Hostname: page-component-848d4c4894-4hhp2 Total loading time: 0 Render date: 2024-05-26T15:08:41.071Z Has data issue: false hasContentIssue false

Progress in Clinical Neurosciences: Sepsis-Associated Encephalopathy: Evolving Concepts

Published online by Cambridge University Press:  16 December 2016

John X. Wilson*
Affiliation:
Departments of Physiology, the University of Western Ontario, London, Ontario, Canada
G. Bryan Young
Affiliation:
Clinical Neurological Sciences, the University of Western Ontario, London, Ontario, Canada
*
Division of Neurology, Sunnybrook and Women's Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON, Canada M4N 3M5
Rights & Permissions [Opens in a new window]

Abstract:

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

Systemic sepsis commonly produces brain dysfunction, sepsis-associated encephalopathy, which can vary from a transient, reversible encephalopathy to irreversible brain damage. The encephalopathy in the acute phase clinically resembles many metabolic encephalopathies: a diffuse disturbance in cerebral function with sparing of the brain stem. The severity of the encephalopathy, as reflected in progressive EEG abnormalities, often precedes then parallels dysfunction in other organs. Recent research has revealed a number of potentially important, non-mutually exclusive, mechanisms that have therapeutic implications.

Résumé:

RÉSUMÉ:

La septicémie induit communément une dysfonction cérébrale, l'encéphalopathie associée à la septicémie, dont la sévérité varie d'une encéphalopathie transitoire réversible au dommage cérébral irréversible. En phase aiguë, l'encéphalopathie ressemble cliniquement à plusieurs autres encéphalopathies métaboliques: une perturbation diffuse de la fonction cérébrale épargnant le tronc cérébral. L'encéphalopathie, comme en témoigne les anomalies progressives observées à l'ÉEG, précède souvent la dysfonction des autres organes puis évolue parallèlement à cette dysfonction. Des recherches récentes ont révélé plusieurs mécanismes potentiellement importants, qui ne sont pas mutuellement exclusifs et qui ont des implications thérapeutiques.

Type
Review Article
Copyright
Copyright © The Canadian Journal of Neurological 2003

