Minocycline attenuates ethanol-induced cell death and microglial activation in the developing spinal cord

Alcohol. 2019 Sep:79:25-35. doi: 10.1016/j.alcohol.2018.12.002. Epub 2018 Dec 7.

Abstract

Developmental exposure to ethanol may cause fetal alcohol spectrum disorders (FASD), and the immature central nervous system (CNS) is particularly vulnerable to ethanol. In addition to vulnerability in the developing brain, we previously showed that ethanol also caused neuroapoptosis, microglial activation, and neuroinflammation in the spinal cord. Minocycline is an antibiotic that inhibits microglial activation and alleviates neuroinflammation. We sought to determine whether minocycline could protect spinal cord neurons against ethanol-induced damage. In this study, we showed that minocycline significantly inhibited ethanol-induced caspase-3 activation, microglial activation, and the expression of pro-inflammatory cytokines in the developing spinal cord. Moreover, minocycline blocked ethanol-induced activation of glycogen synthase kinase 3 beta (GSK3β), a key regulator of microglial activation. Meanwhile, minocycline significantly restored ethanol-induced inhibition of protein kinase B (AKT), mammalian target of the rapamycin (mTOR), and ERK1/2 signaling pathways, which were important pro-survival signaling pathways for neurons. Together, minocycline may attenuate ethanol-induced damage to the developing spinal cord by inhibiting microglial activation/neuroinflammation and by restoring the pro-survival signaling.

Keywords: Alcohol; Fetal alcohol spectrum disorders; Glycogen synthase kinase 3; Inflammation; Neuroprotection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology*
  • Apoptosis / drug effects*
  • Caspase 3 / metabolism
  • Cytokines / metabolism
  • Ethanol / adverse effects
  • Female
  • Glycogen Synthase Kinase 3 beta / metabolism
  • MAP Kinase Signaling System
  • Male
  • Mice
  • Microglia / drug effects*
  • Minocycline / pharmacology*
  • Neurogenic Inflammation / drug therapy
  • Proto-Oncogene Proteins c-akt / metabolism
  • Spinal Cord / drug effects*
  • Spinal Cord / growth & development
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Anti-Bacterial Agents
  • Cytokines
  • Ethanol
  • mTOR protein, mouse
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Caspase 3
  • Minocycline