Ethanol induces apoptotic death of developing β-endorphin neurons via suppression of cyclic adenosine monophosphate production and activation of transforming growth factor-β1-linked apoptotic signaling

Ping Chen Cui, Peter Kuhn, Kirti Chaturvedi, Nadka Boyadjieva, Dipak K. Sarkar

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

The mechanism by which ethanol induces β-endorphin (β-EP) neuronal death during the developmental period was determined using fetal rat hypothalamic cells in primary cultures. The addition of ethanol to hypothalamic cell cultures stimulated apoptotic cell death of β-EP neurons by increasing caspase-3 activity. Ethanol lowered the levels of adenylyl cyclase (AC)7 mRNA, AC8 mRNA, and/or cAMP in hypothalamic cells, whereas a cAMP analog blocked the apoptotic action of ethanol on β-EP neurons. The AC inhibitor dideoxyadenosine (DDA) increased cell apoptosis and reduced the number of β-EP neurons, and it potentiated the apoptotic action of ethanol on these neurons. β-EP neurons in hypothalamic cultures showed immunoreactivity to transforming growth factor-β1 (TGF-β1) protein. Ethanol and DDA increased TGF-β1 production and/or release from hypothalamic cells. A cAMP analog blocked the activation by ethanol of TGF-β1 in these cells. TGF-β1 increased apoptosis of β-EP neurons, but it did not potentiate the action of ethanol or DDA actions on these neurons. TGF-β1 neutralizing antibody blocked the apoptotic action of ethanol on β-EP neurons. Determination of TGF-β1-controlled cell apoptosis regulatory gene levels in hypothalamic cell cultures and in isolated β-EP neurons indicated that ethanol, TGF-β1, and DDA similarly alter the expression of these genes in these cells. These data suggest that ethanol increases β-EP neuronal death during the developmental period by cellular mechanisms involving, at least partly, the suppression of cAMP production and activation of TGF-β1-linked apoptotic signaling.

Original languageEnglish (US)
Pages (from-to)706-717
Number of pages12
JournalMolecular Pharmacology
Volume69
Issue number3
DOIs
StatePublished - Mar 2006

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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