Stressmastcells.pdf

0271-0749/02/2202-0103/0Journal of Clinical Psychopharmacology Copyright 2002 by Lippincott Williams & Wilkins, Inc.
GUEST EDITORIAL
Mast Cells and Stress—A Psychoneuroimmunological
Perspective
Tufts University School of Medicine, Boston, Massachusetts The complexity of interactions among neurotransmit- well known for their involvement in allergic and ana- ters and neuromodulators in the brain continues to ex- phylactic reactions20; then, surface bound immunoglobu- pand. The involvement of immune molecules has added lin E (IgE) complexes with specific antigen, causing de- a new dimension. An important new contributor that is of granulation, like a foil package of popcorn popping until interest to psychopharmacology is a unique cell, named the contents overflow.21 Many of these molecules are pre- “mast cell” by Paul Erlich in 1887 because its numerous formed and stored in almost 500 secretory granules, metachromatic granules reminded him of a “well-fed while others are made do novo during or following stim- cell” (German ϭ Mastzellen).1 These cells are particularly ulation.22,23 It is fascinating that one cell should have such active in atopic individuals, who also have higher inci- plethora and diversity of potent molecules that include dences of affective disorders.2–5 Moreover, the allergy arachidonic acid products, biogenic amines, chemoat- season has been shown to affect mood and cognitive tractants, cytokines, growth factors, neuropeptides, pro- function in these patients.6 Stress is known to exacerbate teoglycans, and proteolytic enzymes (Table 2). Although many neuroinflammatory conditions7, but, until recently, the mast cell is ubiquitous in the body—including the mast cells were not suspected of being involved in con- brain, which does not suffer from allergic reactions be- ditions such as dermatoses8, irritable bowel syndrome9, cause IgE does not cross the blood-brain barrier—de- interstitial cystitis10, migraines11, and multiple sclerosis granulation occurs only in about 10% or so of atopic indi- (MS).12 Although Hans Seyle wrote the first definitive viduals. Moreover, increasing evidence indicates that work on stress13 and one on mast cells14, he did not link some molecules are released from mast cells without de- the two at that time. The effect of acute stress is particu- granulation, a process termed “differential release” and larly evident in systemic mastocytosis, a rare condition first reported for serotonin.24 Other biogenic amines25, characterized by abnormal proliferation and activation of arachidonic acid products26, and cytokines27 may also be mast cells.15,16 For these patients, and possibly many oth- released differentially. The morphological appearance of ers who have a neuroinflammatory syndrome with an af- this process is characterized by a more subtle set of fective component worsened by stress (Table 1), when changes within the electron dense content of the secre- anxiety rises, they know there will be a flare-up in symp- tory granules28 and has been called “piece-meal degranu- toms, which may include flushing of the skin, intestinal lation”29 or “intergranular activation”.30 The type(s) of upset, palpitations, migraines, and changes in mood and molecule(s) released may vary from person to person, cognitive function.12 These latter symptoms could be due and/or from organ to organ, depending on hormonal and to activation of brain mast cells, which are plentiful in the psychological state and the specific trigger.
