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Markers of apoptosis induction and proliferation in the orbitofrontal cortex in alcohol dependence.

ABSTRACT: Alcohol-dependent (ALC) subjects exhibit glial and neuronal pathology in the prefrontal cortex (PFC). However, in many patients, neurophysiological disturbances are not associated with catastrophic cell depletion despite prolonged alcohol abuse. It is still unclear how some relevant markers of a cell's propensity to degenerate or proliferate are changed in the PFC of ALC subjects without major neurological disorders.Levels of pro-apoptotic caspase 8 (C8), X-linked inhibitor of apoptosis protein (XIAP), direct IAP binding protein with low pI (DIABLO), proliferating cell nuclear antigen (PCNA), and density of cells immunoreactive for proliferation marker Ki-67 (Ki-67-IR) were measured postmortem in the left orbitofrontal cortex (OFC) of 29 subjects with alcohol dependence and 23 nonpsychiatric comparison subjects.Alcohol subjects had significantly higher levels of the 14 kDa C8 fragment (C8-14), an indicator of C8 activation. However, there was no change in the levels of DIABLO, XIAP, or in the DIABLO/XIAP ratio. PCNA protein level and density of Ki-67-IR cells were not significantly changed in alcoholics, although PCNA levels were increased in older ALC subjects as compared to controls.Significant increase of a C8 activation indicator was found in alcoholism, but without significant changes in XIAP level, DIABLO/XIAP ratio, or Ki-67 labeling. These results would help to explain the absence of catastrophic cell loss in the PFC of many Brigman subjects, while still being consistent with an alcoholism-related vulnerability to slow decline in glial cells and neurons in the OFC of alcoholics.

SUBMITTER: Whittom A

PROVIDER: S-EPMC4244601 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Markers of apoptosis induction and proliferation in the orbitofrontal cortex in alcohol dependence.

Whittom Angela A Villarreal Ashley A Soni Madhav M Owusu-Duku Beverly B Meshram Ashish A Rajkowska Grazyna G Stockmeier Craig A CA Miguel-Hidalgo Jose J JJ

Alcoholism, clinical and experimental research 20141101 11

<h4>Background</h4>Alcohol-dependent (ALC) subjects exhibit glial and neuronal pathology in the prefrontal cortex (PFC). However, in many patients, neurophysiological disturbances are not associated with catastrophic cell depletion despite prolonged alcohol abuse. It is still unclear how some relevant markers of a cell's propensity to degenerate or proliferate are changed in the PFC of ALC subjects without major neurological disorders.<h4>Methods</h4>Levels of pro-apoptotic caspase 8 (C8), X-lin ...[more]

PMID: 25421516

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Project description:BackgroundActivation of the innate immune system may play a role in the development of alcohol use disorders (AUDs), which often originate with adolescent alcohol abuse. A key player in the innate immune system is microglia, the activation of which occurs along a spectrum from proinflammatory, or M1-like, to anti-inflammatory, or M2-like, phenotypes.MethodsAdolescent, male rats were gavaged with ethanol (EtOH) or isocaloric control diet every 8 hours for 4 days and then sacrificed at 0, 2, 7, and 14 days later. Microglia were isolated from the entorhinal cortex and hippocampus by Percoll gradient centrifugation, labeled with surface antigens for activation, and analyzed by flow cytometry. Polarization states of microglia, defined as CD11b+ CD45low cells, were determined by the expression of M1 surface markers, major histocompatibility complex (MHC) II, CD32, and CD86, and M2 surface marker, CD206 (mannose receptor). Cytokine gene expression was measured by reverse transcriptase polymerase chain reaction.ResultsIsolated cells were a highly enriched population (>95% pure) of microglia/macrophages according to CD11b immunoreactivity. EtOH rats showed the most dramatic increases in microglia activation markers CD11b and CD45, and M1 (MHC-II) and M2 (CD206) markers at T2, when additional M1 markers CD86 and CD32 were also increased. Surprisingly, proinflammatory gene expression of CCL2, IL-1β, IL-6, and TNF-α generally was decreased at all time points in EtOH rats except for IL-6 which was increased at T0 and TNF-α which was not changed at T0 in either region. Simultaneously, BDNF expression was increased at T2 and T7, while IGF1 and TGF-β gene expression was decreased. Arginase was also increased at T0 in hippocampus, but not changed by alcohol otherwise.ConclusionsThese data show that microglia phenotype after alcohol dependence is not a simple M1 or M2 classification, though more indicators of an anti-inflammatory phenotype were observed. Determining microglia phenotype is critical for understanding their role in the development of AUDs.

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Markers of apoptosis induction and proliferation in the orbitofrontal cortex in alcohol dependence.

Publications

Markers of apoptosis induction and proliferation in the orbitofrontal cortex in alcohol dependence.

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