Hostname: page-component-586b7cd67f-2brh9 Total loading time: 0 Render date: 2024-11-29T10:57:43.595Z Has data issue: false hasContentIssue false
  • English
  • Français

The acute and sensitization effects of tumor necrosis factor-α: implications for immunotherapy as well as psychiatric and neurological conditions

Published online by Cambridge University Press:  24 June 2014

Shawn Hayley ,
Zul Merali  and
Hymie Anisman
Shawn Hayley*
Affiliation:
Institute of Neuroscience, Carleton University, Ottawa
Zul Merali
Affiliation:
Institute of Mental Health Research, Royal Ottawa Hospital, Ottawa, Ontario, Canada
Hymie Anisman
Affiliation:
Institute of Neuroscience, Carleton University, Ottawa Institute of Mental Health Research, Royal Ottawa Hospital, Ottawa, Ontario, Canada
*
Shawn Hayley, Life Science Research Building, Carleton University, Ottawa, Ontario K1S 5B6 Canada. Tel: + (613) 520–2699; Fax: + (613) 520–4052; E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

In addition to their role as signaling molecules of the immune system, cytokines may participate in central neurotransmission. Variations of the central and/or peripheral levels of the proinflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-β (IL-1β), impact on neuroendocrine processes as well as central neurotransmitter activity. To a considerable extent, these effects are reminiscent of those elicited by psychogenic stressors. The current review describes recent findings consistent with a role for these cytokines in the neurochemical and behavioral manifestations of clinical depression, as well as the cellular death associated with cerebral ischemia. Moreover, the increasing use of cytokines in the immunotherapeutic treatment of various autoimmune diseases (e.g. rheumatoid arthritis) and cancers prompted us to consider the potential role of central processes in subserving the mood-related side-effects elicited by these treatments. Finally, a single administration of TNF-α has been shown to elicit a time-dependent sensitization effect, wherein the behavioral and neurochemical responses elicited by later cytokine treatment are greatly enhanced. Thus, particular attention was devoted to the possibility that elevated levels of TNF-α, through either exogenous (e.g. immunotherapy) or endogenous (e.g. brain damage or stressors) means may sensitize neurotransmitter or second messenger pathways important for the pathology. Given the time-dependent nature of cytokine sensitization effects, the schedule of cytokine administration during immunotherapy, or the timing of cytokine up-regulation in response to traumatic or stressful events may favor the development of sensitized central processes, which may influence clinical outcome.

Keywords

cytokineTNF-α? sensitizationsicknesscorticosteronemonoaminedepressionstrokeimmunotherapy
Type
Review Article
Information
Acta Neuropsychiatrica , Volume 14 , Issue 6 , December 2002 , pp. 322 - 335
Copyright
Copyright © Acta Neuropsychiatrica 2002

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Illei, GG, Lipsky, PE. Novel, non-antigen-specific therapeutic approaches to autoimmune/inflammatory diseases. Curr Opin Immunol 2000;12: 712–718.CrossRefGoogle ScholarPubMed
Prud'homme, GJ, Lawson, BR, Theofilopoulos, AN. Anticytokine gene therapy of autoimmune diseases. Expert Opin Biol Ther 2001;1: 359–373.CrossRefGoogle ScholarPubMed
Xiang, J. Targeting cytokines to tumors to induce active antitumor immune responses by recombinant fusion proteins. Hum Antibodies 1999;9: 23–36.Google ScholarPubMed