Anatomical and functional associations have been re- Mast cells are found in most parts of the body and are ported between mast cells and neurons.31,32 Scanningelectron microscopy has documented mast cells close to Address requests for reprints to: Theoharis C. Theoharides, PhD, endothelial cells and to neuronal processes.33 Molecules MD, Department of Pharmacology and Experimental Therapeutics, released from nerves34–36, such substance P (SP), neu- Internal Medicine, Biochemistry, and Psychiatry Tufts University rotensin (NT), nerve growth factor (NGF), and opioids37 School of Medicine, New England Medical Center, Boston, Massa-chusetts. Address e-mail to: [email protected] could trigger mast cells (Table 3), from which histamine J CLIN PSYCHOPHARMACOL, VOL 22/NO 2, APRIL 2002 TABLE 1. Neuroinflammatory syndromes with an affective could stimulate neuronal depolarization38, which could lead to further activation of mast cells. Moreover, mast cell derived chondroitin sulfate or heparin complexes with NGF and extends its half-life from a few minutes to many hours.39,40 Therefore, mast cell activation could lead to abnormal nerve proliferation (i.e., in neurofibro- matosis I).41 Intracranial mast cells could also be acti- vated by stimulation of the trigeminal42, sympathetic43, or sphenopalatine44 nerves and by acute restraint stress45, in the absence of any allergic diathesis. Some molecules from these mast cells could have direct ef-fects on the brain, while others could make the blood-brain barrier “leaky” and permit circulating chemicalsto enter the brain.46,47 Breakdown of the blood-brain bar-rier has been shown to precede any clinical or radi- Epinephrine, dopamine, phenylalanine (not synthesized, but taken Vasodilation, angiogenesis, mitogenesis, pain Tissue damage, pain, angiotensin II synthesis Cartilage synthesis, antiinflammatory, NGF stabilization Connective tissue synthesis, NGF stabilization Inflammation, leukocyte proliferation/activation Inflammation, vascular adhesion molecule expression Platelet activation & serotonin release CSF, colony stimulating factor; INF␥, interferon-␥; MIF, macrophage inflammatory factor; b-FGF, fibroblast growth factor; NGF, nerve growth factor; TGF-␤, transforming growth factor-␤; TNF-␣, tumor necrosis factor-␣; SRIF, somatostatin; GM-CSF, granulcyte monocyte-colony stimu-lating factor.
J CLIN PSYCHOPHARMACOL, VOL 22/NO 2, APRIL 2002 TABLE 3. Triggers of mast cell activation quent release of histamine60 and IL-6.61 This action ofhistamine is not blocked by the usual antihistamines and appears to be mediated through the type 3 hista- mine receptor.62 IL-6, a key inflammatory cytokine63, is known be released from the hearts of patients with acute coronary syndrome, and is now considered a crit- Detergents; food additives; xenoestrogens ical player in coronary artery disease.64 Stress-induced Contrast media used in radiologyCytokines cardiac mast cell activation may be involved in unstable angina and myocardial infarction triggered by acute stress.65–67 Acute stress also results in bladder68 and in- Local anesthetics; neuromuscular junction blockers, opioids testinal69,70 mast cell activation, which may explain why symptoms in interstitial cystitis (IC) and irritable bowel Nerve growth factor, NGF; stem cell factor, SCF syndrome (IBS) patients worsen under stress.
Corticotropin-releasing hormone or factor (CRH or Adrenocorticotropic hormone, ACTH; corticotropin releasing CRF) is the first molecule released under stress and ac- hormone, CRH; estradiol; parathormone, PTH; urocortin, Ucn tivates the hypothalamic-pituitary-adrenal (PHA) axis.71 We have shown that CRH72 and structurally related uro- Bradykinin; calcitonin gene related peptide, CGRP; myelin basic cortin73 are powerful triggers of mast cell activation in protein, MBP; neurotensin, NT; somatostatin, SRIF; substance the skin. In fact, urocortin was 10 times more potent P, SP; vasoactive intestinal peptide, VIP than CRH and much more potent than SP.73 These actions were mimicked by acute stress74 and may be responsible for stress-induced alopecia areata.75 Such findings and the presence of both CRH and CRH recep- tors in the skin76 have led to the hypothesis that the skin has the equivalent of a local “pituitary-adrenal axis”.77 Recent findings showed that hypothalamic mast cell ac- tivation by chemical78 or immunologic means79 trig- Bacterial (Clostridium difficile); insect (fire ants); jelly fish (man gered activation of the HPA axis. This action could be mediated either through activation of CRH neurons di- rectly