Suppression of cerebral aneurysm formation in rats by a tumor necrosis factor–α inhibitor

Abstract

Object Although cerebral aneurysmal subarachnoid hemorrhage is a devastating disease for humans, effective medical treatments have not yet been established. Recent reports have shown that regression of some inflammatory-related mediators has protective effects in experimental cerebral aneurysm models. This study corroborated the effectiveness of tumor necrosis factor–α (TNF-α) inhibitor for experimentally induced cerebral aneurysms in rats. Methods Five-week-old male rats were prepared for induction of cerebral aneurysms and divided into 3 groups, 2 groups administered different concentrations of a TNF-α inhibitor (etanercept), and 1 control group. One month after aneurysm induction, 7-T MRI was performed. The TNF-α inhibitor groups received subcutaneous injection of 25 μg or 2.5 μg of etanercept, and the control group received subcutaneous injection of normal saline every week. The TNF-α inhibitor administrations were started at 1 month after aneurysm induction to evaluate its suppressive effects on preexisting cerebral aneurysms. Arterial circles of Willis were obtained and evaluated 3 months after aneurysm induction. Results Rats administered a TNF-α inhibitor experienced significant increases in media thickness and reductions in aneurysmal size compared with the control group. Immunohistochemical staining showed that treatment with a TNF-α inhibitor suppressed matrix metalloproteinase (MMP)–9 and inducible nitric oxide synthase (iNOS) expression through the luminal surface of the endothelial cell layer, the media and the adventitia at the site of aneurysmal formation, and the anterior cerebral artery–olfactory artery bifurcation. Quantitative polymerase chain reaction also showed suppression of MMP-9 and iNOS by TNF-α inhibitor administration. Conclusions Therapeutic administration of a TNF-α inhibitor significantly reduced the formation of aneurysms in rats. These data also suggest that TNF-α suppression reduced some inflammatory-related mediators that are in the downstream pathway of nuclear factor-κB.

Nonsteroidal Anti-Inflammatory Drugs: A Potential Pharmacological Treatment for Intracranial Aneurysm

“…In addition, TNF-α and NO released by the macrophages can also directly activate the NF-κB pathway (Fig. 3) [6, 18]. iNOS increases NO levels leading to the generation of ROS and subsequent oxidative stress in animal and human aneurysm models [6].…”

“…3) [17]. Treatment of rodents with the TNF-α inhibitor etanercept slows IA formation which is associated with reduced NF-κB activity and subsequent inhibition of iNOS and MMP expression [18]. …”

Involvement of neutrophils in machineries underlying the rupture of intracranial aneurysms

“…4b) and form the auto-amplification loop to accumulate in lesions leading to the formation of inflammatory microenvironment at the prospective site of rupture like macrophages in lesions [7,16]. Considering the crucial contribution of TNF-α or PGE 2 in the pathogenesis of IAs [7,[19][20][21], neutrophils in addition to macrophages presumably play a pivotal role in the maintenance and exacerbation of inflammatory responses facilitating the degenerative changes in lesions. The involvement of inflammatory responses in lesions in the process leading to rupture has also been supported by the observation studies that the usage of drugs with anti-inflammatory effects like statins and non-steroidal anti-inflammatory drugs reduces the risk of SAH due to rupture of IAs [22,23].…”

Molecular events regulating the pathogenesis of intracranial aneurysms: Special insight on hemodynamics and chronic inflammation

“…Infiltrating macrophages in intracranial arterial walls produce various proteinases [8], leading to the degradation of extracellular matrix and facilitating the progression of the disease. Furthermore, macrophages produce cytokines like TNF-α and make inflammation being expanding and exacerbating [10,27,28]. In this step, machineries to amplify inflammation and to become chronic function in macrophages.…”