Felszeghy Klára, Banisadr Ghazal, Rostène William, Nyakas Csaba, Haour France
INSERM E0350, Hôpital St-Antoine, FR-75574 Paris, France.
Neuroimmunomodulation. 2004;11(6):404-13. doi: 10.1159/000080151.
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.
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.
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.
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.
缺氧/缺血（H/I）可在新生大鼠脑内引发快速且严重的脑损伤，对中枢神经系统的结构和功能成熟产生长期影响。炎症介质促成了这些永久性病理变化，而这些变化对皮质类固醇治疗敏感。由于趋化因子受体CXCR4对SDF-1α/CXCL12配体具有特异性，可调节凋亡和神经再生过程，因此在新生大鼠脑内H/I后2天，对该受体进行了定量分析，并与地塞米松（DEX）治疗相关联。
7日龄雄性大鼠在单侧颈动脉结扎后经历90分钟缺氧（H/I），并在48小时后处死。糖皮质激素预处理的动物在缺氧前5小时皮下注射0.5微克/克DEX。使用胶质纤维酸性蛋白和甲酚紫染色评估脑损伤程度，将其分为坏死区和半暗带样区域。使用[(125)I]SDF-1α作为配体，通过定量放射自显影法测定CXCR4受体的密度。
H/I导致颈动脉结扎同侧出现大量损伤，损伤扩展至皮质、纹状体、海马和丘脑区域，而对侧半球明显未受影响。DEX通过主要减少坏死区域来减小损伤大小。H/I导致半暗带样区域CXCR4受体结合显著增加。DEX预处理降低了半暗带中CXCR4受体密度，并减轻了星形细胞增生。此外，DEX显著降低了死亡率，并缩短了缺氧后功能恢复时间。
受影响脑区中CXCR4趋化因子受体结合的快速增强表明，SDF-1α/CXCR4可能在新生大鼠脑内缺氧诱导的炎症反应中发挥作用。CXCR4表达和星形细胞增生的减弱可能通过影响新生大鼠脑内H/I诱导的炎症级联反应，促成DEX预处理的神经保护作用。
