4-Aminopyridine Improves Spatial Memory in a Murine Model of HIV-1 Encephalitis

Neurophysiology Laboratory, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA.
Journal of Neuroimmune Pharmacology (Impact Factor: 4.11). 06/2009; 4(3):317-27. DOI: 10.1007/s11481-009-9161-7
Source: PubMed

ABSTRACT HIV-1-associated neurocognitive disorders (HAND) remains a significant source of morbidity in the era of wide spread use of highly active antiretroviral therapy. Disease is precipitated by low levels of viral growth and glial immune activation within the central nervous system. Blood borne macrophage and microglia affect a proinflammatory response and release viral proteins that affects neuronal viability and leads to death of nerve cells. Increasing evidence supports the notion that HAND is functional channelopathy, but proof of this concept remains incomplete. Based on their role in learning and memory processes, we now posit that voltage-gated potassium (K(v)) channels could be a functional substrate for disease. This was tested in the severe combined immunodeficient (SCID) mouse model of HIV-1 encephalitis (HIVE) by examining whether the K(v) channel blocker, 4-aminopyridine (4-AP), could affect behavioral, electrophysiological, and morphological measures of learning and memory. HIVE SCID mice showed impaired spatial memory in radial arm water maze tests. Electrophysiology studies revealed a reduction of long-term potentiation (LTP) in the CA1 region of the hippocampus. Importantly, systemic administration of 4-AP blocked HIV-1-associated reduction of LTP and improved animal performance in the radial arm water maze. These results support the importance of K(v) channel dysfunction in disease but, more importantly, provide a potential target for adjunctive therapies for HAND.

