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Inflammasome-IL-1β Signaling Mediates Ethanol Inhibition of Hippocampal Neurogenesis.

Zou J, Crews FT - Front Neurosci (2012)

Bottom Line: Ethanol and neuroinflammation are known to reduce neurogenesis.Blockade of IL-1β synthesis with inflammasome inhibitors Parthenolide and Bay11708 significantly reversed ethanol inhibited neurogenesis.Furthermore, we also found that IL-1β and inflammasome proteins NALP1 and NALP3 are increased in hippocampal neurons and astrocytes in postmortem alcoholic human brain.

View Article: PubMed Central - PubMed

Affiliation: Bowles Center for Alcohol Studies, The University of North Carolina at Chapel Hill Chapel Hill, NC, USA.

ABSTRACT
Regulation of hippocampal neurogenesis is poorly understood, but appears to contribute to mood and cognition. Ethanol and neuroinflammation are known to reduce neurogenesis. We have found that ethanol induces neuroinflammation supporting the hypothesis that ethanol induction of neuroinflammation contributes to ethanol inhibition of neurogenesis. To identify the key proinflammatory molecule that may be responsible for ethanol-impaired neurogenesis we used an ex vivo model of organotypic hippocampal-entorhinal cortex brain slice cultures. Here, we demonstrated a key role of proinflammatory cytokine IL-1β signaling in mediating ethanol inhibition of neurogenesis. Ethanol inhibition of neurogenesis was reversed by neutralizing antibody to IL-1β or blockade of the IL-1β receptor with antagonist IL-1RIa. Ethanol-impaired neurogenesis is associated with strong induction of IL-1β and inflammasome proteins NALP1 and NALP3 in both neurons and astrocytes. Blockade of IL-1β synthesis with inflammasome inhibitors Parthenolide and Bay11708 significantly reversed ethanol inhibited neurogenesis. Furthermore, we also found that IL-1β and inflammasome proteins NALP1 and NALP3 are increased in hippocampal neurons and astrocytes in postmortem alcoholic human brain. Together, these novel findings demonstrate that targeting inflammasome-IL-1β signaling can normalize ethanol-impaired hippocampal neurogenesis, which may have therapeutic implications for treatment of cognitive impairment associated with hippocampal dysfunction in alcoholics.

No MeSH data available.


Related in: MedlinePlus

Rolipram and anti-oxidant BHT protect from ethanol-impaired neurogenesis. Shown in bar graph (A): PDE IV inhibitor rolipram and anti-oxidant BHT increase DCR+ IR and reverse ethanol inhibition of DCX+ IR. ANOVA F(5, 32) = 11.552, p < 0.001, and Fisher post hoc: ***p < 0.001 or **p < 0.01 compared with Control or EtOH4D, n = 6–8. The experiments were repeated with similar results. Representative photographs of DCX+ IR are shown in (B) (control); (C) (EtOH); (D) (Ethanol + BHT, 50 mM, pretreatment for 3 days); and (E) (Ethanol + Rolipram, 500 nM, pretreatment for 3 days; scale bar = 200 μm).
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Figure 9: Rolipram and anti-oxidant BHT protect from ethanol-impaired neurogenesis. Shown in bar graph (A): PDE IV inhibitor rolipram and anti-oxidant BHT increase DCR+ IR and reverse ethanol inhibition of DCX+ IR. ANOVA F(5, 32) = 11.552, p < 0.001, and Fisher post hoc: ***p < 0.001 or **p < 0.01 compared with Control or EtOH4D, n = 6–8. The experiments were repeated with similar results. Representative photographs of DCX+ IR are shown in (B) (control); (C) (EtOH); (D) (Ethanol + BHT, 50 mM, pretreatment for 3 days); and (E) (Ethanol + Rolipram, 500 nM, pretreatment for 3 days; scale bar = 200 μm).

Mentions: We next investigated the effects of anti-inflammatory agents butylated hydroxytoluene (BHT) and rolipram, both found to protect against ethanol induced increased NF-κB transcription of proinflammatory cytokines and neurodegeneration (Crews et al., 2006a). BHT added to HEC slice cultures increased DCX + IR and reversed ethanol reduction of DCX + IR (Figure 9). Rolipram, a PDE IV inhibitor that increases cAMP, PKA activation, and pCREB that protect against ethanol neurotoxicity (Zou and Crews, 2006) also increased DCX + IR and reversed ethanol inhibition of DCX + IR (Figure 9). These studies suggest targeting IL-1β signaling pathway with anti-inflammatory inhibition can reverse ethanol inhibition of neurogenesis.