References

REFERENCES

1. Bone, RC, Sprung, CL, Sibbald, WJ. Definitions of sepsis and multiple organ failure. Crit Care Med 1992; 20: 724726.CrossRefGoogle Scholar
2. Young, GB, Bolton, CF, Austin, TW, et al. The encephalopathy associated with septic illness. Clin Invest Med 1990; 13: 297304.Google ScholarPubMed
3. Young, GB, Bolton, CF, Archibald, YM, Austin, TW, Wells, GA. The electroencephalogram in SAE. J Clin Neurophysiol 1992; 9: 145152.CrossRefGoogle Scholar
4. Bolton, CF, Young, GB, Zochodne, DW. The neurological complications of sepsis. Ann Neurol 1993; 33: 94100.CrossRefGoogle ScholarPubMed
5. Lazosky, A, Young, GB, Phillips, R. Quality of life following severe sepsis. Crit Care Med 2002; (submitted).Google Scholar
6. Jackson, AC, Gilbert, JJ, Young, GB, Bolton, CF. The encephalopathy of sepsis. Can J Neurol Sci 1985; 12: 303307.CrossRefGoogle ScholarPubMed
7. Maekawa, T, Fuji, Y, Sadanitsu, D. Cerebral circulation and metabolism in patients with septic encephalopathy. Am J Emerg Med 1981; 9: 239245.Google Scholar
8. Glauser, MP, Zanetti, G, Baumgartner, JD, Cohen, J. Septic shock: pathogenesis. Lancet 1991; 732736.CrossRefGoogle ScholarPubMed
9. Spain, DA, Wilson, MA, Bar-Natan, MF, Garrison, RN. Nitric oxide synthetase inhibition aggravates intestinal microvascular vasoconstriction and hypoperfusion of bacteremia. J Trauma 1994; 36: 720725.CrossRefGoogle ScholarPubMed
10. Vincent, JL. Microvascular endothelial dysfunction: a renewed appreciation of sepsis pathophysiology. Crit Care 2001; 5: S1–S5.CrossRefGoogle ScholarPubMed
11. Grinnell, BW, Joyce, D. Recombinant human activated protein C: a system modulator of vascular function for treatment of severe sepsis. Crit Care Med 2001; 29: S53–S60.CrossRefGoogle ScholarPubMed
12. Du Moulin, GC, Paterson, D, Hedley-White, J, Broitman, SA. E. coli peritonitis and bacteremia cause increased blood-brain barrier permeability. Brain Res 1995; 340: 261268 CrossRefGoogle Scholar
13. Freund, HR, Ryan, JA, Fischer, JE. Amino acid derangements in patients with sepsis: treatment with branched chain amino acid rich infusions. Ann Surg 1978; 188: 423430.CrossRefGoogle ScholarPubMed
14. Freund, HR, Muggia-Sullam, M, Peiser, J, Melamed, E. Brain neurotransmitter profile is deranged during sepsis and septic encephalopathy in the rat. J Surg Res 1985; 38: 267271.CrossRefGoogle ScholarPubMed
15. Sprung, CL, Cerra, FB, Freund, HR, et al. Amino acid alterations and encephalopathy in the sepsis syndrome. Crit Care Med 1991; 19:753757.CrossRefGoogle ScholarPubMed
16. Basler, T, Meier-Hellmann, A, Bredle, D, Reinhart, K. Amino acid imbalance early in septic encephalopathy. Intensive Care Med 2002; 28: 293298.CrossRefGoogle ScholarPubMed
17. Schafer, DF, Jones, EA. Hepatic encephalopathy and the gammaaminobutyric-acid neurotransmitter system. Lancet 1982; 1: 1820.Google Scholar
18. Moroni, F, Lombardi, G, Carla, V, et al. Increase in the content of quinolinic acid in cerebrospinal fluid and frontal cortex of patients with hepatic failure. J Neurochem 1986; 47: 16671671.CrossRefGoogle ScholarPubMed
19. Mullen, KD, Szauter, KM, Kaminsky-Russ, K. “Endogenous” benzodiazepine activity in body fluids of patients with hepatic encephalopathy. Lancet 1990; 336: 8183.CrossRefGoogle ScholarPubMed
20. Gray, F, Sharshar, T, De La Grandmaison, GL, Annane, D. Neuropathology of septic shock. Neuropathol Appl Neurobiol 2002; 28: 159.CrossRefGoogle Scholar
21. Dantzer, R, Konsman, JP, Bluthe, RM, Kelley, KW. Neural and humoral pathways of communication from the immune system to the brain: parallel or convergent. Auton Neursci 2000; 85: 6065.CrossRefGoogle ScholarPubMed
22. Konsman, JP, Parnet, P, Dantzer, R. Cytokine-induced sickness behaviour: mechanisms and implications. Trends Neurosci 2002;25: 154159.CrossRefGoogle ScholarPubMed
