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

20 Citations (Scopus)

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

Fingerprint

Ketone Bodies
Trans-Activators
Transcription
HIV-1
Neurons
Calcium
Proteins
Mitochondria
Cell death
Reactive Oxygen Species
Brain
Tissue
Membranes
AIDS Dementia Complex
Therapeutics
Substrates
Aptitude
Mitochondrial Membrane Potential
Nervous System Diseases
Blood-Brain Barrier

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Hui, L., Chen, X., Bhatt, D., Geiger, N. H., Rosenberger, T. A., Haughey, N. J., ... 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

Ketone bodies protection against HIV-1 Tat-induced neurotoxicity. / Hui, Liang; Chen, Xuesong; Bhatt, Dhaval; Geiger, Nicholas H.; Rosenberger, Thad A.; Haughey, Norman J.; Masino, Susan A.; Geiger, Jonathan D.

In: Journal of Neurochemistry, Vol. 122, No. 2, 01.07.2012, p. 382-391.

Research output: Contribution to journalArticle

Hui, L, Chen, X, Bhatt, D, Geiger, NH, Rosenberger, TA, Haughey, NJ, Masino, SA & Geiger, JD 2012, 'Ketone bodies protection against HIV-1 Tat-induced neurotoxicity', Journal of Neurochemistry, vol. 122, no. 2, pp. 382-391. https://doi.org/10.1111/j.1471-4159.2012.07764.x
Hui L, Chen X, Bhatt D, Geiger NH, Rosenberger TA, Haughey NJ et al. Ketone bodies protection against HIV-1 Tat-induced neurotoxicity. Journal of Neurochemistry. 2012 Jul 1;122(2):382-391. https://doi.org/10.1111/j.1471-4159.2012.07764.x
Hui, Liang ; Chen, Xuesong ; Bhatt, Dhaval ; Geiger, Nicholas H. ; Rosenberger, Thad A. ; Haughey, Norman J. ; Masino, Susan A. ; Geiger, Jonathan D. / Ketone bodies protection against HIV-1 Tat-induced neurotoxicity. In: Journal of Neurochemistry. 2012 ; Vol. 122, No. 2. pp. 382-391.
@article{00b42d7d0d1947e1b451410c1ee5c674,
title = "Ketone bodies protection against HIV-1 Tat-induced neurotoxicity",
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.",
keywords = "ATP, calcium homeostasis, ketone bodies, mitochondrial membrane potential, neurotoxicity, oxidative stress",
author = "Liang Hui and Xuesong Chen and Dhaval Bhatt and Geiger, {Nicholas H.} and Rosenberger, {Thad A.} and Haughey, {Norman J.} and Masino, {Susan A.} and Geiger, {Jonathan D.}",
year = "2012",
month = "7",
day = "1",
doi = "10.1111/j.1471-4159.2012.07764.x",
language = "English (US)",
volume = "122",
pages = "382--391",
journal = "Journal of Neurochemistry",
issn = "0022-3042",
publisher = "Wiley-Blackwell",
number = "2",

}

TY - JOUR

T1 - Ketone bodies protection against HIV-1 Tat-induced neurotoxicity

AU - Hui, Liang

AU - Chen, Xuesong

AU - Bhatt, Dhaval

AU - Geiger, Nicholas H.

AU - Rosenberger, Thad A.

AU - Haughey, Norman J.

AU - Masino, Susan A.

AU - Geiger, Jonathan D.

PY - 2012/7/1

Y1 - 2012/7/1

N2 - 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.

AB - 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.

KW - ATP

KW - calcium homeostasis

KW - ketone bodies

KW - mitochondrial membrane potential

KW - neurotoxicity

KW - oxidative stress

UR - http://www.scopus.com/inward/record.url?scp=84863315133&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84863315133&partnerID=8YFLogxK

U2 - 10.1111/j.1471-4159.2012.07764.x

DO - 10.1111/j.1471-4159.2012.07764.x

M3 - Article

C2 - 22524563

AN - SCOPUS:84863315133

VL - 122

SP - 382

EP - 391

JO - Journal of Neurochemistry

JF - Journal of Neurochemistry

SN - 0022-3042

IS - 2

ER -