Brain damage due to episodic alcohol exposure in vivo and in vitro: furosemide neuroprotection implicates edema-based mechanism
Brain damage due to episodic alcohol exposure in vivo and in vitro: furosemide neuroprotection implicates edema-based mechanism
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DOI：
10.1096/fasebj.12.2.221
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发表时间：
1998-02-01
期刊：
影响因子：
4.8
通讯作者：
Neafsey, EJ
中科院分区：
文献类型：
--
作者：
Collins, MA;Zou, JY;Neafsey, EJ
用单剂量乙醇（酒精;类似于5 g/kg）连续5至10天插管的成年大鼠，内嗅皮层、齿状回和嗅球发生神经变性，伴有内嗅皮层水肿和电解质（Na+、K+）蓄积。与NMDA受体拮抗剂MK-801共同治疗不会减轻脑损伤;此外，如其他地方所报告，在类似但更压缩的中毒方案中，MK-801以及非NMDA受体和Ca 2+通道拮抗剂不具有神经保护作用。然而，与电解质转运抑制剂/利尿剂呋塞米联合治疗可减少75-85%的酒精依赖性脑皮质损伤，同时防止脑水合作用和电解质升高;嗅球神经变性不会减弱。在体外包裹研究中，大鼠器官型内嗅/海马切片培养物暴露于酒精（50-200 mM）15小时/天，持续6天，反映了体内的间歇性中毒，证明了细胞毒性指示剂乳酸脱氢酶的浓度相关性释放。类似于在体内的研究结果，呋塞米块这种酒精诱导的体外细胞毒性。我们的研究结果显示，呋塞米的神经保护作用表明，脑水肿和肿胀是由间歇性酒精暴露引起的脑损伤的基本事件。呋塞米和相关药物可能是有用的酒精滥用的神经保护剂。我们认为，神经退行性病变引起的部分水肿依赖性氧化应激，但区域选择性的损害可能是最好的解释物理（机械）压缩边缘皮质对相邻的鼓泡和随后的神经元细胞骨架崩溃。这些显然nonexcitotoxic代谢和机械途径反复酒精暴露提出了一个计划。
Adult rats intubated with a single dose of ethanol (alcohol; similar to 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 Ca2+ 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 parcel 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.