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

Abstract

Background: Saccular intracranial aneurysms (IAs) are outpouchings of the vessel wall of intracranial arteries. Rupture of IAs results in subarachnoid hemorrhage which is associated with high morbidity and mortality. Surgical interventions, such as clipping and coiling, have associated risks. Currently, there are no proven pharmacological treatments to prevent the growth or rupture of IAs. Infiltration of proinflammatory cytokines in response to increased wall sheer stress is a hallmark of IA. Nonsteroidal anti-inflammatory drugs (NSAIDs) are being investigated as potential therapeutic agents for reduction in growth and/or prevention of IA through inhibition of inflammatory pathways. Summary: This review will discuss the role of NSAIDs in attenuating the inflammation that drives IA progression and rupture. There are two main subtypes of NSAIDs, nonselective COX and selective COX-2 inhibitors, both of which have merit in treating IA. Evidence will be presented which shows that NSAIDs inhibit several key inflammatory mediators involved in IA progression including nuclear factor-κB, tumor necrosis factor-α, and matrix metalloproteinases. In addition, the role of NSAIDs in limiting inflammatory cell adhesion to endothelial cells and attenuating endothelial cell senescence will be discussed. Key Messages: There is an abundance of basic science and preclinical data that support NSAIDs as a promising treatment for IA. Additionally, a combination treatment strategy of low-dose aspirin given concomitantly with a selective COX-2 inhibitor may result in a reduced side effect profile compared to aspirin or selective COX-2 inhibitor use alone. Several large clinical trials are currently planned to further investigate the efficacy of NSAIDs as an effective nonsurgical treatment for IAs.

The effective interplay of (non-) selective NSAIDs with Neostigmine in animal models of analgesia and inflammation

“…Accordingly, in this study, the anti-inflammatory properties of neostigmine have shown a clear synergistic effect within 24 h when added to celecoxib (Neo + Cele), which then declined after 5 days of the study, an effect that is attributed to Neo rather than Cele. This outcome comes in accordance with the study of Nishyama 31 The positive feedback loop of the Cox-2-PGE 2 -EP 2 -NF-κB signaling pathway is well known to initiate and preserve inflammation (35). Activated Cox-2 increase the production of PGE 2 , that binds to the EP 2 receptor and consequently activates NF-κB; the important inducer of pro-inflammatory cytokine (35,36).…”

In the wall lies the truth: a systematic review of diagnostic markers in intracranial aneurysms

“…Here, they undergo further differentiation and synthesize the inflammatory cytokines and immunoglobulins, as well as activate the complement system. Moreover, vascular inflammation contributes to the alteration of the endothelial function, disruption of the internal elastic lamina and collagen matrix, vasa vasorum activation and proliferation (6,8). Therefore, inflammation promotes other pathophysiologic mechanisms involved in IA formation like oxidative stress, cell adhesion, intraluminal thrombosis and apoptosis, which in turn, facilitate vascular inflammation leading to a kind of vicious circle (6,8,9).…”

“…Moreover, vascular inflammation contributes to the alteration of the endothelial function, disruption of the internal elastic lamina and collagen matrix, vasa vasorum activation and proliferation (6,8). Therefore, inflammation promotes other pathophysiologic mechanisms involved in IA formation like oxidative stress, cell adhesion, intraluminal thrombosis and apoptosis, which in turn, facilitate vascular inflammation leading to a kind of vicious circle (6,8,9). In summary, these processes prompt irreversible anatomical remodeling and functional alteration of the damaged vessel, eventually resulting in IA rupture (1).…”

The effective interplay of (non-) selective NSAIDs with Neostigmine in animal models of analgesia and inflammation

“…Expanding to the previous ndings, a mouse model of Saccular Intracranial Aneurysms has shown that endothelia cells-activated NF-κB activity was suppressed with the administration of the selective Cox-2 inhibitor celecoxib (41). Moreover, the results of the Cox isoforms activity study in the present work come in accordance with a previous work from Nishiyama et al (45), where intrathecal administration of celecoxib resulted in a dose dependent inhibition of the inch response of the formalin test, but had no signi cant effect on the tail ick latency.…”

“…The positive feedback loop of the Cox-2-PGE 2 -EP 2 -NF-κB signaling pathway is well known to initiate and preserve in ammation (41). Activated Cox-2 increase the production of PGE 2 , that binds to the EP 2 receptor and consequently activates NF-κB; the important inducer of pro-in ammatory cytokine (41,42). More than twenty-ve cytokines are controlled directly by NF-κB.…”