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Chronic Binge Alcohol Exacerbates Apoptotic Signaling in Simian Immunodeficiency Virus‐infected Macaques
Author(s) -
Maxi John K.,
Bagby Gregory J.,
Nelson Steve,
Winsauer Peter J.,
Molina Patricia E.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.991.1
Subject(s) - simian immunodeficiency virus , immunology , virology , biology , western blot , virus , biochemistry , gene
HIV‐associated neurocognitive disorder (HAND), characterized by altered pre‐frontal cortex (PFC) mediated behaviors, affects ≈50% of persons living with HIV/AIDS. Alcohol use accelerates the development of HAND. Our studies have shown that chronic binge alcohol administration (CBA) unmasks behavioral deficits in simian immunodeficiency virus (SIV)‐infected macaques. However, the mechanisms underlying these alcohol‐induced behavioral deficits remain unknown. Alcohol administration and HIV/SIV neuronal damage result, at least in part, from excitotoxic NMDA receptor signaling stimulating mitochondrial pro‐apoptotic mechanisms. Recently, it has been recognized that loss of pro‐survival factors, specifically Brain‐Derived Neurotrophic Factor (BDNF), also contributes to alcohol and HIV/SIV‐induced neuronal damage. Thus, we hypothesized that CBA administration to SIV‐infected macaques would result in greater excitotoxic signaling and impaired BDNF‐mediated cell signaling in the PFC, suggesting a potential mechanism underlying exacerbation of HAND. Adult rhesus macaques were fitted with intragastric catheters for the infusion of alcohol (n=3, CBA/SIV, 13–14 g/kg/week) or sucrose (n=3, SUC/SIV), beginning three months prior to inoculation with SIV, and continued for the duration of the study. Animals were euthanized upon reaching end‐stage disease (13 – 23 months post SIV) and PFC tissue was isolated for mRNA and protein analysis by qPCR and Western blot, respectively. PFC tissue from non SIV‐infected macaques (SIV‐, n=3–5) was used to normalize mRNA and protein expression. PFC of CBA/SIV macaques showed increased NMDA receptor subunits NR1 and NR2B relative to dendritic marker MAP2 (1.5‐fold increase), and increased Bax:Bcl‐2 ratio (10‐fold increase), suggesting enhanced excitotoxic apoptotic signaling. Additionally, we found decreased expression of BDNF mRNA (2‐fold reduction); activated BDNF receptor (pTrkB) (15‐fold lower); and pAKT levels (3‐fold reduction) in CBA/SIV animals compared to that of SUC/SIV animals. These findings indicated that CBA exacerbates apoptotic signaling in the PFC of SIV‐infected macaques. We predict these findings implicate increased PFC neuronal apoptosis as a likely mechanism underlying accentuated neurocognitive impairment in CBA/SIV macaques. Support or Funding Information P60AA09803, T32AA07577, F31AA024365