Abstract
Elevated mean IL-9 serum levels have been observed in human neonates who will later develop cerebral palsy. In earlier studies, using a newborn mouse model of excitotoxic lesions mimicking those described in human cerebral palsy, we found that IL-9 pretreatment exacerbated brain damage produced by intracerebral injections of the glutamatergic analog ibotenate. Among its different cell targets, the Th2 cytokine IL-9 is a mast cell growth and differentiation factor that can cause mast cells to release various substances including histamine. In the present study, we sought to determine whether the deleterious effects of IL-9 in our mouse model were mediated by mast cells through histamine release. All mouse pups were pretreated with intraperitoneal injections of IL-9 or saline between postnatal days (P) P1 and P5. Immunohistochemistry for murine mast cell protease-1 performed on P5 showed an increased density of labeled cells in the neopallium of IL-9–treated Swiss pups as compared with controls. Western blot analysis confirmed the increased murine mast cell protease-1 brain content of IL-9–treated Swiss mice. IL-9 pretreatment had no significant effect on ibotenate-induced excitotoxic brain lesions in mast cell–deficient P5 pups (WBB6F1/J kitW/W-v), whereas IL-9 exacerbated these lesions in the control littermates with normal mast cell populations. Finally, cromoglycate or antihistamine drugs significantly reduced ibotenate-induced brain lesions in IL-9–treated Swiss pups. Taken together, these data suggest that recruitment of cerebral mast cells with histamine release may contribute to the exacerbation of neonatal excitotoxic brain lesions produced by IL-9. Neuroprotective strategies targeting mast cells may be useful in some neonates at risk for cerebral palsy.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- mMCP:
-
murine mast cell protease
- NMDA:
-
N-methyl-d-aspartate
- P:
-
postnatal day
- TNF-α:
-
tumor necrosis factor-α
References
Pharoah P, Cooke T, Cooke RW, Rosenbloom L 1990 Birthweight specific trends in cerebral palsy. Arch Dis Child 65: 602–606
Nelson KB, Ellenberg J 1986 Antecedents of cerebral palsy: multivariate analysis of risk. N Engl J Med 315: 81–86
Evrard P, Miladi N, Bonnier C, Gressens P 1992 Normal and abnormal development of the brain. In: Rapin I, Segalowitz SJ (eds) Handbook of Neuropsychology: Child Neuropsychology. Elsevier Science, Amsterdam, pp 11–44
Evrard P, Marret S, Gressens P 1995 Environmental determinants of brain development, with a special emphasis on the excitotoxic cascade at the consecutive developmental steps. In: Rating D (ed) Aktuelle Neuropädiatrie. Ciba-Geigy Verlag, Wehr, pp 22–33
Volpe JJ 1995 Neurology of the Newborn. WB Saunders, Philadelphia, pp 279–313
Murphy DJ, Sellers S, MacKenzie IZ, Yudkin PL, Johnson AM 1995 Case-control study of antenatal and intrapartum risk factors for cerebral palsy in very preterm singleton babies. Lancet 346: 1449–1454
Zupan V, Gonzalez P, Lacaze-Masmonteil T, Boithias C, d'Allest AM, Dehan M, Gabilan JC 1996 Periventricular leukomalacia: risk factors revisited. Dev Med Child Neurol 38: 1061–1067
Nelson KB, Dambrosia JM, Grether JK, Phillips TM 1998 Neonatal cytokines and coagulation factors in children with cerebral palsy. Ann Neurol 44: 665–675
Marret S, Mukendi R, Gadisseux JF, Gressens P, Evrard P 1995 Effect of ibotenate on brain development: an excitotoxic mouse model of microgyria and posthypoxic-like lesions. J Neuropathol Exp Neurol 54: 358–370
Gressens P, Marret S, Hill JM, Brenneman DE, Gozes I, Fridkin M 1997 Vasoactive intestinal peptide prevents excitotoxic cell death in the murine developing brain. J Clin Invest 100: 390–397
Dommergues MA, Patkai J, Renauld JC, Evrard P, Gressens P 2000 Pro-inflammatory cytokines and IL-9 exacerbate excitotoxic lesions of the newborn murine neopallium. Ann Neurol 47: 54–63
Demoulin JB, Renauld JC 1998 Interleukin 9 and its receptor: an overview of structure and function. Int Rev Immunol 16: 345–364
Dropp JJ 1976 Mast cells in mammalian brain. Acta Anat 94: 1–21
Dropp JJ 1979 Mast cells in the human brain. Acta Anat 105: 505–513
Lambracht-Hall M, Dimitriadou V, Theoharides TC 1990 Migration of mast cells in the developing brain. Dev Brain Res 56: 151–159
