title: Neuroprotective effects of the immunomodulatory drug FK506 in a model of HIV1-gp120 neurotoxicity.
abstract: HIV-associated neurocognitive disorders (HAND) continue to be a common morbidity associated with chronic HIV infection. It has been shown that HIV proteins (e.g., gp120) released from infected microglial/macrophage cells can cause neuronal damage by triggering inflammation and oxidative stress, activating aberrant kinase pathways, and by disrupting mitochondrial function and biogenesis. Previous studies have shown that FK506, an immunophilin ligand that modulates inflammation and mitochondrial function and inhibits calcineurin, is capable of rescuing the neurodegenerative pathology in models of Parkinson's disease, Alzheimer's disease, and Huntington's disease. In this context, the main objective of this study was to evaluate if FK506 could rescue the neuronal degeneration and mitochondrial alterations in a transgenic (tg) animal model of HIV1-gp120 neurotoxicity.
  
  
  
  GFAP-gp120 tg mice were treated with FK506 and analyzed for neuropathology, behavior, mitochondrial markers, and calcium flux by two-photon microscopy.
  
  
  
  We found that FK506 reduced the neuronal cell loss and neuro-inflammation in the gp120 tg mice. Moreover, while vehicle-treated gp120 tg mice displayed damaged mitochondria and increased neuro-inflammatory markers, FK506 rescued the morphological mitochondrial alterations and neuro-inflammation while increasing levels of optic atrophy 1 and mitofusin 1. By two-photon microscopy, calcium levels were not affected in the gp120 tg mice and no effects of FK506 were detected. However, at a functional level, FK506 ameliorated the gp120 tg mice hyperactivity in the open field.
  
  
  
  Together, these results suggest that FK506 might be potentially neuroprotective in patients with HAND by mitigating inflammation and mitochondrial alterations.
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, CA, USA.
authors.forename: Jerel A
authors.initials: JA
authors.lastname: Fields
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
authors.forename: Cassia
authors.initials: C
authors.lastname: Overk
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Adame
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
authors.forename: Jazmin
authors.initials: J
authors.lastname: Florio
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Mante
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pineda
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
authors.forename: Paula
authors.initials: P
authors.lastname: Desplats
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Rockenstein
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
authors.forename: Cristian
authors.initials: C
authors.lastname: Achim
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, CA, USA. emasliah@ucsd.edu.|Department of Neurosciences, University of California San Diego, La Jolla, CA, USA. emasliah@ucsd.edu.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004660:Encephalitis / Q000188:drug therapy; D015699:HIV Envelope Protein gp120 / Q000633:toxicity*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009410:Nerve Degeneration / Q000188:drug therapy / Q000209:etiology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000150:complications / Q000188:drug therapy* / Q000209:etiology*; D016559:Tacrolimus / Q000627:therapeutic use*; D022021:Tacrolimus Binding Proteins / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D015699:HIV Envelope Protein gp120; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D022021:Tacrolimus Binding Proteins; D002118:Calcium; D016559:Tacrolimus
keywords: FK506; HIV; Neuro-inflammation; gp120