Increased TUNEL positive cells in human alcoholic brains

Ikegami, Yukihiro; Goodenough, Sharon; Inoue, Yuki; Dodd, Peter R.; Wilce, Peter A.; Matsumoto, Izuru

doi:10.1016/s0304-3940(03)00826-7

Cited by 59 publications

(30 citation statements)

References 11 publications

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“…Endogenous MCP-1 is also known to directly induce neuronal apoptosis (Kalehua et al, 2004). Thus, increased MCP-1 in alcoholic brains could directly cause neuronal damage, and could be one of the mechanisms contributing to alcohol-related neuronal loss and brain atrophy (Brooks, 2000;Harper et al, 2003;Ikegami et al, 2003). Lastly, it has been proposed that MCP-1 can act as a "priming" stimulus for microglia (lowering their "threshold sensitivity"), enhancing their synthesis of proinflammatory cytokines in response to subsequent stimulation (Rankine et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Increased MCP-1 and microglia in various regions of the human alcoholic brain

Crews

2008

Experimental Neurology

445

413

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Cytokines and microglia have been implicated in anxiety, depression, neurodegeneration as well as the regulation of alcohol drinking and other consumatory behaviors, all of which are associated with alcoholism. Studies using animal models of alcoholism suggest that microglia and proinflammatory cytokines contribute to alcoholic pathologies (Crews et al., 2006). In the current study, human postmortem brains from moderate drinking controls and alcoholics obtained from the New South Wales Tissue Resource Center were used to study the cytokine, monocyte chemoattractant protein 1 (MCP-1,CCL2) and microglia markers in various brain regions. Since MCP-1 is a key proinflammatory cytokine induced by chronic alcohol treatment of mice, and known to regulate drinking behavior in mice, MCP-1 protein levels from human brain homogenate were measured using ELISA, and indicated increased MCP-1 concentration in ventral tegmental area (VTA), substantia nigra (SN), hippocampus and amygdala of alcoholic brains as compared with controls. Immunohistochemistry was further performed to visualize human microglia using ionized calcium binding adaptor protein-1 (Iba-1), and Glucose transporter-5 (GluT 5 ). Alcoholics were found to have brain region-specific increases in microglial markers. In cingulate cortex, both Iba-1 and GluT 5 were increased in alcoholic brains relative to controls. Alternatively, no detectable change was found in amygdala nuclei. In VTA and midbrain, only GluT 5 , but not Iba-1 was increased in alcoholic brains. These data suggest that the enhanced expression of MCP-1 and microglia activities in alcoholic brains could contribute to ethanol-induced pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Increased MCP-1 and microglia in various regions of the human alcoholic brain

Crews

2008

Experimental Neurology

445

413

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“…In one study, a significant correlation between astrocytosis (or astrogliosis) and astrocyte degeneration (or astrodegeneration) was observed in cases of frontotemporal dementia (FTD), such that brain tissue expressing minimal to abundant degrees of astrogliosis also showed minimal to severe nuclear degenerahas also been shown that most regressive GFAPpositive astrocytes are apoptotic in AD (Kobayashi et al 2002). In fact, DNA damage in astrocytes has been reported in FTD (Martin et al 2001;Su et al 2000), human alcoholic brains (Ikegami et al 2003), and Pick's disease (Gleckman et al 1999), as evidenced mostly by increased TUNEL positivity in astrocytes.…”

Section: Introductionmentioning

confidence: 98%

Evidence of DNA damage in Alzheimer disease: phosphorylation of histone H2AX in astrocytes

Myung

Zhu

Kruman

et al. 2008

AGE

151

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Phosphorylation of the histone family is not only a response to cell signaling stimuli, but also an important indicator of DNA damage preceding apoptotic changes. While astrocytic degeneration, including DNA damage, has been reported in Alzheimer disease (AD), its pathogenetic significance is somewhat unclear.In an effort to clarify this, we investigated the expression of γH2AX as evidence of DNA damage in astrocytes to elucidate the role of these cells in the pathogenesis of AD. In response to the formation of double-stranded breaks in chromosomal DNA, serine 139 on H2AX, a 14-kDa protein that is a member of the H2A histone family and part of the nucleosome structure, becomes rapidly phosphorylated to generate γH2AX. Using immunocytochemical techniques, we found significantly increased levels of γH2AX in astrocytes in regions know to be vulnerable in AD, i.e., the hippocampal regions and cerebral cortex. These results suggest that astrocytes contain DNA damage, possibly resulting in functional disability, which in turn reduces their support for neurons. These findings further define the role of astrocyte dysfunction in the progression of AD.

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“…In addition, astrocytes are directly affected by exposure to ethanol. Ethanol has been shown to inhibit proliferation of cultured astrocytes (Davies and Vernadakis, 1984;Costa and Guizzetti, 2002;Miller and Luo, 2002;Kane, et al, 1996), and astrocytes in the brains of alcoholics might respond to chronic alcohol misuse with increased cell death in the form of apoptosis (Ikegami, et al, 2003). Either by reduction in the density of astrocytes or due to altered communication between astrocytes, neuronal function in the PFC may be impaired and lead to alterations in alcohol intake and preference.…”

Section: Introductionmentioning

confidence: 99%

Infusion of gliotoxins or a gap junction blocker in the prelimbic cortex increases alcohol preference in Wistar rats

2008

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Postmortem research has revealed that there is a lower density of glial cells in regions of the prefrontal cortex (PFC) of uncomplicated alcoholics when compared with control subjects. Impairment of astrocyte function in the PFC may contribute to malfunction in circuits involved in emotion-and reward-related subcortical centers, heavily connected with the PFC and directly involved in the pathophysiology of addictive behaviours. The hypothesis was tested that infusion of gliotoxins known to injure astrocytes or of a gap junction blocker into the prelimbic area of the rat PFC results in increased preference for ethanol in rats exposed to free choice between water and 10% ethanol. Fluorocitric acid, L-α-aminoadipic acid (AAD) or the gap junction blocker 18-α-glycyrrhetinic acid (AGA) were bilaterally infused once into the rat prelimbic cortex and alcohol preference (ratio of 10% ethanol consumed to total liquid ingested) was measured before and after infusion. Infusion of AAD or AGA dissolved in their vehicles, but not of their vehicles alone, resulted in significant transient increase of preference for 10% ethanol. The present data suggest that impaired integrity of glial cells or the gap junctional communication between them in the rat PFC may contribute to changes in ethanol preference.

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Increased TUNEL positive cells in human alcoholic brains

Cited by 59 publications

References 11 publications

Increased MCP-1 and microglia in various regions of the human alcoholic brain

Increased MCP-1 and microglia in various regions of the human alcoholic brain

Evidence of DNA damage in Alzheimer disease: phosphorylation of histone H2AX in astrocytes

Infusion of gliotoxins or a gap junction blocker in the prelimbic cortex increases alcohol preference in Wistar rats

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