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.
authors.affiliation: Department of Pharmacology, Physiology and Therapeutics, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Hui
authors.forename: Xuesong
authors.initials: X
authors.lastname: Chen
authors.forename: Dhaval
authors.initials: D
authors.lastname: Bhatt
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: Geiger
authors.forename: Thad A
authors.initials: TA
authors.lastname: Rosenberger
authors.forename: Norman J
authors.initials: NJ
authors.lastname: Haughey
authors.forename: Susan A
authors.initials: SA
authors.lastname: Masino
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Geiger
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D015497:HIV-1 / Q000737:chemistry*; D015544:Inositol 1,4,5-Trisphosphate / Q000494:pharmacology; D007657:Ketone Bodies / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D020258:Neurotoxicity Syndromes / Q000517:prevention & control*; D018384:Oxidative Stress / Q000187:drug effects; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors* / Q000633:toxicity*
chemical_list: D015220:Calcium Channels; D007657:Ketone Bodies; D017382:Reactive Oxygen Species; D054322:tat Gene Products, Human Immunodeficiency Virus; D015544:Inositol 1,4,5-Trisphosphate; D000255:Adenosine Triphosphate; D002118:Calcium