Neuroprotective mechanisms of lithium in murine human immunodeficiency virus-1 encephalitis.
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-3beta (GSK-3beta) 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-3beta 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-3beta, 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 Ser202, phospho-beta-catenin, and GSK-3beta. 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.
Dou
Huanyu
H
Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, Nebraska 68198-5880, USA. hegendel@unmc.edu
Ellison
Brent
B
Bradley
Jennifer
J
Kasiyanov
Alexander
A
Poluektova
Larisa Y
LY
Xiong
Huangui
H
Maggirwar
Sanjay
S
Dewhurst
Stephen
S
Gelbard
Harris A
HA
Gendelman
Howard E
HE
D000028:Abortion, Induced; D000818:Animals; D001921:Brain / Q000196:embryology / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018792:Encephalitis, Viral / Q000517:prevention & control*; D005333:Fetus; D015658:HIV Infections / Q000150:complications*; D015497:HIV-1 / Q000187:drug effects*; D015498:HIV-2 / Q000187:drug effects*; D006801:Humans; D008094:Lithium / Q000494:pharmacology*; D008264:Macrophages / Q000821:virology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009000:Monocytes / Q000821:virology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology
D008094:Lithium