Memantine Protects Hippocampal Neuronal Function in Murine Human Immunodeficiency Virus Type 1 Encephalitis

Anderson, Eric; Gendelman, Howard Eliot; Xiong, Huangui

doi:10.1523/jneurosci.1933-04.2004

Cited by 68 publications

(55 citation statements)

References 36 publications

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“…A primary clinical manifestation of HAD is memory and behavioral impairments associated with virus-mediated neuronal dysfunction and injury (Wilkie et al, 1992;Heaton et al, 2004). In support of this, we demonstrated previously that losses in LTP correlate with behavioral and cognitive impairments in HIVE mice (Xiong et al, 1999;Anderson et al, 2003Anderson et al, , 2004Xiong et al, 2003). Our electrophysiological findings suggest that Li can restore hippocampal synaptic transmission during HIVE.…”

Section: Discussionsupporting

confidence: 84%

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

Dou¹,

Ellison²,

Bradléy³

et al. 2005

J. Neurosci.

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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.

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Section: Discussionsupporting

confidence: 84%

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

Dou¹,

Ellison²,

Bradléy³

et al. 2005

J. Neurosci.

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“…Mouse CA1 hippocampal electrophysiology was performed as previously described (67,68). The initial slope of the field excitatory postsynaptic potential (fEPSP) was analyzed and expressed as percentage of basal level (the average of initial slopes from the first 30 min was treated as 100%, i.e., the basal level).…”

Section: Methodsmentioning

confidence: 99%

FGF2 gene transfer restores hippocampal functions in mouse models of Alzheimer's disease and has therapeutic implications for neurocognitive disorders

Kiyota

Ingraham

Jacobsen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

122

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The adult hippocampus plays a central role in memory formation, synaptic plasticity, and neurogenesis. The subgranular zone of the dentate gyrus contains neural progenitor cells with self-renewal and multilineage potency. Transgene expression of familial Alzheimer's disease-linked mutants of β-amyloid precursor protein (APP) and presenilin-1 leads to a significant inhibition of neurogenesis, which is potentially linked to age-dependent memory loss. To investigate the effect of neurogenesis on cognitive function in a relevant disease model, FGF2 gene is delivered bilaterally to the hippocampi of APP+presenilin-1 bigenic mice via an adenoassociated virus serotype 2/1 hybrid (AAV2/1-FGF2). Animals injected with AAV2/1-FGF2 at a pre- or postsymptomatic stage show significantly improved spatial learning in the radial arm water maze test. A neuropathological investigation demonstrates that AAV2/1-FGF2 injection enhances the number of doublecortin, BrdU/NeuN, and c-fos–positive cells in the dentate gyrus, and the clearance of fibrillar amyloid-β peptide (Aβ) in the hippocampus. AAV2/1-FGF2 injection also enhances long-term potentiation in another APP mouse model (J20) compared with control AAV2/1-GFP–injected littermates. An in vitro study confirmed the enhanced neurogenesis of mouse neural stem cells by direct AAV2/1-FGF2 infection in an Aβ oligomer-sensitive manner. Further, FGF2 enhances Aβ phagocytosis in primary cultured microglia, and reduces Aβ production from primary cultured neurons after AAV2/1-FGF2 infection. Thus, our data indicate that virus-mediated FGF2 gene delivery has potential as an alternative therapy of Alzheimer's disease and possibly other neurocognitive disorders.

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“…Inflammatory mediators released by activated microglia (M) contribute to excitotoxic injury at several steps, promoting release of glutamate and inhibiting its uptake by astrocytes (A), augmenting Ca 2+ influx via NMDA receptors and AMPA receptors lacking GluR2 subunits, increasing NO production, and promoting mitochondrial dysfunction and oxidative stress (see text for details). Ab, amyloid-b; PAF, platelet-activating factor; IL-1b, interleukin-1b; TNF-a, tumor necrosis factor-a; Cyt C, cytochrome c with this: NMDA receptor-dependent neuronal loss and neurotransmitter depletion have been observed in rats injected with amyloid-b (Harkany et al 2000) and a retroviral mouse model of HAD (Kustova et al 1998), respectively; glutamate receptor antagonists have prevented decline in synaptic function and learning in other mouse models of HAD and AD (Anderson et al 2004;Minkeviciene et al 2004;Van Dam and De Deyn 2005); and a study of synaptosomes prepared from autopsy tissue from AD patients revealed a decrease in postsynaptic structural protein PSD-95 associated with intact presynaptic terminals, suggesting that postsynaptic degradation might precede the loss of presynaptic terminals (Gylys et al 2004). …”

Section: Hiv-1 Amyloid-b and Excitotoxic Synaptic Injurymentioning

confidence: 99%

Protecting the Synapse: Evidence for a Rational Strategy to Treat HIV-1 Associated Neurologic Disease

Bellizzi

Gelbard

2006

Jrnl NeuroImmune Pharm

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Loss of synaptic integrity and function appears to underlie neurologic deficits in patients with HIV-1-associated dementia (HAD) and other chronic neurodegenerative diseases. Because synaptic injury often long precedes neuronal death and surviving neurons possess a remarkable capacity for synaptic repair and functional recovery, we hypothesize that therapeutic intervention to protect synapses has great potential to improve neurologic function in HAD and other diseases. We discuss findings from both HAD and Alzheimer's disease to demonstrate that the disruption of synaptic structure and function that can occur during excitotoxic injury and neuroinflammation represents a likely substrate for neurologic deficits. Based on available evidence, we provide a rationale for future studies aimed at identifying molecular targets for synaptic protection in neurodegenerative disease. Whereas patients with HAD beginning antiretroviral therapy have shown reversal of neurologic symptoms that is unique for patients with chronic neurodegenerative conditions, we propose that the potential for such reversal is not unique.

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Memantine Protects Hippocampal Neuronal Function in Murine Human Immunodeficiency Virus Type 1 Encephalitis

Cited by 68 publications

References 36 publications

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

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

FGF2 gene transfer restores hippocampal functions in mouse models of Alzheimer's disease and has therapeutic implications for neurocognitive disorders

Protecting the Synapse: Evidence for a Rational Strategy to Treat HIV-1 Associated Neurologic Disease

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