Effects of Gangliosides on Ethanol-Induced Neurodegeneration in the Developing Mouse Brain

Authors

  • Mariko Saito,

    1. Laboratory of Neurobehavior Genetics, The Nathan S. Kline Institute for Psychiatric Research, Orangeburg, New York
    2. Department of Psychiatry, New York University Medical Center, New York, New York
    Search for more papers by this author
  • Rui-Fen Mao,

    1. Laboratory of Neurobehavior Genetics, The Nathan S. Kline Institute for Psychiatric Research, Orangeburg, New York
    Search for more papers by this author
  • Ray Wang,

    1. Laboratory of Neurobehavior Genetics, The Nathan S. Kline Institute for Psychiatric Research, Orangeburg, New York
    Search for more papers by this author
  • Csaba Vadasz,

    1. Laboratory of Neurobehavior Genetics, The Nathan S. Kline Institute for Psychiatric Research, Orangeburg, New York
    2. Department of Psychiatry, New York University Medical Center, New York, New York
    Search for more papers by this author
  • Mitsuo Saito

    1. Division of Analytical Psychopharmacology, The Nathan S. Kline Institute for Psychiatric Research, Orangeburg, New York
    2. Department of Psychiatry, New York University Medical Center, New York, New York
    Search for more papers by this author

  • This work is supported by NIH/NIAAA, Grant R01 AA015355.

Reprint requests: Mariko Saito, The Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, NY 10962; Fax: 845-398-5531; E-mail: marsaito@nki.rfmh.org

Abstract

Background: Ethanol exposure induces apoptotic neurodegeneration in the developing rodent brain during synaptogenesis. This process has been studied as a model for fetal alcohol syndrome. Previously, we have shown that gangliosides and LIGA20 (a semisynthetic derivative of GM1 ganglioside) attenuate ethanol-induced apoptosis in cultured neurons. In the present study, the effects of GM1 and LIGA20 on ethanol-induced apoptotic neurodegeneration were examined using an in vivo neonatal mouse model.

Methods: Seven-day-old C57BL/6By (B6By) mice were pretreated twice with intraperitoneal administration of GM1 (30 mg/kg), LIGA20 (2.5 mg/kg), or saline, followed by subcutaneous injection of either saline or ethanol (2.5 g/kg) twice with a 2 hours interval. Then the brains were: (1) perfusion-fixed 24 hours after the first ethanol injection, and the extent of neurodegeneration was assessed by cupric silver staining of the brain sections, or (2) perfusion-fixed 8 hours after the first ethanol injection, and the sections were immunostained with anti-cleaved (activated) caspase-3 antibody to evaluate caspase-3 activation.

Results: The comparison of cupric silver stained coronal sections indicates that ethanol-induced widespread neurodegeneration in the forebrains of B6By mice was reduced overall by GM1 and LIGA20 pretreatments. The extent of neurodegeneration detected by silver impregnation and activated caspase-3 immunostaining was quantified in the cingulate and retrosplenial cortices, which were the regions most severely affected by ethanol. The results indicate that GM1 and LIGA20 pretreatments induced statistically significant reductions—approximately 50% of the ethanol-treated samples—in silver impregnation and activated caspase-3 immunostaining. No significant differences were observed between saline controls and samples treated with GM1 or LIGA20 alone.

Conclusions: These results indicate that GM1 and LIGA20, which have been shown to be neuroprotective against insults caused by various agents, partially attenuate ethanol-induced apoptotic neurodegeneration in the developing mouse brain.

Ancillary