or the release of IL-6, a CRH independent activa- tor of the HPA axis.80 CRH or urocortin then could befurther released from recruited immune cells.81 Recognizing the involvement of mast cells and regulat- ing their secretion may be more important than simply ad- ographic signs of MS.48 Therefore, it is of interest that dressing the effects of individual mediators. A case in chemical49 or stress-induced stimulation of brain mast point is the clinical report (Pehlivanidis and associates, cells50 increased blood-brain barrier permeability. More- page 221 in this issue) of a young boy mistakenly diag- over, experimental allergic encephalomyelitis could not nosed and unsuccessfully treated for epilepsy. When it be induced in mast cell deficient mice.51 These findings was recognized that his seizures were induced by acute support the possible relationship between intracranial stress and were associated with his mastocytosis, he was mast cells and migraines52, as well as MS53, that are often successfully treated with a combination of the anxiolytic precipitated or worsened by stress.54–57 Dura mast cells antihistamine hydroxyzine and the tricyclic doxepin. The also express estrogen receptors33, a finding that, along efficacy of these compounds may be explained by the fact with the report that estrogen augments mast cell secre- that mast cell activation can be inhibited by certain tri- tion58, may possibly explain the higher incidence of mi- cyclic anxiolytic medications, such as amitriptyline and graines in women or their frequent occurrence during hydroxyzine82, and benzodiazepines.83 In fact, mast cells have been reported to express high affinity benzodi- Many patients also experience tachycardia and ar- azepine receptors.84,85 Hydroxyzine was recently shown to rhythmias related to stress. Such cardiovascular symp- inhibit neurogenic inflammation and experimental aller- toms may be associated with increased sympathetic ac- gic encephalomyelitis in rats.86 In humans, hydroxyzine tivity or reflex tachycardia in response to histamine- has been used successfully to treat acute pain87 and re- induced hypotension. However, such symptoms may mitting-relapsing MS.88 Such anxiolytic molecules could also be explained by the recent finding that acute stress be combined with naturally occurring flavonoids89 or pro- triggers mast cell activation in the heart59, with subse- teoglycans90 for more efficient inhibition of mast cell J CLIN PSYCHOPHARMACOL, VOL 22/NO 2, APRIL 2002 activation. Behavioral modification for stress reduction tem. Part I. Morphology, distribution and histochemistry. J Neu- also contributed to the treatment of the child described in 19. Pang X, Letourneau R, Rozniecki JJ, Wang L, Theoharides TC. De- the case report by Pehlivanidis and associates. We used finitive characterization of rat hypothalamic mast cells. Neuro- this approach because of our finding that training in re- laxation led to a sharp decline in the frequency and sever- 20. Galli SJ. New concepts about the mast cell. N Engl J Med 1993; ity of migraines and the release of the mast cell marker 21. Douglas WW. Involvement of calcium in exocytosis and the exocytosis-vesiculation sequence. Biochem Soc Symp 1974;39:1–28.
The mast cell has been considered an immune gate to 22. Schwartz LB. Mediators of human mast cells and human mast cell subsets. Ann Allergy 1987;58:226–35.
the brain91, as well as a sensor of environmental and 23. Serafin WE, Austen KF. Mediators of immediate hypersensitivity emotional stress.92 It has also been linked to many neu- reactions. N Engl J Med 1987;317:30–4.
ropathological processes.93–95 This versatile role of mast 24. Theoharides TC, Bondy PK, Tsakalos ND, Askenase PW. Differ- ential release of serotonin and histamine from mast cells. Nature cells96 compels a more appropriate name to indicate its polydimensional potential, perhaps “pleiotropocyte” 25. Dvorak AM, Macglashan DW, Jr., Morgan ES, Lichtenstein LM.
Vesicular transport of histamine in stimulated human basophils.
Blood 1996;88:4090–101.
26. Benyon R, Robinson C, Church MK. Differential release of hista- Acknowledgments
mine and eicosanoids from human skin mast cells activated byIgE-dependent and non-immunological stimuli. Br J Pharmacol Aspects of the work discussed were supported by the National Mul- tiple Sclerosis Society, the NIH, as well as by Kos Pharmaceuticals 27. Gagari E, Tsai M, Lantz CS, Fox LG, Galli SJ. Differential release (Miami, FL) and Theta Biomedical Consulting and Development Co.
of mast cell interleukin-6 via c-kit. Blood 1997;89:2654–63.