23. Maes, M. Major depression and the activation of the inflammatory response system. Adv Exp Med Biol 1999; 461: 2546.CrossRefGoogle ScholarPubMed
24. Gautron, L, Lafon, P, Chaigniau, M, Tramu, G, Laye, S. Spatiotemporal analysis of signal transducer and activator of transcription 3 activation in rat brain astrocytes and pituitary following peripheral immune challenge. Neuroscience 2002; 112: 717729.CrossRefGoogle ScholarPubMed
25. Periti, P. Current treatment of sepsis and endotoxaemia. Expert Opin Pharmacother 2000; 1: 12031217.CrossRefGoogle ScholarPubMed
26. Lepper, PM, Held, TK, Schneider, EM, et al. Clinical implications of antibiotic-induced endotoxin release in septic shock. Intensive Care Med 2002; 28(8): 2433.CrossRefGoogle ScholarPubMed
27. Sugaya, K, Chou, S, Xu, SJ, McKinney, M. Indicators of glial activation and brain oxidative stress after intraventricular infusion of endotoxin. Brain Res Mol Brain Res 1998; 58: 19.CrossRefGoogle ScholarPubMed
28. Zhao, ML, Liu, JS, He, D, Dickson DW, Lee SC. Inducible nitric oxide synthase expression is selectively induced in astrocytes isolated from the adult human brain. Brain Res 1998; 813: 402405.CrossRefGoogle ScholarPubMed
29. Tolias, CM, McNeil, CJ, Kazlauskaite, J, Hillhouse, EW. Superoxide generation from constitutive nitric oxide synthase in astrocytes in vitro regulates extracellular nitric oxide availability. Free Radic Biol Med 1999; 26: 99106.CrossRefGoogle ScholarPubMed
30. Sewerynek, E, Abe, M, Chen, L, Ortiz, GG, Reiter, RJ. Oxidative changes in the liver, brain and lens of lipopolysaccharide-treated rats. Arch Med Res 1995; 26: S109–S115.Google ScholarPubMed
31. Korcok, J, Wu, F, Tyml, K, Hammond, RR, Wilson, JX. Sepsis inhibits uptake of ascorbate and redox cycling of dehydroascorbic acid: intracellular ascorbate depletion increases nitric oxide synthase induction and glutamate uptake inhibition. J Neurochem 2002;81: 185193.CrossRefGoogle Scholar
32. Heneka, MT, Schmidlin, A, Wiesinger, H. Induction of argininosuccinate synthetase in rat brain glial cells after striatal microinjection of immunostimulants. J Cerebral Blood Flow Metab 1999; 19: 898907.CrossRefGoogle ScholarPubMed
33. Suzuki, Y, Fujii, S, Numagami, Y, et al. In vivo nitric oxide detection in the septic rat brain by electron paramagnetic resonance. Free Radic Res 1998; 28: 293299.CrossRefGoogle ScholarPubMed
34. Brown, GC. Nitric oxide as a competitive inhibitor of oxygen consumption in the mitochondrial respiratory chain. Acta Physiol Scand 2000; 168: 667674.CrossRefGoogle ScholarPubMed
35. Bolanos, JP, Almeida, A, Stewart, V, et al J. Nitric oxide-mediated mitochondrial damage in the brain: mechanisms and implications for neurodegenerative diseases. J Neurochem 1997; 68: 22272240.CrossRefGoogle ScholarPubMed
36. Nicoletti, VG, Caruso, A, Tendi, EA, et al. Effect of nitric oxide synthase induction on the expression of mitochondrial respiratory chain enzyme subunits in mixed cortical and astroglial cell cultures. Biochimie 1998; 80: 871881.CrossRefGoogle ScholarPubMed
37. McNaught, KS, Jenner, P. Extracellular accumulation of nitric oxide, hydrogen peroxide, and glutamate in astrocytic cultures following glutathione depletion, complex I inhibition, and/or lipopolysaccharide-induced activation. Biochem Pharmacol 2000; 60: 979988.CrossRefGoogle ScholarPubMed
38. Noack, H, Possel, H, Rethfeldt, C, Keilhoff, G, Wolf, G. Peroxynitrite mediated damage and lowered superoxide tolerance in primary cortical glial cultures after induction of the inducible isoform of NOS. Glia 1999; 28: 1324.3.0.CO;2-L>CrossRefGoogle ScholarPubMed
39. Hewett, SJ, Muir, JK, Lobner, D, Symons, A, Choi, DW. Potentiation of oxygen-glucose deprivation-induced neuronal death after induction of iNOS. Stroke 1996; 27: 15861591.CrossRefGoogle ScholarPubMed
