The immunophilin ligand GPI1046 protects neurons from the lethal effects of the HIV‐1 proteins gp120 and Tat by modulating endoplasmic reticulum calcium load
The dysfunction and death of neuronal cells is thought to underlie the cognitive manifestations of human immunodeficiency virus (HIV)‐associated neurological disorders. Although HIV‐infected patients are living longer owing to the effectiveness of anti‐retroviral therapies, the number of patients de...
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| Veröffentlicht in: | Journal of neurochemistry 2006-07, Vol.98 (1), p.146-155 |
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| creator | Caporello, Emily Nath, Avindra Slevin, John Galey, David Hamilton, Greg Williams, Larry Steiner, Joseph P. Haughey, Norman J. |
| description | The dysfunction and death of neuronal cells is thought to underlie the cognitive manifestations of human immunodeficiency virus (HIV)‐associated neurological disorders. Although HIV‐infected patients are living longer owing to the effectiveness of anti‐retroviral therapies, the number of patients developing neurological disorders is on the rise. Thus, there is an escalating need for effective therapies to preserve cognitive function in HIV‐infected patients. Using HIV‐protein‐induced neurotoxicity as a model system, we tested the effectiveness of a non‐immunosuppressive immunophilin ligand to attenuate gp120 and Tat‐induced modification of neuronal function. The immunophilin ligand GPI1046 attenuated endoplasmic reticulum (ER) calcium release induced by gp120 and Tat and protected neurons from the lethal effect of these neurotoxic HIV proteins. Both inositol 1,4,5 trisphosphate (IP3) and ryanodine‐sensitive ER calcium release was attenuated by pre‐incubation with GPI1046. Using the sarco/endoplasmic reticulum calcium pump inhibitor thapsigargin to release ER calcium, we determined that GPI1046 reduced the total ER calcium load. These findings suggest that non‐immunosuppressive immunophilin ligands may be useful neuroprotective drugs in HIV dementia. |
| doi_str_mv | 10.1111/j.1471-4159.2006.03863.x |
| format | Article |
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Although HIV‐infected patients are living longer owing to the effectiveness of anti‐retroviral therapies, the number of patients developing neurological disorders is on the rise. Thus, there is an escalating need for effective therapies to preserve cognitive function in HIV‐infected patients. Using HIV‐protein‐induced neurotoxicity as a model system, we tested the effectiveness of a non‐immunosuppressive immunophilin ligand to attenuate gp120 and Tat‐induced modification of neuronal function. The immunophilin ligand GPI1046 attenuated endoplasmic reticulum (ER) calcium release induced by gp120 and Tat and protected neurons from the lethal effect of these neurotoxic HIV proteins. Both inositol 1,4,5 trisphosphate (IP3) and ryanodine‐sensitive ER calcium release was attenuated by pre‐incubation with GPI1046. Using the sarco/endoplasmic reticulum calcium pump inhibitor thapsigargin to release ER calcium, we determined that GPI1046 reduced the total ER calcium load. These findings suggest that non‐immunosuppressive immunophilin ligands may be useful neuroprotective drugs in HIV dementia.</description><identifier>ISSN: 0022-3042</identifier><identifier>EISSN: 1471-4159</identifier><identifier>DOI: 10.1111/j.1471-4159.2006.03863.x</identifier><identifier>PMID: 16805804</identifier><identifier>CODEN: JONRA9</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Animals ; Apoptosis ; Biological and medical sciences ; calcium ; Calcium - metabolism ; Cell Survival - drug effects ; Cells, Cultured ; Cerebral Cortex - cytology ; Drug Interactions ; Embryo, Mammalian ; Endoplasmic Reticulum - drug effects ; Endoplasmic Reticulum - metabolism ; Gene Products, tat - toxicity ; gp120 ; GPI1046 ; HIV ; HIV Envelope Protein gp120 - toxicity ; Human immunodeficiency virus ; Human immunodeficiency virus 1 ; Human viral diseases ; Immunodeficiencies ; Immunodeficiencies. Immunoglobulinopathies ; Immunopathology ; Infectious diseases ; inositol 1,4,5 trisphosphate ; Medical sciences ; Neurological disorders ; Neurons ; Neurons - drug effects ; Neurons - ultrastructure ; Neurons - virology ; Proteins ; Pyrrolidines - pharmacology ; Rats ; Rats, Sprague-Dawley ; ryanodine ; Tat ; Viral diseases ; Viral diseases of the lymphoid tissue and the blood. 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Although HIV‐infected patients are living longer owing to the effectiveness of anti‐retroviral therapies, the number of patients developing neurological disorders is on the rise. Thus, there is an escalating need for effective therapies to preserve cognitive function in HIV‐infected patients. Using HIV‐protein‐induced neurotoxicity as a model system, we tested the effectiveness of a non‐immunosuppressive immunophilin ligand to attenuate gp120 and Tat‐induced modification of neuronal function. The immunophilin ligand GPI1046 attenuated endoplasmic reticulum (ER) calcium release induced by gp120 and Tat and protected neurons from the lethal effect of these neurotoxic HIV proteins. Both inositol 1,4,5 trisphosphate (IP3) and ryanodine‐sensitive ER calcium release was attenuated by pre‐incubation with GPI1046. Using the sarco/endoplasmic reticulum calcium pump inhibitor thapsigargin to release ER calcium, we determined that GPI1046 reduced the total ER calcium load. These findings suggest that non‐immunosuppressive immunophilin ligands may be useful neuroprotective drugs in HIV dementia.