Pavone, L, Andrulli, S, Santi, R, Majori, M, Buzio, C. Long-term treatment with low doses of interleukin-2 and interferon-alpha: immunological effects in advanced renal cell cancer. Cancer Immunol Immunother 2001;50: 82–86.CrossRefGoogle ScholarPubMed
Blalock, JE. The syntax of immune-neuroendocrine communication. Immunol Today 1994;15: 504–511.CrossRefGoogle ScholarPubMed
Nguyen, KT, Deak, T, Owens, SMet al. Exposure to acute stress induces brain interleukin-1b protein in the rat. J Neurosci 1998;18: 2239–2246.Google Scholar
Dunn, A J, Wang, J, Ando, T. Effects of cytokines on cerebral neurotransmission. Comparison with the effects of stress. Adv Exp Med Biol 1999;461: 117–127.CrossRefGoogle ScholarPubMed
Maes, M. Major depression and activation of the inflammatory response system. Adv Exp Med Biol 1999;461: 25–46.CrossRefGoogle ScholarPubMed
Musselman, DL, Lawson, DH, Gumnick, JFet al. Paroxetine for the prevention of the depression and neurotoxicity induced by high dose interferon alpha. New Eng J Med 2001;344: 961–966.CrossRefGoogle Scholar
Mrak, RE, Griffin, WS. Interleukin-1 and the immunogenetics of Alzheimer disease. J Neuropathol Exp Neurol 2000;59: 471–476.CrossRefGoogle ScholarPubMed
Woodroofe, MN. Cytokine production in the central nervous system. Neurology 1999;45: S6–S10. CrossRefGoogle ScholarPubMed
Tilders, FJH, Schmidt, ED. Interleukin-1-induced plasticity of hypothalamic CRH neurons and long-term stress hyperresponsiveness. Ann NY Acad Sci 1998;840: 65–73.CrossRefGoogle ScholarPubMed
Schmidt, ED, Janszen, AWJW, Wouterlood, FG, Tilders, FJH. Interleukin-1 induced long-lasting changes in hypothalamic corticotropin-releasing hormone (CRH) neurons and hyperresponsiveness of the hypothalamic-pituitary–adrenal axis. J Neurosci 1995;15: 7417–7426.Google Scholar
Hayley, S, Brebner, K, Lacosta, S, Merali, Z, Anisman, H. Sensitization to the effects of tumor necrosis factor-α: Neuroendocrine, central monoamine and behavioral variations. J Neurosci 1999;19: 5654–5665.Google ScholarPubMed
Hayley, S, Ethier, K, Wall, P, Merali, Z, Anisman, H. Immediate and protracted effects of TNF-alpha: Peripheral vs central sites of action. Brain Beh Immunol 2001;15: 155. Google Scholar
Hayley, S, Lacosta, S, Merali, Z, Van Rooijen, N, Anisman, H. Central monoamine and plasma corticosterone changes induced by a bacterial endotoxin sensitization cross-sensitization effects. Eur J Neurosci 2001;13: 1155–1165.CrossRefGoogle ScholarPubMed
Banks, WA. Cytokines, CVSs, and the blood–brain barrier. In: Ader, R, Felton, DL, Cohen., eds. Psychoneuroimmunology, Vol. 2. New York: Academic Press, 2001: 483–498. Google Scholar
Merrill, JE, Benveniste, EN. Cytokines in inflammatory brain lesions. helpful and harmful. Trends Neurosci 1997;8: 331–338. Google Scholar
Kinouchi, K, Brown, G, Pasternak, G, Donner, DB. Identification and characterization of receptors for tumor necrosis factor-α in the brain. Biochem Biophys Res Commun 1991;181: 1532–1538.CrossRefGoogle Scholar
Cunningham, ET Jr, Desouza, EB. Interleukin-1 receptors in the brain and endocrine tissue. Immunol Today 1993;14: 171–176.Google Scholar
Laflamme, N, Rivest, S. Effects of systemic immunogenic insults and circulating proinflammatory cytokines on the transcription of the inhibitory factor kappaB alpha within specific cellular populations of the rat brain. J Neurochem 1999;73: 309–321.CrossRefGoogle ScholarPubMed
Tancredi, V, D'Arcangelo, G, Grassi, Fet al. Tumor necrosis factor alters synaptic transmission in rat hippocampal slices. Neurosci Lett 1992;146: 176–178.CrossRefGoogle ScholarPubMed
