Inflammation is a major contributor to the pathogenesis of cerebral ischemia and stroke. In the peripheral immune response, caspase-1 activation involves the formation of a macromolecular complex termed the inflammasome. We determined whether nucleotide-binding, leucine-rich repeat, pyrin domain containing 1 (NLRP1), molecular platform consisting of capase-1, apoptosisassociated speck-like protein containing a caspase-activating recruitment domain (ASC), and NLRP1, is expressed in the normal and postischemic brain. Mice underwent thromboembolic stroke to investigate the formation of the inflammasome and subsequent activation of downstream inflammatory responses. Western blot analysis showed expression and activation of interleukin (IL) IL-1b and IL-18 at 24 h after stroke. Size-exclusion chromatography and coimmunoprecipitation analysis showed protein association between NLRP1, ASC, caspase-1, and the X-linked inhibitor of apoptosis protein (XIAP). After ischemia, immunohistochemical analysis revealed inflammasome proteins in neurons, astrocytes, and microglia/macrophages. The potential of the inflammasome as an antiinflammatory target was showed by interference of inflammasome activation resulting in reduced cytokine levels in mice treated after ischemia with a neutralizing antibody against NLRP1. These findings show that the inflammasome complex forms after focal brain ischemia and may be a novel therapeutic target for reducing the detrimental consequences of postischemic inflammation.
Our preliminary experience with the use of PED for the treatment of intradural VA dissecting aneurysms shows promising short-term results, making this technique a feasible and safe treatment option in patients suitable for this approach. However, long-term and larger cohort studies are needed to validate these results.
Many stroke research groups utilize the model of middle cerebral artery occlusion induced by insertion of an intraluminal thread, owing to its pragmatism and reliability of cerebral infarct generation. However, 75% of stroke cases result from a thromboembolic event and 10% from occlusive atherothrombosis in situ. Here, we characterize a mouse model of repeated thromboembolic stroke, which closely mimics the intravascular pathophysiology of arterial thrombus generation from an atherosclerotic plaque, and subsequent release of a thrombus into the cerebral circulation as an embolus. Common carotid artery thrombosis (CCAT) was induced photochemically leading to non-occlusive platelet aggregation in C57/BL6 male mice (n=35), and was followed by mechanical assistance to facilitate release of the thrombus (MRT) and thus promote embolism. Six experimental groups, differing by changes in the surgical protocol, were used for the purpose of determining which such procedure yielded the most reliable and consistent brain infarct volumes with the lowest mortality at 3 days after surgery. The group which best satisfied these conditions was a double insult group which consisted of animals that underwent CCAT for 2 min by means of argon laser irradiation (514.5 nm) at an intensity of ca. 130 W/cm(2), with concomitant injection of erythrosin B (EB) (35 mg/kg infused over those same 2 min), followed by MRT 1 min later; the entire procedure was repeated 24h later. This group showed a percent of brain lesion volume of 15+/-4% (mean+/-S.D.) with no associated 3-day mortality. Compared to a single insult group which sustained a percent brain lesion volume of 7+/-3%, there was a statistically significant (p<0.05) increase in the volume of infarction in the double-insult group.
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