A comparative study of ethanol, hypoglycemia, hypoxia and neurotrophic factor interactions with fetal rat hippocampal neurons: a multi-factor in vitro model developmental ethanol effects.
Fetal alcohol syndrome (FAS) is characterized by numerous central nervous system anomalies, with the hippocampus being particularly vulnerable to developmental ethanol exposure. In addition to direct ethanol neurotoxicity, other conditions resulting from maternal ethanol consumption, such as hypoglycemia and hypoxia, may also contribute to FAS. The present study used a tissue culture system to model multiple conditions which may relate to in vivo FAS, and assessed their relative neurotoxicity with MTT assays. Gestational day 18 rat hippocampal cultures were exposed to varying ethanol concentrations, glucose withdrawal-induced hypoglycemic (gwHG, 16 h) or acute hypoxic (aHP, 2 h) conditions alone, as well as to co-treatments with ethanol and gwHG or aHP. Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) have previously been shown to ameliorate ethanol-, hypoglycemia- and hypoxia-induced neurotoxicity. Therefore, their neuroprotective potential, along with ciliary neurotrophic factor (CNTF), was examined. Neuronal viability was reduced dose-dependently by ethanol, alone or with hypoglycemia or hypoxia. Ethanol + gwHG or aHP was not uniformly additive. NGF treatment provided the most extensive neuroprotection, being effective against ethanol (200 and 400 mg/dl), gwHG, and aHP, alone and combined. BDNF afforded similar protection, but not against ethanol + gwHG. CNTF protected only against aHP. CNTF + BDNF, previously shown to act synergistically, protected against ethanol + aHP up to 800 mg/dl ethanol, but not, paradoxically, against ethanol alone, gwHG, or ethanol + gwHG, all conditions BDNF alone protected against. This study demonstrated that several neurotrophic factors are capable of mitigating neurotoxicity associated with ethanol, hypoglycemia and hypoxia.
Mitchell
J J
JJ
University of Florida Brain Institute, Department of Neuroscience, University of Florida College of Medicine, Gainesville 32610-0244, USA.
Paiva
M
M
Moore
D B
DB
Walker
D W
DW
Heaton
M B
MB
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000633:toxicity*; D000431:Ethanol / Q000633:toxicity*; D063647:Fetal Alcohol Spectrum Disorders / Q000473:pathology; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects / Q000196:embryology; D007003:Hypoglycemia / Q000473:pathology*; D002534:Hypoxia, Brain / Q000473:pathology*; D008959:Models, Neurological; D009414:Nerve Growth Factors / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats
D019208:Brain-Derived Neurotrophic Factor; D002492:Central Nervous System Depressants; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D000431:Ethanol