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cells (primarily neutrophil granulocytes), may potentially Silva et al. [60] explored the therapeutic effect of Ang
be used as a tissue-specific biomarker of inflammation 1-7 in aneurysm-induced mice and found that Ang 1-7
and cerebral aneurysm instability. [55] Previously, Deleo decreased the frequency of morality and IA rupture.
et al. [56] developed a method to access MPO enzymatic The authors believe that Ang 1-7 acts through a Mas
activity as an inflammatory biomarker in a rabbit receptor-dependent pathway as Ang 1-7 administration
model of IA. The group used clinical field strength did not decrease the frequency of aneurysm rupture
MRI and an MPO specific paramagnetic substrate, in Mas KO mice. To investigate the applicability of
[60]
di-5-hydroxytryptamide of gadopentetate dimeglumine, Ang 1-7 as a therapeutic option, immunostaining was
as an MR contrast agent. Following endovascular performed on human cerebral aneurysms to confirm Mas
injection of Escherichia coli lipopolysaccharide, which receptor presence. Immunostaining for Mas receptors
resulted in inflammatory cell infiltration into the was found to be positive in unruptured and ruptured
aneurysm wall and increased active MPO expression, aneurysms. The expression of Mas receptors was also
the investigators found the MR enhancement ratios identified in the intima and media layers of control human
[60]
were consistent with the inflammatory changes. [56] cerebral arteries. These data suggest Angiotensin 1-7
Ultimately, these studies suggest enzymatically specific mediated targeting of the Mas receptor pathway may be
MR imaging may help identify aneurysms with a an efficacious noninvasive treatment modality.
significant rupture propensity.
Aoki et al. [27] found that in aneurysm-induced rats,
These studies further highlight inflammation’s role in the activation of NF-κB in the arterial wall of earlier
the progression and rupture of cerebral aneurysms. stages of aneurysmal development corresponded with
In vivo targeted molecular imaging may ultimately the expression of the downstream pro-inflammatory
provide the needed noninvasive metric required for genes, vascular cell adhesion molecule-1 (VCAM-1)
optimal management of IA. Given the strong association and MCP-1. The group explored the inhibitory
of inflammation and macrophage infiltration with IA effects of NF-κB through the use of a synthesized
rupture, IA experts have agreed on the importance of decoy oligodeoxynucleotide (ODN) in a rat model.
these findings and suggested that larger scale studies Investigators found that the facilitation of ODN 1-week
are needed. [53] following aneurysmal induction inhibited VCAM-1
and MCP-1 expression and overall, reduced aneurysm
THERAPEUTICS TARGETING INFLAMMATION size and IEL disruption. [27] In a follow-up study, the
authors used chimeric decoy ODNs against both NF-κB
Studies focused on developing noninvasive IA and proinflammatory transcription factor Ets-1. [61] Aoki
therapeutics reaffirm inflammation’s pathophysiological et al. found that chimeric decoy ODNs reduced IA size
[61]
role in IA formation and progression. Hasan et al. [57] and thickened the walls of existing IAs in a rat model.
investigated the anti-inflammatory effect of acetylsalicylic Rats treated with chimeric decoy ODNs also showed
acid (aspirin) on the progression of aneurysm to rupture. a reduction in MCP-1 expression and macrophage
A secondary analysis of the ISUIA study revealed that the infiltration into the aneurysm wall. If nuclease resistant
aspirin decreased patients’ risk of aneurysm rupture by ODNs can be administered transorally or transvenously,
60%. Furthermore, the group found ruptured aneurysms these findings suggest that NF-κB and Ets-1 are both
had higher levels of cyclooxygenase-2 (COX-2) and potential therapeutic targets in human IAs. [61]
microsomal prostaglandin E2 synthase 1 (mPGES-1)
expression. An exploration of acetylsalicylic acid’s Additionally, Aoki et al. [19] tested the effects of tolylsam,
[58]
effect on inflammatory mediators through ferumoxytol a selective inhibitor of the gelatinases MMP-2, MMP-9,
enhanced MRI and immunostaining found aspirin-treated and MMP-12, in a rat model. Facilitation of tolylsam
patients to have both decreased macrophage did inhibit aneurysm progression, as the rate of
infiltration and COX-2 and mPGES-1 expression. [52] advanced aneurysms in the tolylsam group was lower;
These pro-inflammatory enzymes were found to be however, the incidence of aneurysm development in
overexpressed in ruptured IA tissue. Taken together, these the tolylsam group and control group was not different.
findings suggest that low doses of aspirin (81 mg daily The authors concluded that the tolylsam may delay
for 3 months) may effectively attenuate inflammation in aneurysm progression rather than formation. [19]
IA, preventing acute SAH. [57]
Granulocytes were found to be present in the cerebral
Angiotensin 1-7 has also been explored as a potential aneurysm wall. [17] Specifically, Ishibashi et al. [17]
therapeutic option as Ang 1-7 is an antagonist to Ang 2. reaffirmed mast cells’ role in aneurysm pathogenesis
Ang 2 has been shown to increase the expression of by administering in a rat model the mast cell inhibitor,
various pro-inflammatory cytokines as well as promote tranilast (N-(3,4-dimethoxycinnamoyl) anthranilic acid;
blood vessel extracellular matrix remodeling. [59] Peña Kissei Pharmaceutical, Nagano, Japan) and emedastine

82 Neuroimmunol Neuroinflammation | Volume 2 | Issue 2 | April 15, 2015