Plata-Salaman, CR, Oomura, Y, Kai, Y. Tumor necrosis factor and interleukin-1 beta: suppression of food intake by direct action in the central nervous system. Brain Res 1988;448: 106–114.CrossRefGoogle ScholarPubMed
O'Connor, JJ, Coogan, AN. Actions of the proinflammatory cytokine IL-1β on central synaptic transmission. Exp Physiol 1999;84: 601–614.CrossRefGoogle Scholar
Dantzer, R. Cytokine-induced sickness behavior. Mechanisms Implications Brain Beh Immun 2000;14: 88. Google Scholar
Gaykema, RP, Goehler, LE, Tilders, FJet al. Bacterial endotoxin induces fos immunoreactivity in primary afferent neurons of the vagus nerve. Neuroimmunomodulation 1998;5: 234–240.CrossRefGoogle ScholarPubMed
Tsumori, C, Shibasaki, T, Hotta, Met al. Interleukin-1beta administered intracerebroventricularly stimulates the release of noradrenaline in the hypothalamic paraventricular nucleus via prostaglandin in the rat. J Endocrol 1998;45: 127–130. CrossRefGoogle Scholar
Breder, CD, Tsujimoto, M, Terano, Y, Scott, DW, Saper, C. Distribution and characterization of tumor necrosis factor-α-like immunoreactivity in the murine central nervous system. J Comp Neurol 1993;337: 543–567.CrossRefGoogle Scholar
Rothwell, NJ. Annual review prize lecture cytokines – killers in the brain? J Physiol 1999;514: 3–17.CrossRefGoogle Scholar
Anisman, H, Hayley, S, Merali, Z. Behavioral and central neurochemical consequences of cytokine challenge. In: Bienenstock, J, Gorzynski, R, Berczi, I, eds. Neuroimmune Biology: New Foundation of Biology. Amsterdam: Elsevier Science, 2001: 141–161. Google Scholar
Buttini, M, Boddeke, H. Peripheral lipopolysaccharide stimulation induces interleukin-1β messenger RNA in rat brain microglial cells. Neuroscience 1995;65: 523–530.CrossRefGoogle Scholar
Lee, S, Rivier, C. Hypophysiotropic role and hypothalamic gene expression of corticotropin-releasing factor and vasopressin in rats injected with interleukin-1 beta systemically or into the brain ventricles. J Neuroendocrinol 1994;6: 217–224.CrossRefGoogle Scholar
Watanobe, H, Takebe, K. Intrahypothalamic infusion with interleukin-1 beta stimulates the release of corticotropin-releasing hormone and arginine vasopressin and the plasma adrenocorticotropin in freely moving rats: a comparative perfusion of the paraventricular nucleus and the median eminence. Neuroendocrinology 1993;57: 593–599.CrossRefGoogle Scholar
Rivier, C, Vale, W. Interaction of corticotropin-releasing factor and arginine vasopressin on adrenocorticotropin secretion in vivo. Endocrinology 1983;113: 939–942.CrossRefGoogle Scholar
Ando, T, Dunn, AJ. Mouse tumor necrosis factor-alpha increases brain tryptophan concentrations and norepinephrine metabolism while activating the HPA axis in mice. Neuroimmunomod 1999;6: 319–329. CrossRefGoogle Scholar
Brebner, K, Hayley, S, Merali, Z, Anisman, H. Synergistic effects of interleukin-1β, interleukin-6 and tumor necrosis factor-α: Central monoamine, corticosterone and behavioral variations. Neuropsychopharmacol 2000;22: 566–580. CrossRefGoogle Scholar
Bernardini, R, Kamilaris, TC, Calogero, AEet al. Interactions between tumor necrosis factor-α, hypothalamic corticotropin-releasing hormone, and adrenocorticotropin secretion in the rat. Endocrinology 1990;126: 2876–2881.CrossRefGoogle ScholarPubMed
Turnbull, AV, Pitossi, FJ, Lebrun, J-Jet al. Inhibition of tumor necrosis factor-α within the CNS markedly reduces the plasma adrenocorticotropin response to peripheral local inflammation in rats. J Neurosi 1997;17: 3262–3273. Google ScholarPubMed
