Sepsis inhibits recycling and glutamate-stimulated export of ascorbate by astrocytes

被引:23
作者
Wilson, JX
Dragan, M
机构
[1] SUNY Buffalo, Dept Exercise & Nutr Sci, Buffalo, NY 14214 USA
[2] Univ Western Ontario, Dept Physiol & Pharmacol, London, ON N6A 5C1, Canada
基金
加拿大自然科学与工程研究理事会;
关键词
ascorbate; astrocytes; brain; dehydroascorbic acid; glucose transporter; glutamate; interferon-gamma; lipopolysaccharide; NADPH oxidase; nitric oxide synthase; sepsis; vitamin C; free radicals;
D O I
10.1016/j.freeradbiomed.2005.05.020
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Sepsis causes brain dysfunction. Because neurotransmission requires high ascorbate and low dehydroascorbic acid (DHAA) concentrations in brain extracellular fluid, the effect of septic insult on ascorbate recycling (i.e., uptake and reduction of DHAA) and export was investigated in primary rat and mouse astrocytes. DHAA raised intracellular ascorbate to physiological levels but extracellular ascorbate only slightly. Septic insult by lipopolysaccharide and interferon-gamma increased ascorbate recycling in astrocytes permeabilized with saponin but decreased it in those with intact plasma membrane. The decrease was due to inhibition of the glucose transporter (GLUT1) that translocates DHAA because septic insult slowed uptake of the nonmetabolizable GLUT1 substrate 3-O-methylglucose. Septic insult also abolished stimulation by glutamate of ascorbate export. Specific nitric oxide synthase (NOS) inhibitors and nNOS and iNOS deficiency failed to alter the effects of septic insult. Inhibitors of NADPH oxidase generally did not protect against septic insult, because only one of those tested (diphenylene iodonium) increased GLUT1 activity and ascorbate recycling. We conclude that astrocytes take up DHAA and use it to synthesize ascorbate that is exported in response to glutamate. This mechanism may provide the antioxidant on demand to neurons under normal conditions, but it is attenuated after septic insult. (c) 2005 Elsevier Inc. All rights reserved.
引用
收藏
页码:990 / 998
页数:9
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