Impaired Spatial Cognition and Synaptic Potentiation in a Murine Model of Human Immunodeficiency Virus Type 1 Encephalitis

Zink, Walter E.; Anderson, Eric; Boyle, Jeffrey; Hock, Lynette M.; Rodriguez-Sierra, Jorge F.; Xiong, Huangui; Gendelman, Howard Eliot; Persidsky, Yuri

doi:10.1523/jneurosci.22-06-02096.2002

Cited by 70 publications

(63 citation statements)

References 58 publications

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“…learning and memory), the MCM-mediated increase of K + current may contribute to the cognitive dysfunction seen in patients with HAD. Previously, we demonstrated severe combined immunodeficient (SCID) mice injected with HIV-1-infected monocyte-derived macrophages in the basal ganglia exhibit impaired performance in Morris water maze tests (Zink et al 2002;Anderson et al 2003). We have also now demonstrated MCM+ enhances neuronal outward currents, namely I A and I K .…”

Section: -Aminopyridine Ameliorates Hiv-1-associated Neuronal Dysfunmentioning

confidence: 90%

“…This MCM-associated enhancement of outward K + currents may represent a link between neuronal dysfunction and cognitive decline. Thus, we supposed a systematic administration of a K + channel antagonist might lead to the improvement of learning and memory in SCID mice with HIV-1 encephalitis, a mouse model recapitulating many aspects of HIV disease in human and consistently exhibiting impaired LTP in the hippocampus (Zink et al 2002;Anderson et al 2003). We found the systemic administration of 4-aminopyridine (4-AP) significantly improved animal performance in radial-arm water maze tests (Keblesh and Xiong, unpublished data).…”

Section: -Aminopyridine Ameliorates Hiv-1-associated Neuronal Dysfunmentioning

confidence: 99%

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Voltage-gated Potassium Channels in Human Immunodeficiency Virus Type-1 (HIV-1)-associated Neurocognitive Disorders

Keblesh

Xiong

2008

J Neuroimmune Pharmacol

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Human immunodeficiency virus type-1 (HIV-1)-associated dementia (HAD), a severe form of HIV-associated neurocognitive disorders (HAND), describes the cognitive impairments and behavioral disturbances which afflict many HIV-infected individuals. Although the precise mechanism leading to HAD is incompletely understood, it is commonly accepted its progression involves a critical mass of infected and activated mononuclear phagocytes (brain perivascular macrophages and microglia) releasing immune and viral products in the brain. These cellular and viral products induce neuronal dysfunction and injury via various signaling pathways. Emerging evidence indicates voltage-gated potassium (K v ) channels, key regulators of cell excitability and animal behavior (learning and memory), are involved in the pathogenesis of HAD/HAND. Here we survey the literature and find that HAD-related alterations in cellular and viral products can increase neuronal K v channel activity, leading to neuronal dysfunction and cognitive deficits. Thus, neuronal K v channels may be a new target in the effort to develop therapies for HAD and perhaps other inflammatory neurodegenerative disorders.

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Section: -Aminopyridine Ameliorates Hiv-1-associated Neuronal Dysfunmentioning

confidence: 90%

Section: -Aminopyridine Ameliorates Hiv-1-associated Neuronal Dysfunmentioning

confidence: 99%

Voltage-gated Potassium Channels in Human Immunodeficiency Virus Type-1 (HIV-1)-associated Neurocognitive Disorders

Keblesh

Xiong

2008

J Neuroimmune Pharmacol

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“…In our previous studies, we demonstrated that synaptic dysfunction peaked in HIVE animals 7 d after HIV-1-infected MDM injection and that these functional deficits persisted for Ͼ15 d (Zink et al, 2002;Anderson et al, 2003). To assess the physiological basis of Li-induced neuroprotection, we analyzed LTP activity using hippocampal slides that were prepared from shamoperated (controls) and from HIV mice with and without Li treatment.…”

Section: Physiology Of Li-induced Neuroprotectionmentioning

confidence: 99%

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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“…This model recapitulates the pathologic and pathophysiological features of human HIVE (including giant cell encephalitis, neuronal injury, neuroinflammatory responses and cognitive abnormalities showed in human disease (Persidsky et al, 1996;Zink et al, 2002)). Moreover, the model allows testing of antiretroviral drugs for therapeutic efficacy in preventing viral spread in a BBB protected CNS (Limoges et al, 2000.…”

Section: Antiretroviral Effects Of P85 and Antiretroviral Therapy In mentioning

confidence: 89%

Novel Delivery System Enhances Efficacy of Antiretroviral Therapy in Animal Model for HIV-1 Encephalitis

Spitzenberger

Heilman

Diekmann

et al. 2006

J Cereb Blood Flow Metab

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Most potent antiretroviral drugs (e.g., HIV-1 protease inhibitors) poorly penetrate the blood-brain barrier. Brain distribution can be limited by the efflux transporter, P-glycoprotein (P-gp). The ability of a novel drug delivery system (block co-polymer P85) that inhibits P-gp, to increase the efficacy of antiretroviral drugs in brain was examined using a severe combined immunodeficiency (SCID) mouse model of HIV-1 encephalitis (HIVE). Severe combined immunodeficiency mice inoculated with HIV-1 infected human monocyte-derived macrophages (MDM) into the basal ganglia were treated with P85, antiretroviral therapy (ART) (zidovudine, lamivudine and nelfinavir (NEL)), or P85 and ART. Mice were killed on days 7 and 14, and brains were evaluated for levels of viral infection. Antiviral effects of NEL, P85, or their combination were evaluated in vitro using HIV-1 infected MDM and showed antiretroviral effects of P85 alone. In SCID mice injected with virus-infected MDM, the combination of ART-P85 and ART alone showed a significant decrease of HIV-1 p24 expressing MDM (25% and 33% of controls, respectively) at day 7 while P85 alone group was not different from control. At day 14, all treatment groups showed a significant decrease in percentage of HIV-1 infected MDM as compared with control. P85 alone and combined ART-P85 groups showed the most significant reduction in percentage of HIV-1 p24 expressing MDM (8% to 22% of control) that were superior to the ART alone group (38% of control). Our findings indicate major antiretroviral effects of P85 and enhanced in vivo efficacy of antiretroviral drugs when combined with P85 in a SCID mouse model of HIVE.

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Impaired Spatial Cognition and Synaptic Potentiation in a Murine Model of Human Immunodeficiency Virus Type 1 Encephalitis

Cited by 70 publications

References 58 publications

Voltage-gated Potassium Channels in Human Immunodeficiency Virus Type-1 (HIV-1)-associated Neurocognitive Disorders

Voltage-gated Potassium Channels in Human Immunodeficiency Virus Type-1 (HIV-1)-associated Neurocognitive Disorders

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

Novel Delivery System Enhances Efficacy of Antiretroviral Therapy in Animal Model for HIV-1 Encephalitis

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