title: Novel p75 neurotrophin receptor ligand stabilizes neuronal calcium, preserves mitochondrial movement and protects against HIV associated neuropathogenesis.
abstract: Human immunodeficiency virus (HIV) rapidly penetrates into the brain and establishes a persistent infection of macrophages/microglia. Activation of these cells by HIV results in the secretion of soluble factors that destabilize neuronal calcium homeostasis, encourage oxidative stress and result in neural damage. This damage is thought to underlie the cognitive-motor dysfunction that develops in many HIV-infected patients. Studies have suggested that neurotrophins may protect neurons from the toxic effects of HIV-associated proteins. To better understand the pathogenic mechanisms and the neuroprotective potential of neurotrophin ligands, we evaluated neuronal damage, calcium homeostasis and mitochondrial functions after exposure of cultured rat neurons directly to HIV gp120 or to conditioned medium from human monocyte-derived macrophages treated with gp120. We then assessed the ability of a new non-peptide p75 neurotrophin receptor ligand, LM11A-31, to stabilize calcium homeostasis and prevent the development of pathology. Each toxic challenge resulted in a delayed accumulation of intracellular calcium coupled to a decrease in the rate of calcium clearance from the cell. The delayed calcium accumulation correlated with the development of focal dendritic swellings (beading), cytoskeletal damage and impaired movement of mitochondria. Addition of LM11A-31 to the cultures at nanomolar concentrations eliminated cell death, significantly reduced the pathology, suppressed the delayed accumulation of calcium and restored mitochondrial movements. The potent neuroprotection and the stabilization of calcium homeostasis indicate that LM11A-31 may have excellent potential for the treatment of HIV-associated neurodegeneration.
authors.affiliation: Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, United States. Electronic address: meekerr@neurology.unc.edu.
authors.forename: Rick B
authors.initials: RB
authors.lastname: Meeker
authors.affiliation: Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, United States.
authors.forename: Winona
authors.initials: W
authors.lastname: Poulton
authors.affiliation: Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, United States.
authors.forename: Gillian
authors.initials: G
authors.lastname: Clary
authors.affiliation: Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Schriver
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, United States.
authors.forename: Frank M
authors.initials: FM
authors.lastname: Longo
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology; D015658:HIV Infections / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007532:Isoleucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009025:Morpholines / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D020318:Rats, Long-Evans; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism*
chemical_list: D015699:HIV Envelope Protein gp120; C575077:LM11A-31; D009025:Morpholines; D020800:Receptor, Nerve Growth Factor; D007532:Isoleucine; D002118:Calcium
keywords: Dementia; Encephalitis; Inflammation; LM11A-31; Nerve growth factor; Viral infection