Nixon Peter F
Department of Biochemistry and Molecular Biology (PFN), The University of Queensland, St Lucia, Queensland, Australia.
Alcohol Clin Exp Res. 2008 Aug;32(8):1339-49. doi: 10.1111/j.1530-0277.2008.00727.x. Epub 2008 Jul 9.
The earliest observed effect in the pathogenesis of experimental Wernicke's encephalopathy and of ethanol intoxication in rats is impairment of the blood cerebrospinal fluid (CSF) barrier at the choroid plexus (CP). For an explanation, these observations direct attention to the role of the CP in maintaining glutamate homeostasis in the CSF.
Characteristics of the CP epithelium (CPE) are reviewed, focusing on its role in removal of glutamate from the CSF and its potential for impairment by ethanol oxidation or by thiamin-deficient glucose oxidation.
The export of glutamate from CSF to blood at the CP is energy dependent, saturable, and stereospecific. However, the incapacity of the CP to convert glutamate to other metabolites makes it vulnerable to glutamate accumulation should alpha-ketoglutarate dehydrogenase activity be decreased. Elsewhere ethanol metabolism and thiamin-deficiency independently decrease the activity of this mitochondrial enzyme. We argue that they have the same effect within the mitochondria-rich CPE, thereby decreasing energy production necessary for export of glutamate from CSF to blood; diverting its energy metabolism to further glutamate production; and impairing its blood CSF barrier function. This impairment appears to be mediated by glutamate and is attenuated by MK801 but whether it involves one of the CPE glutamate receptors is yet uncertain. This impairment exposes the CSF and hence the paraventricular brain extracellular fluid to neuroactive substances from the blood, including further glutamate, explaining the paraventricular location of neuropathology in Wernicke's encephalopathy. Other organs normally protected from blood by a barrier are affected also by ethanol abuse and by thiamin deficiency, namely the eye, peripheral nerves, and the testis. Much less is known regarding the function of these barriers.
Impairment of the CP by ethanol intoxication and by thiamin-deficient carbohydrate metabolism has a common, rational explanation that can guide future research.
在实验性韦尼克脑病和大鼠乙醇中毒的发病机制中，最早观察到的效应是脉络丛（CP）处血脑脊液（CSF）屏障受损。为了解释这一现象，这些观察结果将注意力引向了CP在维持脑脊液中谷氨酸稳态方面的作用。
综述脉络丛上皮（CPE）的特征，重点关注其在从脑脊液中清除谷氨酸的作用以及乙醇氧化或硫胺素缺乏的葡萄糖氧化对其造成损害的可能性。
在脉络丛处，谷氨酸从脑脊液向血液的转运是能量依赖的、可饱和的且具有立体特异性。然而，如果α-酮戊二酸脱氢酶活性降低，脉络丛将谷氨酸转化为其他代谢产物的能力不足，使其易受谷氨酸积累的影响。在其他地方，乙醇代谢和硫胺素缺乏会独立降低这种线粒体酶的活性。我们认为，它们在富含线粒体的脉络丛上皮细胞中具有相同的作用，从而减少了谷氨酸从脑脊液向血液转运所需的能量产生；将其能量代谢转向进一步产生谷氨酸；并损害其血脑脊液屏障功能。这种损害似乎由谷氨酸介导，且可被MK801减轻，但它是否涉及脉络丛上皮细胞谷氨酸受体之一尚不确定。这种损害使脑脊液以及脑室旁脑细胞外液暴露于来自血液的神经活性物质，包括更多的谷氨酸，这解释了韦尼克脑病中神经病理学病变位于脑室旁的原因。其他通常由屏障保护免受血液影响的器官，如眼睛、周围神经和睾丸，也会受到乙醇滥用和硫胺素缺乏的影响。关于这些屏障的功能，我们所知甚少。
乙醇中毒和硫胺素缺乏的碳水化合物代谢对脉络丛的损害有一个共同且合理的解释，这可以为未来的研究提供指导。