Zhuang X, Silverman AJ, Silver R 1999 Distribution and local differentiation of mast cells in the parenchyma of the forebrain. J Comp Neurol 408: 477–488
Gill CJ, Rissman EF 1998 Mast cells in the neonate musk shrew brain: implications for neuroendocrine immune reactions. Dev Brain Res 111: 129–136
Silver R, Silverman AJ, Vitkovic L, Lederhendler I 1996 Mast cell in the brain: evidence and functional significance. Trends Neurosci 1: 25–31
Dines KC, Powell HC 1997 Mast cell interactions with the nervous system: relationship to mechanisms of disease. J Neuropathol Exp Neurol 6: 627–640
Zhuang X, Silverman AJ, Silver R 1999 Distribution and local differentiation of mast cells in the parenchyma of the forebrain. J Comp Neurol 408: 477–488
Marret S, Bonnier C, Raymaekers JM, Delpech A, Evrard P, Gressens P 1999 Systemic administration of anti-NOS and anti-glycine protects against excitotoxic lesions in the developing mouse brain. Pediatr Res 45: 337–341
Redecker C, Lutzenburg M, Gressens P, Evrard P, Witte OW, Hagemann G 1998 Patterns of excitability changes and glucose metabolism in experimentally induced cortical dysplasias. Cereb Cortex 8: 623–634
Bac P, Maurois P, Dupont C, Pages N, Stables JP, Gressens P, Evrard P, Vamecq J 1998 Magnesium-deficiency-dependent audiogenic seizures (MDDASs) in adult mice: a nutritional model for discriminatory screening of anticonvulsant drugs and original assessment of neuroprotection properties. J Neurosci 18: 4363–4373
Scudamore CL, McMillian L, Thornton EM, Wright SH, Newlands GF, Miller HR 1997 Mast cell heterogeneity in the gastrointestinal tract: variable expression of mouse mast cell protease-1 (mMCP-1) in intraepithelial mucosal mast cells in nematode-infected and normal BALB/c mice. Am J Pathol 150: 1661–1672
Wershill BK, Galli SJ 1994 The analysis of mast cell function in vivo using mast-cell deficient mice. Adv Exp Med Biol 347: 39–54
Mehler MK, Rozental R, Dougherty M, Spray DC, Kessler JA 1993 Cytokine regulation of neuronal differentiation of hippocampal progenitor cells. Nature 362: 62–65
Delvalle J, Wang L, Gantz I, Yamada T 1992 Characterisation of H2 receptor: linkage to both adenylyl cyclase and (Ca2+) signalling systems. Am J Physiol 263: G967–G972
Mitsuhashi M, Payan DG 1992 Functional diversity of histamine and histamine receptors. J Invest Dermatol 98( suppl): 8–11
Wang L, Gantz I, Delvalle J 1996 Histamine H2 receptor activates adenylate cyclase and PLC via separate GTP-dependent pathways. Am J Physiol 271: G613–G620
Purcell WM, Doyle KM, Westgate C, Atterwill CK 1996 Characterisation of a functional polyamine site on rat mast cells: association with a NMDA receptor macrocomplex. J Neuroimmunol 65: 49–53
Godfraind C, Louahed J, Faulkner H, Vink A, Warnier G, Grencis R, Renauld JC 1998 Intraepithelial infiltration by mast cells with both connective tissue-type and mucosal-type characteristics in gut, trachea, and kidneys of IL-9 transgenic mice. J Immunol 160: 3989–3996
Author information
Authors and Affiliations
Corresponding author
Additional information
Supported by the INSERM, the Fondation pour la Recherche Médicale, the Fondation Grace de Monaco, and the Société d'Etudes et de Soins pour les Enfants Paralysés et Polymalformés.
Rights and permissions
About this article
Cite this article
Patkai, J., Mesples, B., Dommergues, MA. et al. Deleterious Effects of IL-9–Activated Mast Cells and Neuroprotection by Antihistamine Drugs in the Developing Mouse Brain. Pediatr Res 50, 222–230 (2001). https://doi.org/10.1203/00006450-200108000-00010
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/00006450-200108000-00010
This article is cited by
-
In situ immune response and mechanisms of cell damage in central nervous system of fatal cases microcephaly by Zika virus
Scientific Reports (2018)
-
Neurogenic inflammation after traumatic brain injury and its potentiation of classical inflammation
Journal of Neuroinflammation (2016)
-
The role of mast cells in ischemia and reperfusion injury
Inflammation Research (2014)
-
Mast Cells as Early Responders in the Regulation of Acute Blood–Brain Barrier Changes after Cerebral Ischemia and Hemorrhage
Journal of Cerebral Blood Flow & Metabolism (2010)
-
Inflammation processes in perinatal brain damage
Journal of Neural Transmission (2010)
