Neuroprotective mechanisms of lithium in murine human immunodeficiency virus-1 encephalitis

Huanyu Dou, Brent Ellison, Jennifer Bradley, Alexander Kasiyanov, Larisa Y. Poluektova, Huangui Xiong, Sanjay Maggirwar, Stephen Dewhurst, Harris A. Gelbard, Howard E. Gendelman

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

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-3β (GSK-3β) inhibition leading to downstream blockade of β-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-3β 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-3β, and key kinase substrates such as β-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-β-catenin, and GSK-3β. 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.

Original languageEnglish (US)
Pages (from-to)8375-8385
Number of pages11
JournalJournal of Neuroscience
Volume25
Issue number37
DOIs
StatePublished - Sep 14 2005

Keywords

  • Glycogen synthase kinase-3β
  • HIV-1 encephalitis
  • Lithium
  • Monocyte-derived macrophages
  • Neurodegeneration
  • Neuroprotection

ASJC Scopus subject areas

  • Neuroscience(all)

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