Ethanol Promotes Apoptosis in Cerebellar Granule Cells by Inhibiting the Trophic Effect of NMDA

Bhave, Sanjiv V.; Hoffman, Paula L.

doi:10.1046/j.1471-4159.1997.68020578.x

Cited by 135 publications

(90 citation statements)

References 32 publications

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“…In agreement with previous reports performed on granule cells from 8-day-old rat, we observed that ethanol provokes apoptosis of granule neurons in primary culture (25). The ethanol-induced neuronal death exhibited the characteristic features of apoptosis including cell shrinkage, nuclear condensation, and DNA fragmentation (26).…”

Section: Effects Of Pacap On Ethanol-induced Granule Cell Apoptosissupporting

confidence: 92%

“…It has been established that ethanol induces cell death by inhibition of N-methyl-D-aspartate receptor function (6,25,42). In particular, during a critical period of brain development, ethanol impairs N-methyl-D-aspartate-mediated brain-derived neurotrophic factor expression, leading to excessive granule cell loss (6,43,44).…”

Section: Effects Of Pacap On Ethanol-induced Granule Cell Apoptosismentioning

confidence: 99%

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Pituitary adenylate cyclase-activating polypeptide protects rat cerebellar granule neurons against ethanol-induced apoptotic cell death

Vaudry

Rousselle

Basille

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

147

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Alcohol exposure during development can cause brain malformations and neurobehavioral abnormalities. In view of the teratogenicity of ethanol, identification of molecules that could counteract the neurotoxic effects of alcohol deserves high priority. Here, we report that pituitary adenylate cyclase-activating polypeptide (PACAP) can prevent the deleterious effect of ethanol on neuronal precursors. Exposure of cultured cerebellar granule cells to ethanol inhibited neurite outgrowth and provoked apoptotic cell death. Incubation of granule cells with PACAP prevented ethanol-induced apoptosis, and this effect was not mimicked by vasoactive intestinal polypeptide, suggesting that PAC1 receptors are involved in the neurotrophic activity of PACAP. Ethanol exposure induced a strong increase of caspase-2, -3, -6, -8, and -9 activities, DNA fragmentation, and mitochondrial permeability. Cotreatment of granule cells with PACAP provoked a significant inhibition of all of the apoptotic markers investigated although the neurotrophic activity of PACAP could only be ascribed to inhibition of caspase-3 and -6 activities. These data demonstrate that PACAP is a potent protective agent against ethanol-induced neuronal cell death. The fact that PACAP prevented ethanol toxicity even when added 2 h after alcohol exposure, suggests that selective PACAP agonists could have potential therapeutic value for the treatment of fetal alcohol syndrome.cerebellum ͉ fetal alcohol syndrome ͉ development ͉ caspases

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Section: Effects Of Pacap On Ethanol-induced Granule Cell Apoptosissupporting

confidence: 92%

Section: Effects Of Pacap On Ethanol-induced Granule Cell Apoptosismentioning

confidence: 99%

Pituitary adenylate cyclase-activating polypeptide protects rat cerebellar granule neurons against ethanol-induced apoptotic cell death

Vaudry

Rousselle

Basille

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

147

View full text Add to dashboard Cite

show abstract

“…This suggests that added D-serine in conjunction with glutamate, spontaneously released from vesicles in S-K5 (Mellor et al, 1998), is able to activate NMDAR. The finding that glycine (100 lM) has no detectable effect on apoptosis and on survival promoting activity of NMDA (Bhave & Hoffman, 1997) suggests that NMDAR complex is more sensitive to D-serine than to glycine.…”

Section: Discussionmentioning

confidence: 99%

Contribution of serine racemase/d‐serine pathway to neuronal apoptosis

et al. 2012

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SummaryRecent data indicate that age-related N-methyl-D-aspartate receptor (NMDAR) transmission impairment is correlated with the reduction in serine racemase (SR) expression and D-serine content. As apoptosis is associated with several diseases and conditions that generally occur with age, we investigated the modulation of SR ⁄ D-serine pathway during neuronal apoptosis and its impact on survival. We found that in cerebellar granule neurons (CGNs), undergoing apoptosis SR/D-serine pathway is crucially regulated. In the early phase of apoptosis, the expression of SR is reduced, both at the protein and RNA level through pathways, upstream of caspase activation, involving ubiquitin proteasome system (UPS) and c-Jun N-terminal kinases (JNKs). Forced expression of SR, together with treatment with NMDA and D-serine, blocks neuronal death, whereas pharmacological inhibition and Sh-RNA-mediated suppression of endogenous SR exacerbate neuronal death. In the late phase of apoptosis, the increased expression of SR contribute to the last, NMDAR-mediated, wave of cell death. These findings are relevant to our understanding of neuronal apoptosis and NMDAR activity regulation, raising further questions as to the role of SR/D-serine in those neuro-pathophysiological processes, such as aging and neurodegenerative diseases characterized by a convergence of apoptotic mechanisms and NMDAR dysfunction.

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“…However, targets of ethanol, and the subsequent signal transduction pathways, which lead to the mitochondrial apoptotic pathways, are largely unknown. Previous studies using cultured neurons indicate that ethanol perturbs functions of neurotrophic factors (such as brain-derived neurotrophic factor and insulin-like growth factor-I) probably through blockade of NMDA receptors [7][8][9] leading to the inhibition of PI3K [8,9]. The suppression of Akt [4] and activation of GSK-3 [10], downstream effects of PI3K inhibition, have also been reported in the developing brain exposed to ethanol.…”

Section: Introductionmentioning

confidence: 99%

Lithium blocks ethanol-induced modulation of protein kinases in the developing brain

Chakraborty

Shimada

Mao

et al. 2008

Biochemical and Biophysical Research Communications

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Lithium has been shown to be neuroprotective against various insults including ethanol exposure. We previously reported that ethanol-induced apoptotic neurodegeneration in the postnatal day 7 (P7) mice is associated with decreases in phosphorylation levels of Akt, glycogen synthase kinase-3β (GSK-3β), and AMP-activated protein kinase (AMPK), and alteration in lipid profiles in the brain. Here, P7 mice were injected with ethanol and lithium, and the effects of lithium on ethanol-induced alterations in phosphorylation levels of protein kinases and lipid profiles in the brain were examined. Immunoblot and immunohistochemical analyses showed that lithium significantly blocked ethanolinduced caspase-3 activation and reduction in phosphorylation levels of Akt, GSK-3β and AMPK. Further, lithium inhibited accumulation of cholesterol ester (ChE) and Nacylphosphatidylethanolamine (NAPE) triggered by ethanol in the brain. These results suggest that Akt, GSK-3β, and AMPK are involved in ethanol-induced neurodegeneration and the neuroprotective effects of lithium by modulating both apoptotic and survival pathways.

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Ethanol Promotes Apoptosis in Cerebellar Granule Cells by Inhibiting the Trophic Effect of NMDA

Cited by 135 publications

References 32 publications

Pituitary adenylate cyclase-activating polypeptide protects rat cerebellar granule neurons against ethanol-induced apoptotic cell death

Pituitary adenylate cyclase-activating polypeptide protects rat cerebellar granule neurons against ethanol-induced apoptotic cell death

Contribution of serine racemase/d‐serine pathway to neuronal apoptosis

Lithium blocks ethanol-induced modulation of protein kinases in the developing brain

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