(Brookline, MA). Thanks are due to Mr. Barry Silverstein for continu- 28. Kops SK, Theoharides TC, Cronin CT, Kashgarian MG, Askenase ous encouragement and to Miss. Yahsin Tien for her patience and PW. Ultrastructural characteristics of rat peritoneal mast cells un-dergoing differential release of serotonin without histamine and without degranulation. Cell Tissue Res 1990;262:415–24.
29. Dvorak AM, Tepper RI, Weller PF, et al. Piecemeal degranulation References
of mast cells in the inflammatory eyelid lesions of interleukin-4transgenic mice. Evidence of mast cell histamine release in 1. Galli SJ. New insights into “the riddle of the mast cells”: microen- vivo by diamine oxidase-gold enzyme-affinity ultrastructiral cyto- vironmental regulation of mast cell development and phenotypic heterogeneity. Lab Invest 1990;62:5–33.
30. Letourneau R, Pang X, Sant GR, Theoharides TC. Intragranular ac- 2. Marshall PS. Allergy and depression: a neurochemical threshold tivation of bladder mast cells and their association with nerve model of the relation between the illnesses. Psychol Bull 1994; processes in interstitial cystitis. Br J Urol 1996;77:41–54.
31. Newson B, Dahlström A, Enerbäck L, Ahlman H. Suggestive evi- 3. Nasr S, Altman EG, Meltzer HY. Concordance of atopic and affec- dence for a direct innervation of mucosal mast cells. Neuro- tive disorders. J Affect Disord 1981;3:291–6.
4. Matussek P, Agerer D, Seibt G. Allergic disorders in depressed pa- 32. Stead RH, Tomioka M, Quinonez G, Simon GT, Felten SY, Bi- tients. Compr Psychiatry 1983;24:25–34.
enenstock J. Intestinal mucosal mast cells in normal and nema- 5. Graham DT, Wolf S. The relation of eczema to attitude and to vas- tode-infected rat intestines are in intimate contact with peptider- cular reactions of the human skin. J Lab Clin Med 1953;42:238–54.
gic nerves. Proc Natl Acad Sci USA 1987;84:2975–9.
6. Marshall PS, Colon EA. Effects of allergy season on mood and 33. Rozniecki JJ, Dimitriadou V, Lambracht-Hall M, Pang X, Theo- cognitive function. Ann Allergy 1993;71:251–8.
harides TC. Morphological and functional demonstration of rat 7. Rosch PJ. Stress and illness. JAMA 1979;242:427–8.
dura mast cell-neuron interactions in vitro and in vivo. Brain Res 8. Katsarou-Katsari A, Filippou A, Theoharides TC. Effect of stress and other psychological factors on the pathophysiology and treat- 34. Foreman JC. Neuropeptides and the pathogenesis of allergy. Al- ment of dermatoses. Int J Immunopathol Pharmacol 1999;12:7–11.
9. Mayer EA, Naliboff BD, Chang L, Coutinho SV. V. Stress and irri- 35. Goetzl EJ, Chernov T, Renold F, Payan DG. Neuropeptide regula- table bowel syndrome. Am J Physiol 2001;280:G519–24.
tion of the expression of immediate hypersensitivity. J Immunol 10. Theoharides TC, Kempuraj D, Sant GR. Mast cell involvement in interstitial cystitis: a review of human and experimental evidence.
36. Goetzl EJ, Cheng PPJ, Hassner A, Adelman DC, Frick OL, Speed- haran SP. Neuropeptides, mast cells and allergy: novel mecha- 11. Olness K, Hall H, Rozniecki JJ, Schmidt W, Boucher W, Theo- nisms and therapeutic possibilities. Clin Exp Allergy 1990;20: harides TC. Mast cell activation in children with migraine before and after training in self-regulation. Headache 1999;39:101–7.