40. Guerra-Romero, L, Tureen, JH, Fournier, MA, Makrides, V, Tauber, MG. Amino acids in cerebrospinal and brain interstitial fluid in experimental pneumococcal meningitis. Pediatr Res 1993; 33:510513.CrossRefGoogle ScholarPubMed
41. Lin, HC, Wan, FJ, Kang, BH, Wu, CC, Tseng, CJ. Systemic administration of lipopolysaccharide induces release of nitric oxide and glutamate and c-fos expression in the nucleus tractus solitarii of rats. Hypertension 1999; 33: 12181224.CrossRefGoogle ScholarPubMed
42. Lin, HC, Kang, BH, Wan, FJ, Huang, ST, Tseng, CJ. Reciprocal regulation of nitric oxide and glutamate in the nucleus tractus solitarii of rats. Eur J Pharmacol 2000; 407: 8389.CrossRefGoogle ScholarPubMed
43. Yousef, KA, Lang, CH. Modulation of endotoxin-induced changes in hemodynamics and glucose metabolism by an N-methyl-D-aspartate receptor antagonist. Shock 1994; 1: 335342.CrossRefGoogle ScholarPubMed
44. Willard, LB, Hauss-Wegrzyniak, B, Danysz, W, Wenk, GL. The cytotoxicity of chronic neuroinflammation upon basal forebrain cholinergic neurons of rats can be attenuated by glutamatergic antagonism or cyclooxygenase-2 inhibition. Exp Brain Res 2000;134: 5865.CrossRefGoogle ScholarPubMed
45. Koppel, BS, Hauser, WA, Politis, C, Van Duin, D, Daras, M. Seizures in the critically ill: the role of imipenem. Epilepsia 2001; 42:15901593.CrossRefGoogle ScholarPubMed
46. Cebers, G, Cebere, A, Kovacs, AD, et al. Increased ambient glutamate concentration alters the expression of NMDA receptor subunits in cerebellar granule neurons. Neurochem Int 2001; 39: 151160.CrossRefGoogle ScholarPubMed
47. Lievens, J, Bernal, F, Forni, C, Mahy, N, Kerkerian-Le Goff, L. Characterization of striatal lesions produced by glutamate uptake alteration: cell death, reactive gliosis, and changes in GLT1 and GADD45 mRNA expression. Glia 2000; 29: 222232.3.0.CO;2-0>CrossRefGoogle ScholarPubMed
48. Sorg, O, Horn, TF, Yu, N, Gruol, DL, Bloom, FE. Inhibition of astrocyte glutamate uptake by reactive oxygen species: role of antioxidant enzymes. Mol Med 1997; 3: 431440.CrossRefGoogle ScholarPubMed
49. Trotti, D, Danbolt, NC, Volterra, A. Glutamate transporters are oxidant-vulnerable: a molecular link between oxidative and excitotoxic neurodegeneration? Trends Pharmacol Sci 1998; 19:328334.CrossRefGoogle ScholarPubMed
50. Young Shin, C, Woong Choi, J, Ryun Ryu, J, et al. Immunostimulation of rat primary astrocytes decreases intracellular ATP level. Brain Res 2001; 902: 198204.CrossRefGoogle Scholar
51. Innocenti, B, Parpura, V, Haydon, PG. Imaging extracellular waves of glutamate during calcium signaling in cultured astrocytes. J Neurosci 2000; 20: 18001808.CrossRefGoogle ScholarPubMed
52. Peters, CE, Korcok, J, Gelb, AW, Wilson, JX. Anesthetic concentrations of propofol protect against oxidative stress in primary astrocyte cultures: comparison with hypothermia. Anesthesiology 2001; 94: 313321.CrossRefGoogle ScholarPubMed
53. Wilson, JX. Antioxidant defense of the brain: a role for astrocytes. Can J Physiol Pharmacol 1997; 75: 11491163.CrossRefGoogle Scholar
54. Galley, HF, Davies, MJ, Webster, NR. Ascorbyl radical formation in patients with sepsis: effect of ascorbate loading. Free Radic Biol Med 1996; 20: 139143.CrossRefGoogle ScholarPubMed
55. Heinz-Erian, P, Achmuller, M, Berger, H, et al. Cerebrospinal fluid and plasma levels of vitamin C in children. Padiatr Padol 1985;20: 4954.Google ScholarPubMed
56. Galley, HF, Davies, MJ, Webster, NR. Xanthine oxidase activity and free radical generation in patients with sepsis syndrome. Crit Care Med 1996; 24: 16491653.CrossRefGoogle ScholarPubMed
57. Schorah, CJ, Downing, C, Piripitsi, A, et al. Total vitamin C, ascorbic acid, and dehydroascorbic acid concentrations in plasma of critically ill patients. Am J Clin Nutr 1996; 63: 760765.CrossRefGoogle ScholarPubMed
