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

TitleNeuroprotective effects of the immunomodulatory drug FK506 in a model of HIV1-gp120 neurotoxicity.
Publication TypeJournal Article
Year of Publication2016
AuthorsFields, JA, Overk, C, Adame, A, Florio, J, Mante, M, Pineda, A, Desplats, P, Rockenstein, E, Achim, C, Masliah, E
JournalJ Neuroinflammation
Date Published2016 05 24
KeywordsAnalysis of Variance, Animals, Calcium, Calcium-Binding Proteins, Disease Models, Animal, Encephalitis, HIV Envelope Protein gp120, Immunosuppressive Agents, Interleukin-6, Internal, Mice, Microfilament Proteins, Mitochondria, Nerve Degeneration, Nerve Tissue Proteins, Neurotoxicity Syndromes, Tacrolimus, Tacrolimus Binding Proteins, Treatment Outcome

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.

Alternate JournalJ Neuroinflammation
PubMed ID27220536
PubMed Central IDPMC4879748
Grant ListP50 AG005131 / AG / NIA NIH HHS / United States
R01 AG043384 / AG / NIA NIH HHS / United States
U24 MH100928 / MH / NIMH NIH HHS / United States
R01 MH062962 / MH / NIMH NIH HHS / United States
F32 NS083426 / NS / NINDS NIH HHS / United States
P30 MH062512 / MH / NIMH NIH HHS / United States
U01 MH083506 / MH / NIMH NIH HHS / United States