Our results support the notion that lithium has heretofore unrecognized capacity to mitigate the neurodegenerative effects and improve functional outcomes in TBI.
尽管创伤性脑损伤（TBI）被认为是中枢神经系统（CNS）创伤导致死亡的主要原因之一，但目前尚无有效的治疗方法能够减轻其影响。锂是治疗双相情感障碍的主要药物，已被证明在各种神经退行性疾病如中风中具有神经保护作用。然而，在此项研究之前，尚未将其作为 TBI 的创伤后治疗进行研究。为了评估锂在 TBI 后是否具有有益作用，在损伤后给予 1.5 mEq/kg 的锂剂量。通过苏木精和伊红染色在损伤后 3 天和 3 周进行评估，发现锂治疗可减少病变体积。2.0 和 3.0 mEq/kg 的锂剂量也可显著减少损伤后 3 天的病变体积，治疗窗至少在损伤后 3 小时。锂在损伤后 3 天可减轻 TBI 诱导的神经元死亡、小胶质细胞激活和环氧化酶-2 诱导。此外，锂治疗可减少 TBI 诱导的基质金属蛋白酶-9 表达并维持血脑屏障的完整性。至于行为结果，锂治疗可减少旷场测试中的焦虑样行为，并改善旋转棒和走棒测试中的短期和长期运动协调能力。锂可强烈增加糖原合酶激酶-3β（GSK-3β）的丝氨酸磷酸化，表明锂的保护作用的潜在机制是通过增加该激酶的磷酸化并抑制其活性来触发的。我们的结果支持了这样一种观点，即锂具有以前未被认识到的能力，可以减轻 TBI 的神经退行性影响并改善其功能结果。