58. Benito, E, Bosch, MA. Impaired phosphatidylcholine biosynthesis and ascorbic acid depletion in lung during lipopolysaccharide-induced endotoxaemia in guinea pigs. Mol Cell Biochem 1997;175: 117123.CrossRefGoogle ScholarPubMed
59. Block, F, Schwarz, M. Vitamin B6 and vitamin C status in elderly patients with infections during hospitalization. Ann Nutr Metab 1997; 82: 344352.Google Scholar
60. Metnitz, PG, Bartens, C, Fischer, M, et al. Antioxidant status in patients with acute respiratory distress syndrome. Intensive Care Med 1999; 25: 180185.CrossRefGoogle ScholarPubMed
61. Armour, J, Tyml, K, Lidington, D, Wilson, JX. Ascorbate prevents microvascular dysfunction in the skeletal muscle of the septic rat. J Appl Physiol 2001; 90: 795803.CrossRefGoogle ScholarPubMed
62. Garcia, R, Abarca, S, Municio, AM. Adrenal gland function in reversible endotoxic shock. Circ Shock 1990; 30: 365374.Google ScholarPubMed
63. Rojas, C, Cadenas, S, Herrero, A, Mendez, J, Barja, G. Endotoxin depletes ascorbate in the guinea pig heart. Protective effects of vitamins C and E against oxidative stress. Life Sci 1996; 59: 649657.CrossRefGoogle Scholar
64. Castro, M, Caprile, T, Astuya, A, et al. High-affinity sodium-vitamin C co-transporters (SVCT) expression in embryonic mouse neurons. J Neurochem 2001; 78: 815823.CrossRefGoogle ScholarPubMed
65. Korcok, J, Yan, R, Siushansian, R, Dixon, SJ, Wilson, JX. Sodiumascorbate cotransport controls intracellular ascorbate concentration in primary astrocyte cultures expressing the SVCT2 transporter. Brain Res 2000; 881: 144151.CrossRefGoogle ScholarPubMed
66. Daskalopoulos, R, Korcok, J, Tao, L, Wilson, JX. Accumulation of intracellular ascorbate from dehydroascorbic acid by astrocytes is decreased after oxidative stress and restored by propofol. Glia 2002; 39: 124132.CrossRefGoogle ScholarPubMed
67. Siushansian, R, Tao, L, Dixon, SJ, Wilson, JX. Cerebral astrocytes transport ascorbic acid and dehydroascorbic acid through distinct mechanisms regulated by cyclic AMP. J Neurochem 1997; 68:23782385.CrossRefGoogle ScholarPubMed
68. Rose, RC. Cerebral metabolism of oxidized ascorbate. Brain Res 1993; 628: 4955.CrossRefGoogle ScholarPubMed
69. Fornai, F, Saviozzi, M, Piaggi, S, et al. Localization of a glutathione dependent dehydroascorbate reductase within the central nervous system of the rat. Neuroscience 1999; 94: 937948.CrossRefGoogle ScholarPubMed
70. Song, JH, Shin, SH, Ross, GM. Oxidative stress induced by ascorbate causes neuronal damage in an in vitro system. Brain Res 2001;895: 6672.CrossRefGoogle Scholar
71. Moazzam, FN, Bremm, JJ, Yong, SL, et al. Endotoxin potentiates hepatocyte apoptosis in cholestasis. J Am Coll Surg 2002; 194: 731739.CrossRefGoogle ScholarPubMed
72. Hotchkiss, RS, Tinsley, KW, Swanson, PE, Karl, IE. Endothelial cell apoptosis in sepsis. Crit Care Med 2002; 30: S225–S228.CrossRefGoogle ScholarPubMed
73. Chen, G, Goeddel, DV. TNF-R1 signaling: a beautiful pathway. Science 2002; 296: 16341635.CrossRefGoogle ScholarPubMed
74. Mandell, GL, Sandle, MA. Antimicrobial agents: penicillins, cephalosporins and other beta-lactam antibiotics. In: Gilman, AG, Goodman, LS, Rall, TW, Murad, F, (Eds). Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 7th ed. New York: Macmillan, 1985: 11151149.Google Scholar
75. Shedlofsky, SI, Israel, BC, McClain, CJ, et al. Endotoxin administration to humans inhibits cytochrome P450-mediated drug metabolism. J Clin Invest 1994; 94: 22092214.CrossRefGoogle ScholarPubMed
76. Wijdicks, EFM, Sharbrough, FW. New-onset seizures in critically ill patients. Neurology 1993; 43: 10241042.CrossRefGoogle ScholarPubMed
77. Pauloucek, FP, Rodvold, KA. Evaluation of theophylline overdoses and toxicities. Ann Emerg Med 1988; 17: 135144.CrossRefGoogle Scholar
