Noninvasive Vagus Nerve Stimulation Prevents Ruptures and Improves Outcomes in a Model of Intracranial Aneurysm in Mice

Abstract

Background and Purpose-Inflammation is a critical determinant of aneurysmal wall destabilization, growth and rupture risk. Targeting inflammation may suppress aneurysm rupture. Vagus nerve stimulation (VNS) has been shown to suppress inflammation both systemically and in the central nervous system. Therefore, we tested the effect of a novel non-invasive transcutaneous VNS approach on aneurysm rupture and outcome in a mouse model of intracranial aneurysm formation with wall inflammation. Methods-Aneurysms were induced by a single stereotaxic injection of elastase into the cerebrospinal fluid at the skull base, combined with systemic deoxycorticosterone-salt hypertension, without or with high-salt diet, for mild or severe outcomes, respectively. Cervical VNS (two 2-minute stimulations 5 minutes apart) was delivered once a day starting the day after elastase injection for the duration of follow up. Transcutaneous stimulation of the femoral nerve (FNS) served as control. Multiple aneurysms developed in the circle of Willis and its major branches, resulting in spontaneous ruptures and subarachnoid hemorrhage, neurological deficits and mortality.

Efficacy profile of noninvasive vagus nerve stimulation on cortical spreading depression susceptibility and the tissue response

“…We herein identify an e cacious medium intensity of noninvasive VNS paradigm, in line with prior work showing e cacy in stroke, intracranial aneurysms and epilepsy [23,24]. Noninvasive VNS paradigms in clinical migraine studies vary depending on the purpose.…”

Vascular Macrophages as Therapeutic Targets to Treat Intracranial Aneurysms

“…Berberine, an alkaloid from Coptis chinensis , has been shown to inhibit macrophage activation and infiltration in ICAs by modulation of the phospho-focal adhesion kinase (pFAK)/Grp78/unfolded protein response signaling pathway and reduced the elaboration of inflammatory factors from macrophages such as MCP-1, IL-1β, IL-6, TNF-α, and MMPs ( 68 ). Intriguingly, cutaneous non-invasive vagus nerve stimulation has been shown to reduce aneurysm rupture rates and improve outcomes after aneurysm rupture, and may implicate reduced MMP-9 expression as a potential mechanism of action ( 69 ). Suppression of MMP-9 expression in macrophages and polarization of macrophages/microglia to the M2 phenotype has already been shown to stem from vagus nerve stimulation-mediated modulation of inflammatory pathways ( 69 , 70 ).…”

“…Intriguingly, cutaneous non-invasive vagus nerve stimulation has been shown to reduce aneurysm rupture rates and improve outcomes after aneurysm rupture, and may implicate reduced MMP-9 expression as a potential mechanism of action ( 69 ). Suppression of MMP-9 expression in macrophages and polarization of macrophages/microglia to the M2 phenotype has already been shown to stem from vagus nerve stimulation-mediated modulation of inflammatory pathways ( 69 , 70 ). Taken together, there are multiple strategies at the level of inflammation and macrophage modulation that have translational potential in human disease.…”

Fluoroquinolones-Associated Disability: It Is Not All in Your Head

“…One important aspect of the anti-inflammatory response mediated by the vagus nerve includes attenuating the inflammatory process associated with aneurysms. There is evidence that vagus nerve stimulation (VNS) reduces aneurysm rupture rate and improves the survival rate when compared with control femoral nerve stimulation in mice [135]. Therefore, vagus nerve dysfunction may then have the opposite effect: an increased rate of aneurysm development and rupture.…”