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.

除了其对双相情感障碍和抑郁症的公认治疗活性外，锂还对神经退行性疾病（如创伤性脑损伤 (TBI)）发挥神经保护作用。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机制在很大程度上是未知的。在此，我们测试了锂 (2 mmol/kg) 在寒冷诱发的 TBI 后的预防和急性作用。在这两种情况下，锂治疗导致梗塞体积和细胞凋亡减少。其急性治疗导致 Akt、ERK-1/2 和 GSK-3 α/β 磷酸化增加。有趣的是，它的预防性治疗反而导致 Akt、ERK-1/2、p38、JNK-1 的磷酸化中度降低，而 GSK-3 α/β 的磷酸化显着降低。然后，我们测试了低剂量 (0.2 mmol/kg) 和高剂量 (2 mmol/kg) 锂的亚急性（35 天随访）作用，发现高剂量锂组的活动性最强，因此在悬尾试验中受压程度最低. 通过明暗测试评估焦虑水平，所有组的焦虑水平都随着时间的推移而下降，但锂对焦虑样行为没有影响。当在特定脑区评估损伤和药物治疗的亚急性影响时，高剂量锂组的梗死体积显着减少。与其他大脑区域相比，在两个锂治疗组中均观察到海马萎缩，这在两个半球的低剂量锂组中均显着，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以保护神经元免受 TBI 的影响。然而，长期特别低剂量的锂会导致海马萎缩和神经发生减少。