78. Wesiinger, JR, Bellorin-Font, E. Magnesium and phosphorous. Lancet 1988; 352: 391396.CrossRefGoogle Scholar
79. Haynes, GR, Bailey, MK. Excessive use of hetastarch: an iatrogenic cause of bleeding and hypocalcemia. Anesth Analg 2000; 90: 14551456.CrossRefGoogle ScholarPubMed
80. Slogoff, S, Giris, KZ, Keats, AS. Etiologic factors in neuropsychologic complications associated with cardiopulmonary bypass. Anesth Analg 1982; 61: 903911.CrossRefGoogle Scholar
81. Zochodne, DW, Bolton, CF, Wells, GA, et al. Critical illness polyneuropathy: a complication of sepsis and multiple organ failure. Brain 1987; 110: 819842.CrossRefGoogle ScholarPubMed
82. Pine, RW, Wertz, MJ, Lennard, ES. Determinants of organ malfunction or death in patients with intra-abdominal sepsis. Arch Surg 1983; 118: 242249.CrossRefGoogle ScholarPubMed
83. Nonaka, A, Manabe, T, Tobe, T. Effect of a new synthetic free radical scavenger, 2-octadecyl ascorbic acid, on the mortality in mouse endotoxemia. Life Sci 1990; 47: 19331939.CrossRefGoogle ScholarPubMed
84. Armour, J, Tyml, K, Lidington, D, Wilson, JX. Ascorbate protects the microvasculature in septic skeletal muscle. FASEB J 2001; 15:A50.Google Scholar
85. Dwenger, A, Funck, M, Lueken, B, Schweitzer, G, Lehmann, U. Effect of ascorbic acid on neutrophil functions and hypoxanthine/ xanthine oxidase-generated, oxygen-derived radicals. Eur J Clin Chem Clin Biochem 1992; 30: 187191.Google ScholarPubMed
86. Cadenas, S, Rojas, C, Barja, G. Endotoxin increases oxidative injury to proteins in guinea pig liver: protection by dietary vitamin C. Pharmacol Toxicol 1998; 82: 1118.CrossRefGoogle ScholarPubMed
87. Bowie, AG, O’Neill, LA. Vitamin C inhibits NF-KB activation by TNF via the activation of p38 mitogen-activated protein kinase. J Immunol 2000; 165: 71807188.CrossRefGoogle ScholarPubMed
88. Jackson, TS, Xu, AM, Vita, JA, Keaney, JF. Ascorbate prevents the interaction of superoxide and nitric oxide only at very high physiological concentrations. Circ Res 1998; 83: 916922.CrossRefGoogle ScholarPubMed
89. Kirsch, M, De Groot, H. Ascorbate is a potent antioxidant against peroxynitrite-induced oxidation reactions – Evidence that ascorbate acts by re-reducing substrate radicals produced by peroxynitrite. J Biol Chem 2000; 275: 1670216708.CrossRefGoogle ScholarPubMed
90. Galley, HF, Walker, BE, Howdle, PD, Webster, NR. Regulation of nitric oxide synthase activity in cultured human endothelial cells: effect of antioxidants. Free Radic Biol Med 1996; 21: 97101.CrossRefGoogle ScholarPubMed
91. Wu, F, Wilson, JX, Tyml, K. Ascorbate inhibits iNOS expression in endotoxin- and IFNy-stimulated skeletal muscle endothelial cells. FEBS Lett 2002; 520: 122126.CrossRefGoogle ScholarPubMed
92. Huang, M, Liu, W, Li, Q, Wu, CF. Endogenous released ascorbic acid suppresses ethanol-induced hydroxyl radical production in rat striatum. Brain Res 2002; 944: 9096.CrossRefGoogle ScholarPubMed
93. Schroder, J, Kahlke, V, Staubach, KH, Zabel, P, Stuber, F. Gender differences in human sepsis. Arch Surg 1998; 133: 12001205.CrossRefGoogle ScholarPubMed
94. Azcoitia, I, Garcia-Ovejero, D, Chowen, JA, Garcia-Segura, LM. Astroglia play a key role in the neuroprotective actions of estrogen. Prog Brain Res 2001; 132: 469478.CrossRefGoogle ScholarPubMed
95. Dodel, RC, Du, Y, Bales, KR, Gao, F, Paul, SM. Sodium salicylate and ??-estradiol attenuate nuclear transcription factor NF-KB translocation in cultured rat astroglial cultures following exposure to amyloid A ?(1–40) and lipopolysaccharides. J Neurochem 1999; 73: 14531460.CrossRefGoogle ScholarPubMed
96. Winterle, JS, Mill, T, Harris, T, Goldbeck, RA. Absolute kinetic characterization of ??-estradiol as a radical-scavenging, anti-oxidant synergist. Arch Biochem Biophys 2001; 392: 233244.CrossRefGoogle ScholarPubMed