Blood-brain barrier disruption induced by hemoglobin in vivo: Involvement of up-regulation of nitric oxide synthase and peroxynitrite formation.

Accumulating evidence has demonstrated that up-regulation of nitric oxide synthase (NOS) and subsequent peroxynitrite (ONOO(-)) formation exert a devastating effect on the damage of BBB in multiple diseases. However, considerably less attention has been focused on the role of NOS/ONOO(-) in BBB disruption after intracerebral hemorrhage (ICH). Using an experimental stroke model by injecting hemoglobin (Hb) into the caudate nucleus of male Sprague Dawley rats, we explored the role of NOS/ONOO(-) in BBB disruption after ICH. Brain edema content, behavioral changes, alterations of TJ proteins (claudin-5 and ZO-1), expression of neuronal NOS (nNOS), inducible NOS (iNOS) and endothelial NOS (eNOS), formation of 3-nitrotyrosine (3-NT), as well as NO production were investigated. Hb in the rat brain led to a significant brain edema production and neurological deficits. Overexpressed NOS was concomitant with large quantities of 3-NT formation. Moreover, sites of enhanced nNOS, iNOS, eNOS and 3-NT immunoreactivity were colocalized with diminished or discontinuous ZO-1 and/or claudin-5 staining as evidenced by Western blot and immunofluorescence, indicating the involvement of NOS and ONOO(-) in the BBB disruption. Meaningfully, levels of 3-NT in serum, which had a similar tendency with that of in brain tissues (r=0.934, P<0.001), had a marked correlation with brain edema content (r=0.782, P<0.001) and neurological deficits (r=0.851, P<0.001). We concluded that ONOO(-) formation by the upregulation of NOS may play a central role in promoting the BBB damage following ICH. Moreover, ONOO(-) may be a promising biomarker for the judgment or prediction of brain injury and clinical prognosis after ICH.

Ding R ，Chen Y ，Yang S ，Deng X ，Fu Z ，Feng L ，Cai Y ，Du M ，Zhou Y ，Tang Y ... -  《-》

The inhibitory effect of mesenchymal stem cell on blood-brain barrier disruption following intracerebral hemorrhage in rats: contribution of TSG-6.

Chen M ，Li X ，Zhang X ，He X ，Lai L ，Liu Y ，Zhu G ，Li W ，Li H ，Fang Q ，Wang Z ，Duan C ... -  《Journal of Neuroinflammation》

Peroxynitrite decomposition catalyst prevents matrix metalloproteinase-9 activation and neurovascular injury after hemoglobin injection into the caudate nucleus of rats.

Hemoglobin (Hb) is a major constituent of blood and a potent mediator of oxidative or nitrative stress after intracerebral hemorrhage (ICH). Our previous study demonstrated that Hb could induce abundant peroxynitrite (ONOO(-)) formation in vivo, which may be involved in the blood-brain barrier (BBB) disruption, however, the drug intervention is absent and also the underlying mechanism. Using an experimental stroke model by injecting Hb into the caudate nucleus of male Sprague-Dawley rats, we assessed the role of ONOO(-) decomposition catalyst, 5,10,15,20-tetrakis (4-sulfonatophenyl) porphyrinato iron(III) [FeTPPS] in the activation of MMP-9 and Hb-induced neurovascular injuries. 3-Nitrotyrosine (3-NT, as an index of ONOO(-) formation) and NF-κB expression was measured by western blot (WB) and immunohistochemistry (IHC)/immunofluorescence (IF). Activity of MMP was evaluated by in situ zymography. Neurovascular injury was assessed using zonula occludens-1 (ZO-1) by WB and IF, fibronectin (FN) and neuron-specific nuclear protein (NeuN) IHC. Perihematomal cell death was determined by TUNEL assay. Behavioral outcome was measured by modified neurological severity score (mNSS) test. At the injured striata, profuse 3-NT was produced and mainly expressed in neutrophils and microglia/macrophages. 3-NT formation significantly colocalized with nuclear factor-κB (NF-κB) expression. In situ zymography showed that gelatinase activity was mostly co-localized with neurons and blood vessel walls and partly with neutrophils and microglia/macrophages. Enhanced 3-NT production, NF-κB induction and MMP-9 activation were obviously reduced after FeTPPS treatment. Hb-induced injury to tight junction protein (ZO-1), basal lamina of FN-immunopositive microvasculature and neural cells was evidently ameliorated by FeTPPS. In addition, apoptotic cell numbers as well as behavioral deficits were also improved. The present study shows that the administration of the ONOO(-) decomposition catalyst FeTPPS protects against Hb-induced neurovascular injuries and improves neurological function, which possibly in part by suppressing MMP-9 activation.

Ding R ，Feng L ，He L ，Chen Y ，Wen P ，Fu Z ，Lin C ，Yang S ，Deng X ，Zeng J ，Sun G ... -  《-》

Hemoglobin-induced nitric oxide synthase overexpression and nitric oxide production contribute to blood-brain barrier disruption in the rat.

Yang S ，Chen Y ，Deng X ，Jiang W ，Li B ，Fu Z ，Du M ，Ding R ... -  《-》

Tempol alleviates intracerebral hemorrhage-induced brain injury possibly by attenuating nitrative stress.

Wanyong Y ，Zefeng T ，Xiufeng X ，Dawei D ，Xiaoyan L ，Ying Z ，Yaogao F ... -  《-》