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.
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 (IP(3)) 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.
authors.affiliation: Department of Neurology, John Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Caporello
authors.forename: Avindra
authors.initials: A
authors.lastname: Nath
authors.forename: John
authors.initials: J
authors.lastname: Slevin
authors.forename: David
authors.initials: D
authors.lastname: Galey
authors.forename: Greg
authors.initials: G
authors.lastname: Hamilton
authors.forename: Larry
authors.initials: L
authors.lastname: Williams
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Steiner
authors.forename: Norman J
authors.initials: NJ
authors.lastname: Haughey
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D015696:Gene Products, tat / Q000633:toxicity*; D015699:HIV Envelope Protein gp120 / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects* / Q000648:ultrastructure / Q000821:virology; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C104949:GPI 1046; D015696:Gene Products, tat; D015699:HIV Envelope Protein gp120; D011759:Pyrrolidines; D002118:Calcium