Sulfated polymannuroguluronate, a novel anti-acquired immune deficiency syndrome drug candidate, decreased vulnerability of PC12 cells to human immunodeficiency virus tat protein through attenuating calcium overload.
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.
Hui
Bin
B
Department of Pharmacology, Marine Drug and Food Institute, Ocean University of China, Qingdao, China.
Li
Jing
J
Geng
Mei Yu
MY
D015526:AIDS Dementia Complex / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D020013:Calcium Signaling / Q000187:drug effects* / Q000502:physiology; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D015497:HIV-1 / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D009410:Nerve Degeneration / Q000188:drug therapy / Q000378:metabolism / Q000821:virology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000821:virology*; D016716:PC12 Cells; D011134:Polysaccharides / Q000494:pharmacology*; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000998:Antiviral Agents; D007527:Isoenzymes; D011134:Polysaccharides; C489185:sulfated polymannuroguluronate; D054322:tat Gene Products, Human Immunodeficiency Virus; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D048052:Mitogen-Activated Protein Kinase 3; D053148:Caspase 3