Johnson, EO, Kamilaris, TC, Chrousos, GP, Gold, PW. Mechanisms of stress: a dynamic overview of hormonal and behavioral homeostasis. Neuro Biobehav Rev 1992;16: 115–130. CrossRefGoogle Scholar
Kobayashi, H, Fukata, J, Murakami, Net al. Tumor necrosis factor receptors in the pituitary cells. Brain Res 1997;758: 45–50.CrossRefGoogle Scholar
Ritchie, PK, Ashby, M, Knight, HH, Judd, AM. Dopamine increases interleukin 6 release and inhibits tumor necrosis factor release from rat adrenal zona glomerulosa cells in vitro. Eur J Endocrinol 1996;134: 610–616.CrossRefGoogle ScholarPubMed
Lacosta, S, Merali, Z, Anisman, H. Influence of interleukin-1 on exploratory behaviors, plasma ACTH and cortisol, and central biogenic amines in mice. Psychopharmacol 1998;137: 351–361. CrossRefGoogle Scholar
Dunn, AJ. The role of interleukin-1 and tumor necrosis factor alpha in the neurochemical and neuroendocrine responses to endotoxin. Brain Res Bull 1992;6: 807–812. CrossRefGoogle Scholar
Shintani, F, Kanba, S, Nakaki, Tet al. Interleukin-1β augments release of norepinephrine, dopamine and serotonin in the rat anterior hypothalamus. J Neurosci 1993;13: 3574–3581.Google Scholar
Mohankumar, PS, Quadri, SK. Systemic administration of interleukin-1 stimulates norepinephrine release in the paraventricular nucleus. Life Sci 1993;52: 1961–1967.CrossRefGoogle Scholar
Kamikawa, H, Hori, T, Nakane, H, Aou, S, Tashiro, N. IL-1beta increases norepinephrine level in rat frontal cortex. involvement of prostanoids, NO, and glutamate. Am J Physiol 1998;275: R803–R810.Google ScholarPubMed
Anisman, H, Zalcman, S, Zacharko, R M. The impact of stressors on immune and central neurotransmitter activity: Bidirectional communication. Rev Neurosci 1993;4: 147–180.CrossRefGoogle Scholar
Kalivas, PW, Stewart, J. Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity. Brain Res Rev 1991;16: 223–244.CrossRefGoogle ScholarPubMed
Janeway, CA. Host defense against infection. In: Janeway, CA, Travers, P, Walport, M, Capra, JD, eds. Immunobiology: the Immune System in Health and Disease. New York: Elsevier Science, 1999: 378–380. Google Scholar
Burdon, D, Tiedje, T, Pfeffer, K, Vollmer, E, Zabel, P. The role of tumor necrosis factor in the development of multiple organ failure in a murine model. Crit Care Med 2000;28: 1962–1967.CrossRefGoogle Scholar
Hayley, S, Staines, WM, Merali, Z, Anisman, H. Time- dependent sensitization of corticotropin releasing hormone, arginine vasopressin and c-fos immunoreactivity within the mouse brain in response to tumor necrosis factor-α. Neuroscience 2001;106: 137–148.CrossRefGoogle ScholarPubMed
Kelly, O, Hayley, S, Kokkinidis, L, Anisman, H. Histaminergic modulation of the behavioral and neuorchemical sensitization effects elicited by tumour necrosis factor-α. Soc Neurosci 2001: 27. Google Scholar
Gutierrez, EG, Banks, WA, Kastin, AJ. Murine tumor necrosis factor alpha is transported from blood to brain in the mouse. J Neuroimmunol 1993;47: 169–176.CrossRefGoogle ScholarPubMed
Maier, SF, Goehler, LE, Fleshner, M, Watkins, LR. The role of the vagus nerve in cytokine-to-brain communication. Ann N Y Acad Sci 1998;840: 289–300.CrossRefGoogle ScholarPubMed
Libert, C, Van Bladel, S, Brouckaert, P, Shaw, A, Fiers, W. Involvement of the liver, but not of IL-6, in IL-1 induced desensitization to the lethal effects of tumor necrosis factor. J Immunol 1991;146: 2625–2632.Google Scholar
Bafaloukos, D, Fountzilas, G, Skarlos, Det al. Subcutaneous low doses of interleukin-2 and recombinant interferon alpha with carboplatin and vinblastine in patients with advanced melanoma. Oncology 1998;55: 48–52.CrossRefGoogle Scholar
