Istanbul Medipol University, Regenerative and Restorative Medical Research Center, Istanbul, Turkey; Istanbul Medipol University, Faculty of Medicine, Dept. of Physiology, Istanbul, Turkey.
Istanbul Medipol University, Regenerative and Restorative Medical Research Center, Istanbul, Turkey; Istanbul Medipol University, Faculty of Medicine, Dept. of Pharmacology, Istanbul, Turkey.
Behav Brain Res. 2020 Aug 17;392:112719. doi: 10.1016/j.bbr.2020.112719. Epub 2020 May 30.
Apart from its well-established therapeutic activity on bipolar disorder and depression, lithium exerts neuroprotective activity upon neurodegenerative disorders, such as traumatic brain injury (TBI). However, the cellular signaling mechanisms mediating lithium's neuroprotective activity and long-term dose- and time-dependent effects on close and remote proximity are largely unknown. Herein, we tested prophylactic and acute effects of lithium (2 mmol/kg) after cold- induced TBI. In both conditions, treatments with lithium resulted in reduced infarct volume and apoptosis. Its acute treatment resulted in the increase of Akt, ERK-1/2 and GSK-3 α/β phosphoylations. Interestingly, its prophylactic treatment instead resulted in decreased phosphorylations of Akt, ERK-1/2, p38, JNK-1 moderately and GSK-3 α/β significantly. Then, we tested subacute (35-day follow-up) role of low (0.2 mmol/kg) and high dose (2 mmol/kg) lithium and revealed that high dose lithium group was the most mobile so the least depressed in the tail suspension test. Anxiety level was assessed by light-dark test, all groups' anxiety levels were decreased with time, but lithium had no effect on anxiety like behavior. When subacute effects of injury and drug treatment were evaluated on the defined brain regions, infarct volume was decreased in the high dose lithium group significantly. In contrast to other brain regions, hippocampal atrophies were observed in both lithium treatment groups, which were significant in the low dose lithium group in both hemispheres, which was associated with the reduced cell proliferation and neurogenesis. Our data demonstrate that lithium treatment protects neurons from TBI. However, long term particularly low-dose lithium causes hippocampal atrophy and decreased neurogenesis.
除了在双相情感障碍和抑郁症方面的既定治疗活性外，锂还对神经退行性疾病具有神经保护活性，例如创伤性脑损伤 (TBI)。然而，介导锂的神经保护活性以及对近距离和远距离的长期剂量和时间依赖性影响的细胞信号转导机制在很大程度上尚不清楚。在此，我们测试了锂（2 mmol/kg）在冷诱导的 TBI 后的预防和急性作用。在这两种情况下，锂的治疗都导致梗塞体积减小和细胞凋亡减少。其急性治疗导致 Akt、ERK-1/2 和 GSK-3α/β磷酸化增加。有趣的是，其预防治疗反而导致 Akt、ERK-1/2、p38、JNK-1 的磷酸化适度减少，而 GSK-3α/β显著减少。然后，我们测试了亚急性（35 天随访）低剂量（0.2 mmol/kg）和高剂量（2 mmol/kg）锂的作用，结果表明高剂量锂组的移动性最高，因此在悬尾试验中抑郁程度最低。通过明暗试验评估焦虑水平，所有组的焦虑水平随时间降低，但锂对焦虑样行为没有影响。当评估损伤和药物治疗的亚急性作用对定义的脑区时，高剂量锂组的梗塞体积显著减小。与其他脑区相反，在锂处理组中观察到海马萎缩，在低剂量锂组中在两个半球中均显著，这与细胞增殖和神经发生减少有关。我们的数据表明，锂治疗可保护神经元免受 TBI。然而，长期特别是低剂量锂会导致海马萎缩和神经发生减少。
