Potential Contribution of Nuclear Factor-κB to Cerebral Vasospasm after Experimental Subarachnoid Hemorrhage in Rabbits

Abstract

Nuclear factor-jB (NF-jB) plays a key role in inflammation, which is involved in the development of cerebral vasospasm after subarachnoid hemorrhage (SAH). In the present study, we assessed the potential role of NF-jB in regulation of cerebral vasospasm. Nuclear factor-jB DNA-binding activity was measured in cultured vascular smooth muscle cells (VSMCs) treated with hemolysate and pyrrolidine dithiocarbamate (PDTC, 80 lmol/L), an inhibitor of NF-jB. Forty-two rabbits were divided into three groups: control, SAH, and PDTC groups (n = 14 for each group). The caliber of the basilar artery was evaluated. Nuclear factor-jB DNA-binding activity and the gene expression levels of cytokines and adhesion molecules in the basilar artery were measured. Immunohistochemical study was performed to assess the expression and localization of tumor necrosis factor (TNF)-a, intercellular adhesion molecule (ICAM)-1, and myeloperoxidase (MPO). It was observed that NF-jB DNA-binding activity was significantly increased by treatment with hemolysate in cultured VSCMs, but this increase was suppressed by pretreatment with PDTC. Severe vasospasm was observed in the SAH group, which was attenuated in the PDTC group. Subarachnoid hemorrhage could induce increases of NF-jB DNA-binding activity and the gene expression levels of TNF-a, interleukin (IL)-1b, ICAM-1, and vascular cell adhesion molecule (VCAM)-1, which were reduced in the PDTC group. Immunohistochemical study demonstrated that the expression levels of TNF-a, ICAM-1, and MPO were all increased in the SAH group, but these increases were attenuated in the PDTC group. Our results suggest that NF-jB is activated in the arterial wall after SAH, which potentially leads to vasospasm development through induction of inflammatory response.

Neuroprotective Efficacy from a Lipophilic Redox-Modulating Mn(III) N-Hexylpyridylporphyrin, MnTnHex-2-PyP: Rodent Models of Ischemic Stroke and Subarachnoid Hemorrhage

“…Mechanisms of efficacy of MnTnHex-2-PyP in SAH will be the subject of further investigation. Evidence from the MCAO model reported above suggests that MnTnHex-2-PyP effects on NF-B activation and inflammatory gene expression may be involved in this mechanism of vasospasm progression (Zhou et al, 2007), but this remains to be tested. It is noteworthy that although not performed concurrently but examined in an identical SAH model, the effect size of MnTnHex-2-PyP exceeded that of simvastatin when treatment was begun postictus (e.g., after SAH MCA diameter increased by 24% with simvastatin versus 48% with MnTnHex-2-PyP) .…”

Cytosolic Ca2+Oscillations in Human Cerebrovascular Endothelial Cells after Subarachnoid Hemorrhage

“…The perivascular-activated monocytes after SAH have been reported as one major source of ET-1 that can cause delayed CVS (Fassbender et al, 2000). There may be a possible link of CVS to SAH-induced Ca 2 + oscillations through inflammation, because inactivation of NF-kB by pyrolidine dithiocarbamate or antisense oligonucleotids attenuates vasospasm in animal models of SAH (Ono et al, 1998;Zhou et al, 2007). In analogy to the reduction of Ca 2 + oscillation frequency and NF-kB activation, xestospongin, and thapsigargin reduced the expression of VCAM-1.…”

“…This may result in the transmigration of T-cells and monocytes into the vessel wall (De Martin et al, 2000). In addition, both NF-kB and VCAM-1 have been shown to be involved in the pathogenesis of CVS after SAH (Kaynar et al, 2004;Polin et al, 1998;Zhou et al, 2007). The intracellular Ca 2 + concentration regulates the function of the endothelial barrier between blood and the surrounding tissue.…”

Hemolysate-induced Expression of Intercellular Adhesion Molecule-1 and Monocyte Chemoattractant Protein-1 Expression in Cultured Brain Microvascular Endothelial Cells via Through ROS-dependent NF-κB Pathways

“…Our previous studies demonstrated that hemolysate is associated with an increase in NF-jB-binding activity in vascular smooth muscle cells (Zhou et al 2007). In order to examine the involvement of NF-jB in ICAM-1 and MCP-1 expression, BMECs were treated with hemolysate, and the translocation of NF-jB was measured by Western blot.…”