Capuron, L, Bluthe, RM, Dantzer, R. Cytokines in clinical psychiatry. Am J Psychiatry 2001;158: 1163–1164.CrossRefGoogle Scholar
Denicoff, KD, Rubinow, DR, Papa, MZet al. The neuropsychiatric effects of treatment with interleukin-2 and lymphokine-activated killer cells. Ann Intern Med 1987;107: 293–300.CrossRefGoogle ScholarPubMed
Lans, TE, Bartlett, DL, Libutti, SKet al. Role of tumor necrosis factor on toxicity and cytokine production after isolated hepatic perfusion. Clin Cancer Res 2001;7: 784–790.Google Scholar
Wright, P, Braun, R, Babiuk, Let al. Adenovirus-mediated TNF-alpha gene transfer induces significant tumor regression in mice. Cancer Biother Radiopharm 1999;14: 49–57.CrossRefGoogle ScholarPubMed
Beutler, BA. The role of tumor necrosis factor in health and disease. J Rheumatol 1999;26: 16–21.Google Scholar
Petak, I, Houghton, JA. Shared pathways. death receptors and cytotoxic drugs in cancer therapy. Pathol Oncol Res 2001;7: 95–106.CrossRefGoogle ScholarPubMed
Sidhu, RS, Bollon, AP. Tumor necrosis factor activities and cancer therapy – a perspective. Pharmacol Ther 1993;57: 79–128.CrossRefGoogle ScholarPubMed
Budd, GT, Green, S, Baker, LH, Hersh, EP, Weick, JK, Osborne, CK. A Southwest Oncology Group phase II Trial of recombinant tumor necrosis factor in metastatic breast cancer. Cancer 1991;68: 1694–1695.3.0.CO;2-K>CrossRefGoogle Scholar
Lortholary, O, Improvisi, L, Rayhane, N, Gray, F, Fitting, C, Cavaillon, JM, Dromer, F. Cytokine profiles of AIDS patients are similar to those of mice with disseminated Cryptococcus neoformans infection. Infect Immun 1999;67: 6314–6320.Google ScholarPubMed
Ilyin, SE, Plata-Salaman, CR. HIV-1 envelope glycoprotein 120 regulates brain IL-1beta system and TNF-alpha mRNAs in vivo. Brain Res Bull 1997;44: 67–73.CrossRefGoogle ScholarPubMed
Barbara, JA, Van ostade, X, Lopez, A. Tumour necrosis factor-alpha (TNF-alpha): the good, the bad and potentially very effective. Immunol Cell Biol 1996;74: 434–443.CrossRefGoogle ScholarPubMed
Taylor, PC. Anti-TNF therapy for rheumatoid arthritis and other inflammatory diseases. Mol Biotechnol 2001;19: 153–168.CrossRefGoogle ScholarPubMed
Sicotte, NL, Voskuhl, RR. Onset of multiple sclerosis associated with anti-TNF therapy. Neurology 2001;57: 1885–1888.CrossRefGoogle ScholarPubMed
Anisman, H, Merali, Z. Anhedonic and anxiogenic effects of cytokine exposure. Adv Exp Med Biol 1999;461: 199–233.CrossRefGoogle ScholarPubMed
Walker, DL, Davis, M. Double dissociation between the involvement of the bed nucleus of the stria terminalis and the central nucleus of the amygdala in startle increases produced by conditioned versus unconditioned fear. J Neurosci 1997;17: 9375–9383.Google Scholar
Manji, HK, Drevets, WC, Charney, DS. The cellular neurobiology of depression. Nat Med 2001;7: 541–547.CrossRefGoogle Scholar
Guillin, O, Diaz, J, Carroll, P, Griffon, N, Schwartz, J C, Sokoloff, P. BDNF controls dopamine D3 receptor expression and triggers behavioural sensitization. Nature 2001;411: 86–89.CrossRefGoogle ScholarPubMed
Altar, CA. Neurotrophins and depression. Trends Pharmacol Sci 1996;20: 59–61. CrossRefGoogle ScholarPubMed
Loddick, SA, Rothwell, NJ. Neuroprotective effects of human recombinant interleukin-1 receptor antagonist in focal cerebral ischaemia in the rat. J Cereb Blood Flow Metabol 1997;16: 932–940. CrossRefGoogle ScholarPubMed