37. Barke KE, Hough LB. Opiates, mast cells and histamine release.
12. Theoharides TC. Mast cell: a neuroimmunoendocrine master player. Int J Tissue React 1996;18:1–21.
38. Christian EP, Undem BJ, Weinreich D. Endogenous histamine ex- 13. Selye H. The stress of life. New York: McGraw-Hill, 1978.
cites neurones in the guinea-pig superior cervical ganglion in 14. Selye H. The mast cells. Washington, DC: Butterworths, 1965: vitro. J Physiol 1989;409:297–312.
39. Brittis PA, Canning DR, Silver J. Chondroitin sulfate as a regula- 15. Valent P, Escribano L, Parwaresch RM, et al. Recent advances in tor of neuronal patterning in the retina. Science 1992;255:733–6.
mastocytosis research. Summary of the Vienna mastocytosis 40. Lander AD, Fujii DK, Gospodarowicz D, Reichardt LF. Character- meeting 1998. Int Arch Allergy Immunol 1999;120:1–7.
ization of a factor that promotes neurite outgrowth: evidence link- 16. Hartmann K, Metcalfe DD. Pediatric mastocytosis. Hematol Oncol ing activity to a heparan sulfate proteoglycan. J Cell Biol 1982; 17. Goldschmidt RC, Hough LB, Glick SD, Padawer J. Mast cells in rat 41. Claman HL. New hope for neurofibromatosis? The mast cell con- thalamus: nuclear localization, sex difference and left-right asym- 42. Dimitriadou V, Buzzi MG, Moskowitz MA, Theoharides TC. Tri- 18. Ibrahim MZ. The mast cells of the mammalian central nervous sys- geminal sensory fiber stimulation induces morphologic changes J CLIN PSYCHOPHARMACOL, VOL 22/NO 2, APRIL 2002 reflecting secretion in rat dura mast cells. Neuroscience 1991; duction of silent myocardial ischemia in patients with coronary artery disease. N Engl J Med 1988;318:1005–12.
43. Keller JT, Dimlich RV, Zuccarello M, Lanker L, Strauss TA, Fritts 67. Jiang W, Babyak M, Krantz DS, et al. Mental stress-induced myo- MJ. Influence of the sympathetic nervous system as well as cardial ischemia and cardiac events. JAMA 1996;275:1651–6.
trigeminal sensory fibres on rat dural mast cells. Cephalalgia 1991; 68. Spanos CP, Pang X, Ligris K, et al. Stress-induced bladder mast cell activation: implications for interstitial cystitis. J Urol 1997; 44. Delepine L, Aubineau P. Plasma protein extravasation induced in the rat dura mater by stimulation of the parasympathetic spheno- 69. Castagliuolo I, Wershil BK, Karalis K, Pasha A, Nikulasson ST, palatine ganglion. Exp Neurol 1997;147:389–400.
Pothoulakis C. Colonic mucin release in response to immobiliza- 45. Theoharides TC, Spanos CP, Pang X, et al. Stress-induced in- tion stress is mast cell dependent. Am J Physiol 1998;274: tracranial mast cell degranulation. A corticotropin releasing hormone-mediated effect. Endocrinology 1995;136:5745–50.
70. Theoharides TC, Letourneau R, Patra P, et al. Stress-induced rat 46. Wahl M, Unterberg A, Beathmann A, Schilling L. Mediators of intestinal mast cell intragranular activation and inhibitory effect blood-brain barrier dysfunction and formation of vasogenic brain of sulfated proteoglycans. Dig Dis Sci 1999;44:87S–93S.
edema. J Cereb Blood Flow Metab 1988;8:621–34.
71. Chrousos GP. The hypothalamic-pituitary-adrenal axis and 47. Abbott NJ. Inflammatory mediators and modulation of blood- immune-mediated inflammation. N Engl J Med 1995;332:1351–62.
brain barrier permeability. Cell Mol Neurobiol 2000;20:131–47.
72. Theoharides TC, Singh LK, Boucher W, et al. Corticotropin- 48. De Vreis HE, Kuiper J, de Boer AG, Van Berkel TJC, Breimer DD.
releasing hormone induces skin mast cell degranulation and The blood-brain barrier in neuroinflammatory diseases. Pharma- increased vascular permeability, a possible explanation for its proinflammatory effects. Endocrinology 1998;139:403–13.
