Basis for Intracranial Aneurysm Formation

Fig. 1

Schema demonstrating our hypothesis for the potential mechanisms underlying the chronicity of inflammation contributing to intracranial aneurysm formation. Note the positive feedback loop consisting of PGE₂ – NF-κB signaling under hemodynamic stress and macrophage infiltration via NF-κB-mediated MCP-1 induction

Future Prospects for the Development of Therapeutic Drugs for IA

The recent experimental results indicate that NF-κB is a potential therapeutic target for IA treatment [4]. The significant suppression of IA formation and growth in animals with NF-κB deficiency or treated with a NF-κB inhibitor, decoy oligonucleotides, further supports this notion [1].

Statins (3-hydroxy-3 methylglutaryl coenzyme A reductase inhibitors) were originally developed as therapeutic drugs for lipid metabolic abnormality. In addition, statins are well recognized as having powerful anti-inflammatory and especially anti-NF-κB effects; known as the pleiotropic effect of statins. Encouraged by this pleiotropic effect of statins, we administered Pitavastatin, one of the statins, to our rat model of IA and demonstrated that Pitavastatin treatment effectively prevented the growth of IAs in rats [3]. Pitavastatin treatment remarkably suppressed the inflammatory responses in IA walls, characterized by NF-κB activation and subsequent induction of the expression of NF-κB-regulating genes, such as MCP-1, VCAM-1, and IL-1β [3]. Furthermore, Pitavastatin treatment effectively inhibited the degenerative change of IA walls, suggesting a preventive effect of Pitavastatin against the rupture of IAs [3]. Other kinds of statins, Simvastatin and Pravastatin, also successfully prevented IA growth through inhibition of inflammation in IA walls, suggesting that statins are potential therapeutic drugs for IAs [2, 9].

Because of these findings from experimental animals, we examined the preventive effect of statins for the rupture of human IAs in a case-controlled clinical study in Japan. As a result, we clarified the inverse relationship between the usage of statins and the occurrence of aneurysmal subarachnoid hemorrhage in the Japanese population. Statins were administered in 9.4 % of cases with ruptured IAs and 26.0 % of cases with unruptured IAs. The usage of statins, therefore, significantly prevented the rupture of preexisting IAs with a relative odds ratio of 0.3 [12].

These studies suggest the potential of statins as therapeutic drugs to prevent the growth and rupture of IAs.

Conclusion

Recent experimental studies using an animal model of IA have revealed the crucial role of long-lasting inflammation in its pathogenesis. In this process, prostaglandin-mediated NF-κB activation plays the role to trigger and amplify the inflammatory responses in IA lesion suggesting the potential of NF-κB as a therapeutic target for IA treatment. Indeed, recent case-control study has demonstrated the suppressive effect of statins on rupture of IAs in human cases through their potent anti-NF-κB effect. In near future, a medical treatment of IA is supposed to be established.

Acknowledgment

The authors are grateful to all of the researchers, collaborators, technical assistants, and secretaries contributing to our studies cited in the present manuscript. We also express our sincere gratitude to the grants supporting our research.

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