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 Eliot Gendelman

Research output: Contribution to journalArticle

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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

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Encephalitis
Lithium
HIV-1
Glycogen Synthase Kinase 3
Catenins
Macrophages
Phosphotransferases
Microtubule-Associated Proteins
SCID Mice
Long-Term Potentiation
Microglia
Neuroprotective Agents
Neurites
HLA Antigens
Phosphatidylinositols
Basal Ganglia
Nervous System Diseases
Astrocytes
Dementia
Western Blotting

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Neuroprotective mechanisms of lithium in murine human immunodeficiency virus-1 encephalitis. / Dou, Huanyu; Ellison, Brent; Bradley, Jennifer; Kasiyanov, Alexander; Poluektova, Larisa Y; Xiong, Huangui; Maggirwar, Sanjay; Dewhurst, Stephen; Gelbard, Harris A.; Gendelman, Howard Eliot.

In: Journal of Neuroscience, Vol. 25, No. 37, 14.09.2005, p. 8375-8385.

Research output: Contribution to journalArticle

Dou, Huanyu ; Ellison, Brent ; Bradley, Jennifer ; Kasiyanov, Alexander ; Poluektova, Larisa Y ; Xiong, Huangui ; Maggirwar, Sanjay ; Dewhurst, Stephen ; Gelbard, Harris A. ; Gendelman, Howard Eliot. / Neuroprotective mechanisms of lithium in murine human immunodeficiency virus-1 encephalitis. In: Journal of Neuroscience. 2005 ; Vol. 25, No. 37. pp. 8375-8385.
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AU - Maggirwar, Sanjay

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