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Brain damage due to episodic alcohol exposure in vivo and in vitro: furosemide neuroprotection implicates edema‐based mechanism
Author(s) -
Collins Michael A.,
Zou Jianyun,
Neafsey Edward J.
Publication year - 1998
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.12.2.221
Subject(s) - neuroprotection , pharmacology , neurodegeneration , chemistry , brain damage , medicine , anesthesia , disease
Adult rats intubated with a single dose of ethanol (alcohol; ∼5 g/kg) for 5 to 10 successive days incur neurodegeneration in the entorhinal cortex, dentate gyrus, and olfactory bulbs accompanied by cerebrocortical edema and electrolyte (Na + , K + ) accumulation. The brain damage is not lessened by cotreatment with the NMDA receptor antagonist MK‐801; also, as reported elsewhere, MK‐801 as well as non‐NMDA receptor and Ca 2+ channel antagonists are not neuroprotective in a similar, but more compressed, intoxication protocol. However, cotreatment with the electrolyte transport inhibitor/diuretic furosemide reduces alcohol‐dependent cerebrocortical damage by 75–85% while preventing brain hydration and electrolyte elevations; olfactory bulb neurodegeneration is not attenuated. In parallel in vitro studies, rat organotypic entorhinal/hippocampal slice cultures exposed to alcohol (50–200 mM) 15 h/day for 6 days, mirroring episodic intoxication in vivo, demonstrate concentration‐related release of the cytotoxic indicator, lactate dehydrogenase. Analogous to the in vivo findings, furosemide blocks this alcohol‐induced in vitro cytotoxicity. Our results showing neuroprotection by furosemide indicate that brain edema and swelling are essential events in the brain damage induced by episodic alcohol exposure. Furosemide and related agents might be useful as neuroprotective agents in alcohol abuse. We suggest that the neurodegeneration is elicited in part by edema‐dependent oxidative stress, but the regional selectivity of the damage may be best explained by physical (mechanical) compression of the limbic cortex against the adjacent tympanic bulla and subsequent neuronal cytoskeletal collapse. A scheme for these apparently nonexcitotoxic metabolic and mechanical pathways initiated by repeated alcohol exposure is proposed.—Collins, M. A., Zou, J.‐Y., Neafsey, E. J. Brain damage due to episodic alcohol exposure in vivo and in vitro: furosemide neuroprotection implicates edema‐based mechanism. FASEB J. 12, 221–230 (1998)