49. Zhuang X, Silverman A-J, Silver R. Brain mast cell degranulation 73. Singh LK, Boucher W, Pang X, et al. Potent mast cell degranula- regulates blood-brain barrier. J Neurobiol 1996;31:393–403.
tion and vascular permeability triggered by urocortin through ac- 50. Esposito P, Gheorghe D, Kandere K, et al. Acute stress increases tivation of CRH receptors. J Pharmacol Exp Ther 1999;288: permeability of the blood-brain-barrier through activation of brain mast cells. Brain Res 2001;888:117–27.
74. Singh LK, Pang X, Alexacos N, Letourneau R, Theoharides TC.
51. Secor VH, Secor WE, Gutekunst C-A, Brown MA. Mast cells are es- Acute immobilization stress triggers skin mast cell degranulation sential for early onset and severe disease in a murine model of via corticotropin releasing hormone, neurotensin and substance multiple sclerosis. J Exp Med 2000;191:813–21.
P: A link to neurogenic skin disorders. Brain Behav Immun 52. Theoharides TC. Mast cells and migraines. Perspect Biol Med 75. Katsarou-Katsari A, Singh LK, Theoharides TC. Alopecia areata 53. Rozniecki JJ, Hauser SL, Stein M, Lincoln R, Theoharides TC. El- and affected skin CRH receptor upregulation induced by acute evated mast cell tryptase in cerebrospinal fluid of multiple scle- emotional stress. Dermatology 2001;203:157–61.
rosis patients. Ann Neurol 1995;37:63–6.
76. Slominski A, Wortsman J, Pisarchik A, et al. Cutaneous expres- 54. Poser CM. Trauma to the central nervous system may result in for- sion of corticotropin-releasing hormone (CRH), urocortin, and mation or enlargement of multiple sclerosis plaques. Arch Neurol CRH receptors. FASEB J 2001;15:1678–93.
77. Slominski A, Wortsman J, Luger T, Paus R, Solomon S. Corti- 55. Goodin DS, Ebers GC, Johnson KP, Rodriguez M, Sibley WA, cotropin releasing hormone and proopiomelanocortin involve- Wolinsky JS. The relationship of MS to physical trauma and psy- ment in the cutaneous response to stress. Physiol Rev 2000;80: chological stress. Neurology 1999;52:1737–45.
56. Mei-Tal V, Meyerowitz S, Engel GL. The role of psychological 78. Gadek-Michalska A, Chlap Z, Turon M, Bugajski J, Fogel WA. The process in a somatic disorder: multiple sclerosis. 1. The emotional intracerebroventicularly administered mast cells degranulator setting of illness onset and exacerbation. Psychosom Med 1970; compound 48/80 increases the pituitary-adrenocortical activity in rats. Agents Actions 1991;32:203–8.
57. Mohr DC, Goodkin DE, Bacchetti P, et al. Psychological stress and 79. Matsumoto I, Inoue Y, Shimada T, Aikawa T. Brain mast cells act the subsequent appearances of new brain MRI lesions in MS. Neu- as an immune gate to the hypothalamic-pituitary-adrenal axis in 58. Vliagoftis H, Dimitriadou V, Boucher W, et al. Estradiol augments 80. Mastorakos G, Chrousos GP, Weber JS. Recombinant interleukin- while tamoxifen inhibits rat mast cell secretion. Int Arch Allergy 6 activates the hypothalamic-pituitary-adrenal axis in humans. J Clin Endocrinol Metab 1993;77:1690–4.
