Neuroprotective Mechanisms of Lithium in Murine Human Immunodeficiency Virus-1 Encephalitis

摘要: Lithium (Li) has garnered considerable interest as a neuroprotective drug for broad range of nervous system disorders. Its activities occur consequence glycogen synthase kinase-3β (GSK-3β) inhibition leading to downstream blockade β-catenin and Tau phosphorylation. In the present study, we investigated Li-mediated mechanisms in laboratory murine human immunodeficiency virus-1 (HIV-1) encephalitis (HIVE) models. tests, Li protected neurons from neurotoxic secretions HIV-1-infected monocyte-derived macrophages (MDMs). This neuroprotection was mediated, part, through phosphatidyl inositol 3-kinase/Akt GSK-3β pathways. To examine effects treatment vivo , MDMs were injected into basal ganglia severe combined immunodeficient mice then administered (60 mg/kg/d). Seven days after MDM injection, killed CNS tissue collected subjected immunocytochemical Western blot assays leukocyte neural antigens, GSK-3β, key kinase substrates such asβ-catenin Tau. Numbers HIV-1 p24 antigen-positive unaltered by HIVE mice. Similarly, greatly increased extent astrocyte microglia activation (10-fold 16-fold, respectively, compared with unmanipulated controls) also Li. contrast, restored HIVE-associated loss microtubule-associated protein-2-positive neurites synaptic density while reducing levels or activity phospho-Tau Ser202, phospho-β-catenin, GSK-3β. Electrophysiological recordings showed diminished long-term potentiation hippocampal slices that Based on these data, use an adjuvant HIV-1-associated dementia is now being pursued.