Abstract
It has been reported that inflammation is involved in brain injury after subarachnoid hemorrhage (SAH). Nuclear factor-κB (NF-κB) is a key transcriptional regulator of inflammatory genes. Here, we used pyrrolidine dithiocarbamate(PDTC), an inhibitor of NF-κB, through intracisternal injection to study the role of NF-κB in delayed brain injury after SAH. A total of 55 rabbits were randomly divided into five groups: the control group; the SAH groups including Day-3, 5, and 7 SAH groups (the rabbits in these groups were sacrificed at 3, 5, 7 days after SAH, respectively); and the PDTC group (n = 11 for each group). Electrophoretic mobility shift assay (EMSA) was performed to detect NF-κB DNA-binding activity. The mRNA levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and intercellular adhesion molecule (ICAM)-1 were evaluated by RT-PCR analysis. Deoxyribonucleic acid fragmentation was detected by TUNEL and p65 immunoactivity was assessed by immunohistochemistry. Our results showed the activation of NF-κB after SAH, especially at day 3 and 5. The activated p65 was detected in neurons. NF-κB DNA-binding activity was suppressed by intracisternal administration of PDTC. Increased levels of the TNF-α, IL-1β, and ICAM-1 mRNA were found in the brain at day 5 after SAH, and which were suppressed in the PDTC group. The number of TUNEL-positive cells also decreased significantly in the PDTC group compared with that in the Day-5 SAH group. These results demonstrated that the activated NF-κB in neurons after SAH plays an important role in regulating the expressions of inflammatory genes in the brain, and ultimately contributes to delayed brain injury.
Highlights
In most developed countries, stroke is the third leading cause of death, 20% of which are due to aneurysmal subarachnoid hemorrhage (SAH)[1]
Localization of activated Nuclear factor-kB (NF-kB) We examined the localization of activated NF-kB in the brain by immunohistochemical staining
It was shown that NF-kB p65 immunoactivity was mainly presented in neurons, especially in the nucleus, which implied that NF-kB was activated after SAH (Fig.2)
Summary
Stroke is the third leading cause of death, 20% of which are due to aneurysmal subarachnoid hemorrhage (SAH)[1]. A previous study demonstrated that SAH could trigger an inflammatory reaction in the brain, which might contribute to cell death[2]. Increasing evidence indicates that inflammatory cytokines and adhesion molecules, such as tumor necrosis factor (TNF)-a, interleukin (IL)-1, IL-6, IL-8, IL-10, intercellular adhesion molecule (ICAM)-1, and vascular cell adhesion molecule (VCAM)-1, are increased in the cerebrospinal fluid (CSF) after SAH[3]. These increased cytokines and adhesion molecules in CSF are correlated with neurological injury, so it is likely that they contribute to brain injury after SAH[4,5]
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