Minami, M, Kuraishi, Y, Yabuuchi, K, Yamazaki, A, Satoh, M. Induction of interleukin-1 beta mRNA in rat brain after transient forebrain ischemia. J Neurochem 1992;58: 390–392.CrossRefGoogle ScholarPubMed
Yamasaki, Y, Matsuura, N, Shozuhara, H, Onodera, H, Itoyama, Y, Kogure, K. Interleukin-1 as a pathogenetic mediator of ischemic brain damage in rats. Stroke 1995;26: 676–680.CrossRefGoogle ScholarPubMed
Touzani, O, Boutin, H, Lefeuvre, Ret al. Interleukin-1 influences ischemic brain damage in the mouse independently of the interleukin-1 type I receptor. J Neurosci 2002;22: 38–43.Google ScholarPubMed
Tchelingerian, JL, Vignais, L, Jacque, C. TNF alpha gene expression is induced in neurones after a hippocampal lesion. Neuroreport 1994;5: 585–588.CrossRefGoogle ScholarPubMed
Chao, CC, Hu, S, Ehrlich, L, Peterson, PK. Interleukin-1 and tumor necrosis factor-alpha synergistically mediate neurotoxicity: involvement of nitric oxide and of N-methyl-d-aspartate receptors. Brain Behav Immun 1995;9: 355–365.CrossRefGoogle ScholarPubMed
Rothwell, NJ, Hopkins, SJ. Cytokines and the nervous system II. actions and mechanisms of action. Trends Pharamcol Sci 1995;18: 130–136. Google ScholarPubMed
McGeer, PL, Kawamata, T, Walker, DG, Akiyama, H, Tooyama, I, McGeer, EG. Microglia in degenerative neurological disease. Glia 1993;7: 84–92.CrossRefGoogle Scholar
Barone, FC, Arvin, B, White, RFet al. Tumor necrosis factor-alpha. A mediator of focal ischemic brain injury. Stroke 1997;28: 1233–1244.CrossRefGoogle Scholar
Lavine, SD, Hofman, FM, Zlokovic, BV. Circulating antibody against tumor necrosis factor-alpha protects rat brain from reperfusion injury. J Cereb Blood Flow Metab 1998;18: 52–58.CrossRefGoogle ScholarPubMed
Meistrell, M E, Botchkina, G I, Wang, Het al. Tumor necrosis factor is a brain damaging cytokine in cerebral ischemia. Shock 1997;8: 341–348.CrossRefGoogle ScholarPubMed
Bruce, A J, Boling, W, Kindy, MSet al. Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors. Nat Med 1996;2: 788–794.CrossRefGoogle ScholarPubMed
Gary, DS, Bruce-Keller, AJ, Kindy, MS, Mattson, MP. Ischemic and excitotoxic brain injury is enhanced in mice lacking the p55 tumor necrosis factor receptor. J Cereb Blood Flow Metab 1998;18: 1283–1287.CrossRefGoogle Scholar
Barger, SW, Horster, D, Furukawa, K, Goodman Krieglstein, J, Mattson, MP. Tumor necrosis factors and protect neurons against amyloid-peptide toxicity: evidence for involvement of a B-binding factor and attenuation of peroxide and Ca2+ accumulation. Proc Natl Acad Sci USA 1995;92: 9328–9332.CrossRefGoogle Scholar
Mattson, MP, Barger, SW, Furukawa, Ket al. Cellular signaling roles of TGF beta, TNF alpha and beta APP in brain injury responses and Alzheimer's disease. Brain Res Rev 1997;23: 47–61.CrossRefGoogle Scholar
Cheng, B, Christakos, S, Mattson, MP. Tumor necrosis factors protect neurons against metabolic-excitotoxic insults and promote maintenance of calcium homeostasis. Neuron 1994;12: 139–153.CrossRefGoogle ScholarPubMed
Mattson, MP, Cheng, B, Baldwin, SAet al. Brain injury and tumor necrosis factors induce calbindin D-28k in astrocytes: evidence for a cytoprotective response. J Neurosci Res 1995;42: 357–370.CrossRefGoogle ScholarPubMed
Streit, WJ, Kincaid-Colton, CA. The brain's immune system. Sci Am 1995;273: 58–61.CrossRefGoogle ScholarPubMed
Benveniste, EN. Cytokine circuits in brain. Implications for AIDS dementia complex. Res Publ Assoc Res Nerv Ment Dis 1994;72: 71–88.Google ScholarPubMed
Barone, FC, Feuerstein, GZ. Inflammatory mediators and stroke: new opportunities for novel therapeutics. J Cereb Blood Flow Metab 1999;19: 819–834.CrossRefGoogle ScholarPubMed