Inflammasome-IL-1β Signaling Mediates Ethanol Inhibition of Hippocampal Neurogenesis.

Zou J, Crews FT - Front Neurosci (2012)

Rolipram and anti-oxidant BHT protect from ethanol-impaired neurogenesis. Shown in bar graph (A): PDE IV inhibitor rolipram and anti-oxidant BHT increase DCR+ IR and reverse ethanol inhibition of DCX+ IR. ANOVA F(5, 32) = 11.552, p < 0.001, and Fisher post hoc: ***p < 0.001 or **p < 0.01 compared with Control or EtOH4D, n = 6–8. The experiments were repeated with similar results. Representative photographs of DCX+ IR are shown in (B) (control); (C) (EtOH); (D) (Ethanol + BHT, 50 mM, pretreatment for 3 days); and (E) (Ethanol + Rolipram, 500 nM, pretreatment for 3 days; scale bar = 200 μm).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 9: Rolipram and anti-oxidant BHT protect from ethanol-impaired neurogenesis. Shown in bar graph (A): PDE IV inhibitor rolipram and anti-oxidant BHT increase DCR+ IR and reverse ethanol inhibition of DCX+ IR. ANOVA F(5, 32) = 11.552, p < 0.001, and Fisher post hoc: ***p < 0.001 or **p < 0.01 compared with Control or EtOH4D, n = 6–8. The experiments were repeated with similar results. Representative photographs of DCX+ IR are shown in (B) (control); (C) (EtOH); (D) (Ethanol + BHT, 50 mM, pretreatment for 3 days); and (E) (Ethanol + Rolipram, 500 nM, pretreatment for 3 days; scale bar = 200 μm).
Mentions: We next investigated the effects of anti-inflammatory agents butylated hydroxytoluene (BHT) and rolipram, both found to protect against ethanol induced increased NF-κB transcription of proinflammatory cytokines and neurodegeneration (Crews et al., 2006a). BHT added to HEC slice cultures increased DCX + IR and reversed ethanol reduction of DCX + IR (Figure 9). Rolipram, a PDE IV inhibitor that increases cAMP, PKA activation, and pCREB that protect against ethanol neurotoxicity (Zou and Crews, 2006) also increased DCX + IR and reversed ethanol inhibition of DCX + IR (Figure 9). These studies suggest targeting IL-1β signaling pathway with anti-inflammatory inhibition can reverse ethanol inhibition of neurogenesis.

Bottom Line: Ethanol and neuroinflammation are known to reduce neurogenesis.Blockade of IL-1β synthesis with inflammasome inhibitors Parthenolide and Bay11708 significantly reversed ethanol inhibited neurogenesis.Furthermore, we also found that IL-1β and inflammasome proteins NALP1 and NALP3 are increased in hippocampal neurons and astrocytes in postmortem alcoholic human brain.

View Article: PubMed Central - PubMed

Affiliation: Bowles Center for Alcohol Studies, The University of North Carolina at Chapel Hill Chapel Hill, NC, USA.

ABSTRACT
Regulation of hippocampal neurogenesis is poorly understood, but appears to contribute to mood and cognition. Ethanol and neuroinflammation are known to reduce neurogenesis. We have found that ethanol induces neuroinflammation supporting the hypothesis that ethanol induction of neuroinflammation contributes to ethanol inhibition of neurogenesis. To identify the key proinflammatory molecule that may be responsible for ethanol-impaired neurogenesis we used an ex vivo model of organotypic hippocampal-entorhinal cortex brain slice cultures. Here, we demonstrated a key role of proinflammatory cytokine IL-1β signaling in mediating ethanol inhibition of neurogenesis. Ethanol inhibition of neurogenesis was reversed by neutralizing antibody to IL-1β or blockade of the IL-1β receptor with antagonist IL-1RIa. Ethanol-impaired neurogenesis is associated with strong induction of IL-1β and inflammasome proteins NALP1 and NALP3 in both neurons and astrocytes. Blockade of IL-1β synthesis with inflammasome inhibitors Parthenolide and Bay11708 significantly reversed ethanol inhibited neurogenesis. Furthermore, we also found that IL-1β and inflammasome proteins NALP1 and NALP3 are increased in hippocampal neurons and astrocytes in postmortem alcoholic human brain. Together, these novel findings demonstrate that targeting inflammasome-IL-1β signaling can normalize ethanol-impaired hippocampal neurogenesis, which may have therapeutic implications for treatment of cognitive impairment associated with hippocampal dysfunction in alcoholics.

No MeSH data available.


Related in: MedlinePlus