Journal Article

Neuroprotective effects of the immunomodulatory drug FK506 in a model of HIV1-gp120 neurotoxicity

Fields, Jerel A., Adame, Anthony, Masliah, Eliezer, Rockenstein, Edward, Florio, Jazmin, Pineda, Andrea, Achim, Cristian, Overk, Cassia, Mante, Michael, Desplats, Paula

2016

Overview

Background 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. Methods GFAP-gp120 tg mice were treated with FK506 and analyzed for neuropathology, behavior, mitochondrial markers, and calcium flux by two-photon microscopy. Results 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. Conclusions Together, these results suggest that FK506 might be potentially neuroprotective in patients with HAND by mitigating inflammation and mitochondrial alterations.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V
• Subject: Analysis of Variance / Animals / Antiviral agents / Biomedical and Life Sciences / Biomedicine / Calcium - metabolism / Calcium-Binding Proteins - metabolism / Care and treatment / Complications and side effects / Disease Models, Animal / Encephalitis - drug therapy / Health aspects / HIV Envelope Protein gp120 - toxicity / HIV infection / Immunology / Immunosuppressive Agents - therapeutic use / Inflammation / Interleukin-6 - metabolism / Mice / Microfilament Proteins - metabolism / Mitochondria - drug effects / Mitochondria - metabolism / Nerve Degeneration - drug therapy / Nerve Degeneration - etiology / Nerve Tissue Proteins - metabolism / Neurobiology / Neurology / Neurosciences / Neurotoxicity Syndromes - complications / Neurotoxicity Syndromes - drug therapy / Neurotoxicity Syndromes - etiology / Risk factors / Tacrolimus - therapeutic use / Tacrolimus Binding Proteins - metabolism / Treatment Outcome