Abstract
Human immunodeficiency virus (HIV)-1 infection of the central nervous system occurs in the vast majority of HIV-infected patients. HIV-associated dementia (HAD) represents the most severe form of HIV-related neuropsychiatric impairment. The pathogenesis of HAD is mediated by disruption of neuronal cell signal pathways, which ultimately triggers neuronal apoptosis. Evidence indicates that a viral gene product, the transactivator of transcription protein (Tat), takes a responsive role to these events. We herein report that sulfated polymannuroguluronate (SPMG), a novel anti-acquired immunodeficiency syndrome drug candidate now in phase II clinical trial, significantly decreased vulnerability of PC12 cells to HIV Tat protein by protecting cells from apoptosis. Furthermore, SPMG potently arrested Tat-triggered PKCdelta and PKCtheta activation and blocked the downstream apoptosis signaling pathways mediated by both ERK1/2 and caspase-3. These molecular mechanisms were attributed to the fact that SPMG reduced Tat-evoked calcium overload. These data demonstrate that SPMG might serve as a valuable therapeutic intervention for Tat-induced neuronal cell death and the subsequent pathologic events of HAD.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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AIDS Dementia Complex / drug therapy*
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AIDS Dementia Complex / metabolism
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AIDS Dementia Complex / physiopathology
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Animals
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Antiviral Agents / pharmacology
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Apoptosis / drug effects
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Apoptosis / genetics
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Calcium Signaling / drug effects*
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Calcium Signaling / physiology
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Caspase 3 / drug effects
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Caspase 3 / metabolism
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Enzyme Activation / drug effects
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Enzyme Activation / physiology
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HIV-1 / drug effects
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HIV-1 / metabolism
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Humans
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Isoenzymes / drug effects
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Isoenzymes / metabolism
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Mitogen-Activated Protein Kinase 3 / drug effects
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Mitogen-Activated Protein Kinase 3 / metabolism
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Models, Biological
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Nerve Degeneration / drug therapy
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Nerve Degeneration / metabolism
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Nerve Degeneration / virology
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Neurons / drug effects*
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Neurons / metabolism
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Neurons / virology*
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PC12 Cells
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Polysaccharides / pharmacology*
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Protein Kinase C / drug effects
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Protein Kinase C / metabolism
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Protein Kinase C-delta / drug effects
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Protein Kinase C-delta / metabolism
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Rats
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Virus Replication / drug effects
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Virus Replication / physiology
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tat Gene Products, Human Immunodeficiency Virus / antagonists & inhibitors*
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tat Gene Products, Human Immunodeficiency Virus / metabolism
Substances
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Antiviral Agents
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Isoenzymes
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Polysaccharides
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sulfated polymannuroguluronate
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tat Gene Products, Human Immunodeficiency Virus
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Protein Kinase C
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Protein Kinase C-delta
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Mitogen-Activated Protein Kinase 3
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Caspase 3