59. Pang X, Alexacos N, Letourneau R, et al. A neurotensin receptor 81. Karalis K, Louis JM, Bae D, Hilderbrand H, Majzoub JA. CRH and antagonist inhibits acute immobilization stress-induced cardiac the immune system. J Neuroimmunol 1997;72:131–6.
mast cell degranulation, a corticotropin-releasing hormone- 82. Theoharides TC, Kops SK, Bondy PK, Askenase PW. Differential re- dependent process. J Pharmacol Exp Ther 1998;287:307–14.
lease of serotonin without comparable histamine under diverse con- 60. Huang M, Pang X, Letourneau L, Boucher W, Theoharides TC. Car- ditions in the rat mast cell. Biochem Pharmacol 1985;34:1389–98.
diac mast cells are increased in apolipoprotein E knockout mice 83. Bidri M, Royer B, Averlant G, Bismuth G, Guillosson JJ, Arock M.
that develop atherosclerosis and release histamine with acute Inhibition of mouse mast cell proliferation and proinflammatory stress. Cardiovasc Res 2002;in press.
mediator release by benzodiazepines. Immunopharmacology 1999; 61. Huang M, Basu S, Pang X, Boucher W, Karalis K, Theoharides TC.
Stress-induced interleukin-6 release in mice is mast cell- 84. Taniguchi T, Wang JK, Spector S. Properties of [3H] diazepam dependent and also involves cardiomyocytes stimulated by uro- binding to rat peritoneal mast cells. Life Sci 1980;27:171–8.
85. Miller LG, Lee-Parritz A, Greenblatt DJ, Theoharides TC. High 62. Levi R, Smith NCE. Histamine H -receptors: a new frontier in my- affinity benzodiazepine receptors on rat peritoneal mast cells and ocaridal ischemia. J Pharmacol Exp Ther 2000;292:825–30.
RBL-1 cells: binding characteristics and effects on granule secre- 63. Papanicolaou D, Wilder RL, Manolagas SC, Chrousos G. The pathophysiologic roles of interleukin-6 in human disease. Ann In- 86. Dimitriadou V, Pang X, Theoharides TC. Hydroxyzine inhibits ex- perimental allergic encephalomyelitis (EAE) and associated brain 64. Schieffer B, Schieffer E, Hilfiker-Kleiner D, et al. Expression of an- mast cell activation. Int J Immunopharmacol 2000;22:673–84.
giotensin II and interleukin-6 in human coronary atherosclerotic 87. Hupert C, Yacoub M, Turgeon LR. Effect of hydroxyzine on mor- plaques. Circulation 2000;101:1372–8.
phine analgesia for the treatment of postoperative pain. Anesth 65. Deanfield JE, Shea M, Kensett M, et al. Silent myocardial is- chaemia due to mental stress. Lancet 1984;2:1001–5.
88. Hauser S, Stein M, Spear K, Theoharides TC. A pilot, double-blind, 66. Rozanski A, Bairey CN, Krantz DS, et al. Mental stress and the in- study using hydroxyzine in remitting-relapsing multiple sclerosis J CLIN PSYCHOPHARMACOL, VOL 22/NO 2, APRIL 2002 (RR-MS). XIVth World Congress of Pharmacology July 7–12, 93. Marshall JS, Waserman S. Mast cells and the nerves - potential in- teractions in the context of chronic disease. Clin Exp Allergy 89. Middleton E, Jr., Kandaswami C, Theoharides TC. The effects of plant flavonoids on mammalian cells:Implications for inflamma- 94. Silver R, Silverman A-J, Vitkovic L, Lederhendler II. Mast cells in tion, heart disease and cancer. Pharmacol Rev 2000;52:673–51.
the brain: evidence and functional significance. Trends Neurosci 90. Theoharides TC, Patra P, Boucher W, et al. Chondroitin sulfate in- hibits connective tissue mast cells. Br J Pharmacol 2000;131: 95. Kines KC, Powell HC. Mast cell interactions with the nervous sys- tem: relationship to mechanisms of disease. J Neuropathol Exp 91. Theoharides TC. Mast cells: the immune gate to the brain. Life Sci 96. Gurish MF, Austen KF. The diverse roles of mast cells. J Exp Med 92. Theoharides TC. Skin mast cells: the universal sensor of environ- mental and emotional stress. Exp Dermatol 2002; in press.

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