Dexamethasone downregulates chemokine receptor CXCR4 and exerts neuroprotection against hypoxia/ischemia-induced brain injury in neonatal rats

K. Felszeghy, Ghazal Banisadr, William Rostène, C. Nyakas, France Haour

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Objective: Hypoxia/ischemia (H/I) induces rapid and massive brain damage in neonatal rat brain, resulting in long-term consequences on structural and functional maturation of the central nervous system. Inflammatory mediators contribute to these permanent pathological changes, which are sensitive to corticoid treatments. Since the chemokine receptor CXCR4, specific for the SDF-1α/CXCL12 ligand, regulates both apoptotic and neuroregeneration processes, this receptor was quantified 2 days following H/I in neonatal rat brain in relation with dexamethasone (DEX) treatment. Methods: Seven-day-old male rats were exposed to a 90-min hypoxia following unilateral carotid ligation (H/I) and were sacrificed 48 h later. Glucocorticoid-pretreated animals were injected subcutaneously 5 h prior to hypoxia with 0.5 μg/g DEX. Glial fibrillary acidic protein and cresyl violet staining were used for assessing the extent of brain lesion subdivided into necrotic and penumbra-like areas. The density of CXCR4 receptors was determined by quantitative autoradiography using [125I]SDF-1α as a ligand. Results: The H/I resulted in a massive lesion ipsilateral to the carotid ligation, which was extended to cortical, striatal, hippocampal and thalamic areas, while the contralateral hemisphere remained apparently unaffected. DEX decreased the lesion size by reducing mainly the necrotic area. H/I induced a marked increase in CXCR4 receptor binding in the penumbra-like areas. DEX pretreatment decreased CXCR4 receptor density in the penumbra and attenuated astrocytosis. Furthermore, DEX strongly lowered mortality rate and reduced functional recovery time right after hypoxia. Conclusion: The rapid enhancement in CXCR4 chemokine receptor binding in the affected brain areas suggests that SDF-1α/CXCR4 may play a role in the hypoxia-induced inflammatory reaction in the neonatal brain. Attenuation of CXCR4 expression and astrogliosis could contribute to the neuroprotective effect of DEX pretreatment via influencing the inflammatory cascade induced by H/I in the neonatal brain.

Original languageEnglish
Pages (from-to)404-413
Number of pages10
JournalNeuroImmunoModulation
Volume11
Issue number6
DOIs
Publication statusPublished - 2004

Fingerprint

Chemokine Receptors
Brain Injuries
Dexamethasone
Down-Regulation
Ischemia
CXCR4 Receptors
Brain
Ligation
Neuroprotection
Hypoxia
Ligands
Corpus Striatum
Gliosis
Glial Fibrillary Acidic Protein
Neuroprotective Agents
Autoradiography
Glucocorticoids
Adrenal Cortex Hormones
Central Nervous System
Staining and Labeling

Keywords

  • Astrocytosis
  • Chemokines
  • CXCR4
  • Dexamethasone
  • Neonatal hypoxic/ischemic brain damage

ASJC Scopus subject areas

  • Endocrinology
  • Neuroscience(all)
  • Immunology

Cite this

Dexamethasone downregulates chemokine receptor CXCR4 and exerts neuroprotection against hypoxia/ischemia-induced brain injury in neonatal rats. / Felszeghy, K.; Banisadr, Ghazal; Rostène, William; Nyakas, C.; Haour, France.

In: NeuroImmunoModulation, Vol. 11, No. 6, 2004, p. 404-413.

Research output: Contribution to journalArticle

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AB - Objective: Hypoxia/ischemia (H/I) induces rapid and massive brain damage in neonatal rat brain, resulting in long-term consequences on structural and functional maturation of the central nervous system. Inflammatory mediators contribute to these permanent pathological changes, which are sensitive to corticoid treatments. Since the chemokine receptor CXCR4, specific for the SDF-1α/CXCL12 ligand, regulates both apoptotic and neuroregeneration processes, this receptor was quantified 2 days following H/I in neonatal rat brain in relation with dexamethasone (DEX) treatment. Methods: Seven-day-old male rats were exposed to a 90-min hypoxia following unilateral carotid ligation (H/I) and were sacrificed 48 h later. Glucocorticoid-pretreated animals were injected subcutaneously 5 h prior to hypoxia with 0.5 μg/g DEX. Glial fibrillary acidic protein and cresyl violet staining were used for assessing the extent of brain lesion subdivided into necrotic and penumbra-like areas. The density of CXCR4 receptors was determined by quantitative autoradiography using [125I]SDF-1α as a ligand. Results: The H/I resulted in a massive lesion ipsilateral to the carotid ligation, which was extended to cortical, striatal, hippocampal and thalamic areas, while the contralateral hemisphere remained apparently unaffected. DEX decreased the lesion size by reducing mainly the necrotic area. H/I induced a marked increase in CXCR4 receptor binding in the penumbra-like areas. DEX pretreatment decreased CXCR4 receptor density in the penumbra and attenuated astrocytosis. Furthermore, DEX strongly lowered mortality rate and reduced functional recovery time right after hypoxia. Conclusion: The rapid enhancement in CXCR4 chemokine receptor binding in the affected brain areas suggests that SDF-1α/CXCR4 may play a role in the hypoxia-induced inflammatory reaction in the neonatal brain. Attenuation of CXCR4 expression and astrogliosis could contribute to the neuroprotective effect of DEX pretreatment via influencing the inflammatory cascade induced by H/I in the neonatal brain.

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