Ketone bodies protection against HIV-1 Tat-induced neurotoxicity

Liang Hui, Xuesong Chen, Dhaval Bhatt, Nicholas H. Geiger, Thad A. Rosenberger, Norman J. Haughey, Susan A. Masino, Jonathan D. Geiger

Research output: Contribution to journalArticle

Abstract

HIV-1-associated neurocognitive disorder (HAND) is a syndrome that ranges clinically from subtle neuropsychological impairments to profoundly disabling HIV-associated dementia. Not only is the pathogenesis of HAND unclear, but also effective treatments are unavailable. The HIV-1 transactivator of transcription protein (HIV-1 Tat) is strongly implicated in the pathogenesis of HAND, in part, because of its well-characterized ability to directly excite neurons and cause neurotoxicity. Consistent with previous findings from others, we demonstrate here that HIV-1 Tat induced neurotoxicity, increased intracellular calcium, and disrupted a variety of mitochondria functions, such as reducing mitochondrial membrane potential, increasing levels of reactive oxygen species, and decreasing bioenergetic efficiency. Of therapeutic importance, we show that treatment of cultured neurons with ketone bodies normalized HIV-1 Tat induced changes in levels of intracellular calcium, mitochondrial function, and neuronal cell death. Ketone bodies are normally produced in the body and serve as alternative energy substrates in tissues including brain and can cross the blood-brain barrier. Ketogenic strategies have been used clinically for treatment of neurological disorders and our current results suggest that similar strategies may also provide clinical benefits in the treatment of HAND.

Original languageEnglish (US)
Pages (from-to)382-391
Number of pages10
JournalJournal of Neurochemistry
Volume122
Issue number2
DOIs
StatePublished - Jul 1 2012

Keywords

  • ATP
  • calcium homeostasis
  • ketone bodies
  • mitochondrial membrane potential
  • neurotoxicity
  • oxidative stress

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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  • Cite this

    Hui, L., Chen, X., Bhatt, D., Geiger, N. H., Rosenberger, T. A., Haughey, N. J., Masino, S. A., & Geiger, J. D. (2012). Ketone bodies protection against HIV-1 Tat-induced neurotoxicity. Journal of Neurochemistry, 122(2), 382-391. https://doi.org/10.1111/j.1471-4159.2012.07764.x