Dexamethasone downregulates chemokine receptor CXCR4 and exerts neuroprotection against hypoxia/ischemia-induced brain injury in neonatal rats.
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-1 alpha/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 microg/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 [(125)I]SDF-1 alpha 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.


CONCLUSIONS
The rapid enhancement in CXCR4 chemokine receptor binding in the affected brain areas suggests that SDF-1 alpha/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.
INSERM E0350, Hôpital St-Antoine, FR-75574 Paris, France.
Klára
K
Felszeghy
Ghazal
G
Banisadr
William
W
Rostène
Csaba
C
Nyakas
France
F
Haour
D000818:Animals; D000831:Animals, Newborn; D001667:Binding, Competitive / Q000187:drug effects / Q000276:immunology; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D020520:Brain Infarction / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D020212:Carotid Artery Injuries / Q000473:pathology / Q000503:physiopathology; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000276:immunology; D003907:Dexamethasone / Q000494:pharmacology*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000473:pathology / Q000503:physiopathology; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D008026:Ligation; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects / Q000276:immunology; D015996:Survival Rate
D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C486264:Cxcr4 protein, rat; D005904:Glial Fibrillary Acidic Protein; D018696:Neuroprotective Agents; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D003907:Dexamethasone