Neuroprotective mechanisms of lithium in murine human immunodeficiency virus-1 encephalitis
Neuroprotective mechanisms of lithium in murine human immunodeficiency virus-1 encephalitis
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DOI：
10.1523/jneurosci.2164-05.2005
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发表时间：
2005-09-14
影响因子：
5.3
通讯作者：
Gendelman, HE
中科院分区：
文献类型：
--
作者：
Dou, HY;Ellison, B;Gendelman, HE
锂（Li）作为一种神经保护药物，广泛用于神经系统疾病，引起了人们的极大兴趣。其神经保护活性是糖原合成酶激酶-3 β（GSK-3 β）抑制导致β-连环蛋白和Tau磷酸化的下游阻断的结果。在本研究中，我们在实验室和小鼠人类免疫缺陷病毒-1（HIV-1）脑炎（HIVE）模型中研究了Li介导的神经保护机制。在实验室测试中，Li保护神经元免受HIV-1感染的单核细胞衍生巨噬细胞（MDM）的神经毒性分泌物的影响。这种神经保护作用部分通过磷脂酰肌醇3-激酶/Akt和GSK-3 β途径介导。为了检查Li治疗在体内的效果，将MDM注射到严重联合免疫缺陷小鼠的基底神经节中，然后给予Li（60 mg/kg/d）。MDM注射后7天，处死小鼠，收集CNS组织，并进行白细胞和神经抗原、GSK-3 β和关键激酶底物（如β-连环蛋白和Tau）的免疫细胞化学和蛋白质印迹测定。HIV-1 p24抗原阳性MDM的数量在HIVE小鼠的Li处理中没有改变。同样，HIVE小鼠中星形胶质细胞和小胶质细胞活化程度的大幅增加（与未操作的对照组相比，分别为10倍和16倍）也未被Li改变。相比之下，Li恢复了HIV相关的微管相关蛋白2阳性神经突和突触密度的损失，同时降低了磷酸化Tau Ser（202）、磷酸化β-连环蛋白和GSK-3 β的水平或活性。电生理记录显示，减少长时程增强HIVE小鼠海马切片恢复李。基于这些数据，现在正在寻求使用Li作为HIV-1相关痴呆症的佐剂。
Lithium (Li) has garnered considerable interest as a neuroprotective drug for a broad range of nervous system disorders. Its neuroprotective activities occur as a consequence of glycogen synthase kinase-3 beta (GSK-3 beta) inhibition leading to downstream blockade of beta-catenin and Tau phosphorylation. In the present study, we investigated Li-mediated neuroprotective mechanisms in laboratory and murine human immunodeficiency virus-1 (HIV-1) encephalitis (HIVE) models. In laboratory tests, Li protected neurons from neurotoxic secretions of HIV-1-infected monocyte-derived macrophages (MDMs). This neuroprotection was mediated, in part, through the phosphatidyl inositol 3-kinase/Akt and GSK-3 beta pathways. To examine the effects of Li treatment in vivo, MDMs were injected into the basal ganglia of severe combined immunodeficient mice and then Li was administered (60 mg/kg/d). Seven days after MDM injection, mice were killed and CNS tissue was collected and subjected to immunocytochemical and Western blot assays for leukocyte and neural antigens,GSK-3 beta,and key kinase substrates such as beta-catenin and Tau. Numbers of HIV-1 p24 antigen-positive MDMs were unaltered by Li treatment of HIVE mice. Similarly, the greatly increased extent of astrocyte and microglia activation in HIVE mice (10-fold and 16-fold, respectively, compared with unmanipulated controls) was also unaltered by Li. In contrast, Li restored HIVE-associated loss of microtubule-associated protein-2-positive neurites and synaptic density while reducing levels or activity of phospho-Tau Ser(202), phospho-beta-catenin, and GSK-3 beta. Electrophysiological recordings showed diminished long-term potentiation in hippocampal slices of HIVE mice that were restored by Li. Based on these data, the use of Li as an adjuvant for HIV-1-associated dementia is now being pursued.