Concomitant aneurysm detection in an intracranial dolichoectasia mouse model using a MicroFil polymer perfusion technique

Zhang, Donghui; Dai, Da Ying; Xing, H; Ding, Yong Hong; Kadirvel, Ramanathan; Kallmes, David F.

doi:10.1136/neurintsurg-2016-012469

Cited by 2 publications

(7 citation statements)

References 11 publications

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“…The difference of mouse model from rabbit model may be the technique of basal cistern elastase injection, in that only surgical cut-downs and ligations of the rabbit common carotid arteries lead to acute blood flow augmentation, cerebral artery dilatation, and vascular wall remodeling [48][49][50]. The IEL fragmentation and thinning of medial SMC layer are common in patients with dolichoectasia [33][34][35], which are consistent features of mouse IADE [30][31][32].…”

Section: Discussionmentioning

confidence: 87%

“…The arterial walls are composed of SMC, elastin, and collagen to maintain integrity, elasticity, and mechanical strength. The matrix metalloproteinase such as MMP-9 released by activated macrophage digests elastin, leading to SMC apoptosis, and impair the mechanical strength and subsequent dolichoectasia formation [30][31][32]51]. In this experimentally induced mouse model, elastase injection and hypertension induction lead to pathological breakdown of IEL and SMC layer, and remodeling by deposition of collagen fibers.…”

Section: Discussionmentioning

confidence: 99%

“…The BBB penetration of MeLioN needs to be further investigated in the next study. Third, we injected elastase into the right basal cistern, but Dai et al [30][31][32] delivered elastase through cisterna magna considering the more frequent occurrence of IADE in the posterior circulation and the basilar artery. We need to further compare the potentially distinctive IADE model features depending on the various elastase administration methods.…”

Section: Discussionmentioning

confidence: 99%

“…MMP is the family of proteolytic enzymes that degrade type IV collagen and elastin and mediate the vascular remodeling 52 . The macrophages and inflammatory cells secrete MMP-9 leading to ECM degradation and dolichoectasia 31 , 51 , 53 - 58 . The immunohistochemistry in this study showed highly expressed MMP-9 in the arterial wall of mouse IADE, which was consistent with findings of RT-PCR.…”

Section: Discussionmentioning

confidence: 99%

“…Creating a proper animal model would shift the treatment paradigm by facilitating a better understanding of the mechanism and clinical translation of promising therapeutic agents. Dai et al introduced the IADE model induced by elastase exposure similar to the abdominal aortic aneurysm (AAA) model [30][31][32]. We describe the modified technique of creating and assessing cerebral arterial wall change induced by a single elastase injection into the basal cistern and induced hypertension.…”

Section: Introductionmentioning

confidence: 99%

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Melittin-loaded Iron Oxide Nanoparticles Prevent Intracranial Arterial Dolichoectasia Development through Inhibition of Macrophage-mediated Inflammation

Vu¹,

Huynh²,

Ryu³

et al. 2021

Int. J. Biol. Sci.

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Rationale: In intracranial arterial dolichoectasia (IADE) development, the feedback loop between inflammatory cytokines and macrophages involves TNF-α and NF-κB signaling pathways and leads to subsequent MMP-9 activation and extracellular matrix (ECM) degeneration. In this proof-of-concept study, melittin-loaded L-arginine-coated iron oxide nanoparticle (MeLioN) was proposed as the protective measure of IADE formation for this macrophage-mediated inflammation and ECM degeneration. Methods: IADE was created in 8-week-old C57BL/6J male mice by inducing hypertension and elastase injection into a basal cistern. Melittin was loaded on the surface of ION as a core-shell structure (hydrodynamic size, 202.4 nm; polydispersity index, 0.158). Treatment of MeLioN (2.5 mg/kg, five doses) started after the IADE induction, and the brain was harvested in the third week. In the healthy control, disease control, and MeLioN-treated group, the morphologic changes of the cerebral arterial wall were measured by diameter, thickness, and ECM composition. The expression level of MMP-9, CD68, MCP-1, TNF-α, and NF-κB was assessed from immunohistochemistry, polymerase chain reaction, and Western blot assay. Results: MeLioN prevented morphologic changes of cerebral arterial wall related to IADE formation by restoring ECM alterations and suppressing MMP-9 expression. MeLioN inhibited MCP-1 expression and reduced CD68-positive macrophage recruitments into cerebral arterial walls. MeLioN blocked TNF-α activation and NF-κB signaling pathway. In the Sylvian cistern, co-localization was found between the CD68-positive macrophage infiltrations and the MeLioN distributions detected on Prussian Blue and T2* gradient-echo MRI, suggesting the role of macrophage harboring MeLioN. Conclusions:The macrophage infiltration into the arterial wall plays a critical role in the MMP-9 secretion. MeLioN, designed for ION-mediated melittin delivery, effectively prevents IADE formation by suppressing macrophage-mediated inflammations and MMP activity. MeLioN can be a promising strategy preventing IADE development in high-risk populations.

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