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Biological and medical sciences</subject><subject>calcium</subject><subject>Calcium - metabolism</subject><subject>Cell Survival - drug effects</subject><subject>Cells, Cultured</subject><subject>Cerebral Cortex - cytology</subject><subject>Drug Interactions</subject><subject>Embryo, Mammalian</subject><subject>Endoplasmic Reticulum - drug effects</subject><subject>Endoplasmic Reticulum - metabolism</subject><subject>Gene Products, tat - toxicity</subject><subject>gp120</subject><subject>GPI1046</subject><subject>HIV</subject><subject>HIV Envelope Protein gp120 - toxicity</subject><subject>Human immunodeficiency virus</subject><subject>Human immunodeficiency virus 1</subject><subject>Human viral diseases</subject><subject>Immunodeficiencies</subject><subject>Immunodeficiencies. Immunoglobulinopathies</subject><subject>Immunopathology</subject><subject>Infectious diseases</subject><subject>inositol 1,4,5 trisphosphate</subject><subject>Medical sciences</subject><subject>Neurological disorders</subject><subject>Neurons</subject><subject>Neurons - drug effects</subject><subject>Neurons - ultrastructure</subject><subject>Neurons - virology</subject><subject>Proteins</subject><subject>Pyrrolidines - pharmacology</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>ryanodine</subject><subject>Tat</subject><subject>Viral diseases</subject><subject>Viral diseases of the lymphoid tissue and the blood. 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Aids</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Caporello, Emily</creatorcontrib><creatorcontrib>Nath, Avindra</creatorcontrib><creatorcontrib>Slevin, John</creatorcontrib><creatorcontrib>Galey, David</creatorcontrib><creatorcontrib>Hamilton, Greg</creatorcontrib><creatorcontrib>Williams, Larry</creatorcontrib><creatorcontrib>Steiner, Joseph P.</creatorcontrib><creatorcontrib>Haughey, Norman J.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Calcium & Calcified Tissue Abstracts</collection><jtitle>Journal of neurochemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Caporello, Emily</au><au>Nath, Avindra</au><au>Slevin, John</au><au>Galey, David</au><au>Hamilton, Greg</au><au>Williams, Larry</au><au>Steiner, Joseph P.</au><au>Haughey, Norman J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The immunophilin ligand GPI1046 protects neurons from the lethal effects of the HIV‐1 proteins gp120 and Tat by modulating endoplasmic reticulum calcium load</atitle><jtitle>Journal of neurochemistry</jtitle><addtitle>J Neurochem</addtitle><date>2006-07</date><risdate>2006</risdate><volume>98</volume><issue>1</issue><spage>146</spage><epage>155</epage><pages>146-155</pages><issn>0022-3042</issn><eissn>1471-4159</eissn><coden>JONRA9</coden><abstract>The dysfunction and death of neuronal cells is thought to underlie the cognitive manifestations of human immunodeficiency virus (HIV)‐associated neurological disorders. Although HIV‐infected patients are living longer owing to the effectiveness of anti‐retroviral therapies, the number of patients developing neurological disorders is on the rise. Thus, there is an escalating need for effective therapies to preserve cognitive function in HIV‐infected patients. Using HIV‐protein‐induced neurotoxicity as a model system, we tested the effectiveness of a non‐immunosuppressive immunophilin ligand to attenuate gp120 and Tat‐induced modification of neuronal function. The immunophilin ligand GPI1046 attenuated endoplasmic reticulum (ER) calcium release induced by gp120 and Tat and protected neurons from the lethal effect of these neurotoxic HIV proteins. Both inositol 1,4,5 trisphosphate (IP3) and ryanodine‐sensitive ER calcium release was attenuated by pre‐incubation with GPI1046. Using the sarco/endoplasmic reticulum calcium pump inhibitor thapsigargin to release ER calcium, we determined that GPI1046 reduced the total ER calcium load. These findings suggest that non‐immunosuppressive immunophilin ligands may be useful neuroprotective drugs in HIV dementia.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>16805804</pmid><doi>10.1111/j.1471-4159.2006.03863.x</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Apoptosis Biological and medical sciences calcium Calcium - metabolism Cell Survival - drug effects Cells, Cultured Cerebral Cortex - cytology Drug Interactions Embryo, Mammalian Endoplasmic Reticulum - drug effects Endoplasmic Reticulum - metabolism Gene Products, tat - toxicity gp120 GPI1046 HIV HIV Envelope Protein gp120 - toxicity Human immunodeficiency virus Human immunodeficiency virus 1 Human viral diseases Immunodeficiencies Immunodeficiencies. Immunoglobulinopathies Immunopathology Infectious diseases inositol 1,4,5 trisphosphate Medical sciences Neurological disorders Neurons Neurons - drug effects Neurons - ultrastructure Neurons - virology Proteins Pyrrolidines - pharmacology Rats Rats, Sprague-Dawley ryanodine Tat Viral diseases Viral diseases of the lymphoid tissue and the blood. Aids |
| title | The immunophilin ligand GPI1046 protects neurons from the lethal effects of the HIV‐1 proteins gp120 and Tat by modulating endoplasmic reticulum calcium load |
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