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.…”

Glycyrrhizin Attenuates Proinflammatory Cytokines through a Peroxisome Proliferator-Activated Receptor-γ-Dependent Mechanism and Experimental Vasospasm in a Rat Model

“…In hippocampus cell cultures, Luo et al [47] suggested that PPAR-γ agonists produce an anti-inflammatory action by inhibiting the activation of the nuclear factor-κB signaling pathway and its associated expressions of inflammatory factors. The induction of these responses is mainly triggered by the activation of nuclear factor-κB and mitogen-activated protein kinase pathways, a consequence common to the stimulation of all PPARs, which has been proven to induce neuron apoptosis [17]. In this study, PPAR-γ and -δ proteins were suppressed in the SAH groups as well as PPAR-γ mRNA.…”

“…An ongoing body of research indicates that two hypotheses include the role of endothelin [6] and free nitric oxide [7], and another role of inflammation in the development and maintenance of delayed vasoconstriction [8,9,10,11,12]. Once SAH occurs, a cascade of cellular and molecular events is elicited by the presence of blood in the subarachnoid space, which will culminate in a vigorous inflammatory response [13,14,15,16,17]. Even though its role in the genesis of cerebral vasospasm has been recognized, the putative importance of inflammatory activity has not been fully emphasized.…”