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Available from: Huangui Xiong, Sep 25, 2015
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    • "HIV-1 gp120 enhances A-type transient outward K+ currents (IA) in neurons, resulting in neuronal apoptosis [4]. Inhibition of the gp120- induced increase of IA attenuates gp120-mediated apoptosis of neurons [4], and improves learning and memory in animals as well [5], [6]. Actually, overactivation of voltage-gated Kv channels can trigger excessive K+ efflux and intracellular K+ depletion, which are early ionic events in apoptotic cascades of neurons [7]. "
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    ABSTRACT: Curcumin is a molecule found in turmeric root that has anti-inflammatory, antioxidant, and anti-tumor properties and has been widely used as both an herbal drug and a food additive to treat or prevent neurodegenerative diseases. To explore whether curcumin is able to ameliorate HIV-1-associated neurotoxicity, we treated a murine microglial cell line (N9) and primary rat cortical neurons with curcumin in the presence or absence of neurotoxic HIV-1 gp120 (V3 loop) protein. We found that HIV-1 gp120 profoundly induced N9 cells to produce reactive oxygen species (ROS), tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1). HIV-1 gp120 also induced apoptosis of primary rat cortical neurons. Curcumin exerted a powerful inhibitory effect against HIV-1 gp120-induced neuronal damage, reducing the production of ROS, TNF-α and MCP-1 by N9 cells and inhibiting apoptosis of primary rat cortical neurons. Curcumin may exert its biological activities through inhibition of the delayed rectification and transient outward potassium (K(+)) current, as curcumin effectively reduced HIV-1 gp120-mediated elevation of the delayed rectification and transient outward K(+) channel current in neurons. We conclude that HIV-1 gp120 increases ROS, TNF-α and MCP-1 production in microglia, and induces cortical neuron apoptosis by affecting the delayed rectification and transient outward K(+) channel current. Curcumin reduces production of ROS and inflammatory mediators in HIV-1-gp120-stimulated microglia, and protects cortical neurons against HIV-1-mediated apoptosis, most likely through inhibition of HIV-1 gp120-induced elevation of the delayed rectification and transient outward K(+) current.
    PLoS ONE 08/2013; 8(8):e70565. DOI:10.1371/journal.pone.0070565 · 3.23 Impact Factor
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    • "This promising data opens the future possibility of using Kv1.3 channel inhibitors as a novel strategy to combat HAND and other neurodegenerative disorders in which the pathophysiological process involves microglia-mediated immune and inflammatory responses. In a previous in vivo study, we demonstrated the administration of Kv channel antagonist 4-AP could ameliorate HIV-1-induced encephalitis and cognitive disorder, improving spatial learning and memory in a severe combined immunodeficient (SCID) mouse model of HIV-1 encephalitis (HIVE) [50]. Nevertheless, as Kv channel blockers selectively target immune cells including macrophage, microglia, and lymphocytes, the therapeutic benefit of this approach must be carefully considered for potential risks to the immune system. "
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    ABSTRACT: Microglia plays a crucial role in the pathogenesis of HIV-1-associated neurocognitive disorders. Increasing evidence indicates the voltage-gated potassium (Kv) channels are involved in the regulation of microglia function, prompting us to hypothesize Kv channels may also be involved in microglia-mediated neurotoxic activity in HIV-1-infected brain. To test this hypothesis, we investigated the involvement of Kv channels in the response of microglia to HIV-1 Tat protein. Treatment of rat microglia with HIV-1 Tat protein (200 ng/ml) resulted in pro-inflammatory microglial activation, as indicated by increases in TNF-α, IL-1β, reactive oxygen species, and nitric oxide, which were accompanied by enhanced outward K(+) current and Kv1.3 channel expression. Suppression of microglial Kv1.3 channel activity, either with Kv1.3 channel blockers Margatoxin, 5-(4-Phenoxybutoxy)psoralen, or broad-spectrum K(+) channel blocker 4-Aminopyridine, or by knockdown of Kv1.3 expression via transfection of microglia with Kv1.3 siRNA, was found to abrogate the neurotoxic activity of microglia resulting from HIV-1 Tat exposure. Furthermore, HIV-1 Tat-induced neuronal apoptosis was attenuated with the application of supernatant collected from K(+) channel blocker-treated microglia. Lastly, the intracellular signaling pathways associated with Kv1.3 were investigated and enhancement of microglial Kv1.3 was found to correspond with an increase in Erk1/2 mitogen-activated protein kinase activation. These data suggest targeting microglial Kv1.3 channels may be a potential new avenue of therapy for inflammation-mediated neurological disorders.
    PLoS ONE 05/2013; 8(5):e64904. DOI:10.1371/journal.pone.0064904 · 3.23 Impact Factor
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    • "References HIVE/SCID mice The cognitive deficits manifest as longer latencies to locate the visible platform on the last day of the MWM acquisition period and during a retention test (probe trial) 8 days later. Evidence of impairments in spatial memory in radial water arm maze Griffin et al. 2004; Keblesh et al. 2009; Zink et al. 2002 Spargue–Dawley rats (HIV-1Tg) Deficits in modified MWM in latency to platform in hidden trials, but did not show a deficit in their memory of the general location of the hidden platform. Deficits in reversal learning and new strategy learning in modified MWM Lashomb et al. 2009; Vigorito et al. 2007 Transgenic mice expressing gp120 MWM learning (visible trials) impairments in 3-month-old. "
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    ABSTRACT: HIV-associated neurocognitive disorders (HAND) continue to be a neurological complication of HIV infection in the era of combined antiretroviral therapy. Hippocampal neurodegeneration and dysfunction occurs as a result of HIV infection, but few studies to date have assesses spatial learning and memory function in patients with HAND. We used the Memory Island (MI) test to study the effects of HIV infection, apolipoprotein E (ApoE) allele status, and cerebral spinal fluid (CSF) ApoE protein levels on spatial learning and memory in our cohort of Hispanic women. The MI test is a virtual reality-based computer program that tests spatial learning and memory and was designed to resemble the Morris Water Maze test of hippocampal function widely used in rodent studies. In the current study, HIV-seropositive women (n = 20) and controls (n = 16) were evaluated with neuropsychological (NP) tests, the MI test, ApoE, and CSF ApoE assays. On the MI, the HIV-seropositive group showed significant reduced learning and delayed memory performance compared with HIV-seronegative controls. When stratified by cognitive performance on NP tests, the HIV-seropositive, cognitively impaired group performed worse than HIV-seronegative controls in ability to learn and in the delayed memory trial. Interestingly, differences were observed in the results obtained by the NP tests and the MI test for ε4 carriers and noncarriers: NP tests showed effects of the ε4 allele in HIV-seronegative women but not HIV-seropositive ones, whereas the converse was true for the MI test. Our findings suggest that the MI test is sensitive in detecting spatial deficits in HIV-seropositive women and that these deficits may arise relatively early in the course of HAND.
    Journal of NeuroVirology 09/2012; 18(6). DOI:10.1007/s13365-012-0128-8 · 2.60 Impact Factor
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