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

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

Lithium Treatment Prevents Neurocognitive Deficit Resulting from Cranial Irradiation

“…These deficits can be accounted for neuronal precursor cell dysfunction in the subgranular zone caused by radiation (11). Published data (22,30) suggest that 7 days of lithium pretreatment with the dose of 40 to 80 mg/kg show the maximal protection from neurodegenerative insults. To determine whether lithium treatment attenuates deficits in cognitive functions caused by radiation, C57/BL6 mice were treated with daily i.p.…”

“…injection daily for 7 days starting on postnatal day 7. Time of treatment and dose of LiCl were chosen based on published data (22,30) and our pilot experiments. The control treatment group received i.p.…”

Links between Progressive HIV-1 Infection of Humanized Mice and Viral Neuropathogenesis

“…A comparative description of previous mouse models of NeuroAIDS is presented in the Supplemental table, S1 (available at http://ajp.amjpathol.org). [1][2][3][4]6,7,[62][63][64][65][66][67][68][69][81][82][83][84][85][86][87][88][89][90] What is reported now can permit future studies of viral neuropathogenesis studies in rodents and for investigations of novel antiretroviral and adjunctive therapies.…”

Novel Neuroprotective GSK-3β Inhibitor Restricts Tat-Mediated HIV-1 Replication

“…In the last 10 years, host-based therapies have shed light on potential targets that had previously not been fully recognized. For instance, robust glycogen synthase kinase-3␤ (GSK-3␤) inhibitors, such as lithium and valproic acid, have been shown to protect against Tat-and gp120-mediated neurotoxicity (59,76,77). Recently, small chemical molecules have taken the spotlight due to their capacity for conferring both potent Tatdependent transcriptional inhibition and cytoprotection from Tat-induced neurotoxicity through mechanisms that remain to be determined (33,78).…”