Treatment with dimethyl fumarate reduces the formation and rupture of intracranial aneurysms: Role of Nrf2 activation

Abstract

Oxidative stress and chronic inflammation in arterial walls have been implicated in intracranial aneurysm (IA) formation and rupture. Dimethyl fumarate (DMF) exhibits immunomodulatory properties, partly via activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway which reduces oxidative stress by inducing the antioxidant response element (ARE). This study evaluated the effects of DMF both in vitro, using tumor necrosis factor (TNF)-α-treated vascular smooth muscle cells (VSMC), and in vivo, using a murine elastase model to induce aneurysm formation. The mice were treated with either DMF at 100 mg/kg/day P.O. or vehicle for two weeks. DMF treatment protected VSMCs from TNF-α-induced inflammation as demonstrated by its downregulation of cytokines and upregulation of Nrf2 and smooth muscle cell markers. At higher doses, DMF also inhibited the pro-proliferative action of TNF-α by increasing apoptosis which protected the cells from aponecrosis. In mice, DMF treatment significantly decreased the incidence of aneurysm formation and rupture, at the same time increasing Nrf2 levels. DMF demonstrated a neuroprotective effect in mice with a resultant inhibition of oxidative stress, inflammation, and fibrosis in the cerebrovasculature. This suggests a potential role for DMF as a rescue therapy for patients at risk for formation and rupture of IAs.

Intermittent Hypoxia Promotes Functional Neuroprotection from Retinal Ischemia in Untreated First-Generation Offspring: Proteomic Mechanistic Insights

“…TMT data acquisition utilized an MS3 approach for data collection, as previously described. 28 Survey scans (MS1) were performed in the Orbitrap utilizing a resolution of 120,000. Data-dependent MS2 scans were performed in the linear ion trap using a collision-induced dissociation of 25%.…”

Acyl‐CoA synthetase long chain family member 4 plays detrimental role in early brain injury after subarachnoid hemorrhage in rats by inducing ferroptosis

“…1,2 SAH is most commonly caused by ruptured intracranial aneurysms. 3 Current treatments of intracranial aneurysms include endovascular coiling and neurosurgical clipping.…”

Comparative bioinformatics analysis between proteomes of rabbit aneurysm model and human intracranial aneurysm with label‐free quantitative proteomics

“…It is believed that the wall shear stress is related to the formation of IA 21 ; it can cause the damage of intracranial arteries. Oxidative stress increased after the injury of intracranial arteries, 22 which cause a series of inflammatory reactions and further aggravate the pathological changes of intracranial artery walls. The pathological changes in IA are mostly characterized by ECM degeneration, internal elastic lamina and media disruption, 23 and impairment of vascular SMCs 24‐27 .…”