Abstract
Stroke is the leading cause of death and disability in humans. Strokes are classified as either ischemic or hemorrhagic. Ischemic stroke accounts for 70–80% of the cases. Inflammation is a key factor in ischemic brain injury. Studies have shown that inflammatory response induced by NLRP3 inflammasome is one of the root causes of brain damage in mice with cerebral ischemia. However, its specific mechanism in cerebral ischemia is still unclear. ADAM8 (a disintegrin and metalloproteases 8) is a transmembrane protein with different functions. It plays an important role in tumors and neuroinflammation-related diseases. However, the role and molecular mechanism of ADAM8 in cerebral ischemia injury are still unclear. This study aims to evaluate the role of ADAM8 in cerebral ischemic injury and explore its signal transduction mechanism. This experiment shows that ADAM8 can significantly cause neurological deficits in MCAO mice and can substantially cause ipsilateral cerebral edema and cerebral infarction in MCAO mice. In addition, ADAM8 can significantly induce cortical cell apoptosis in MCAO mice, leading to the loss of neurons and the expression of proinflammatory factors COX2, iNOS, TNFα, and IL-6. Importantly, we confirmed that ADAM8 mediates the inflammatory response by promoting the activation of NLRP3 inflammasome, microglia, and astrocytes. These results indicate that ADAM8 may be a candidate drug target for the prevention and treatment of the cerebral ischemic injury.
Highlights
Stroke can cause disability and death of patients, and it has become one of the public safety issues affecting human health around the world, and ischemic stroke accounts for more than 71% of the cases[1]
The expression level of ADAM8 protein in mice was analyzed by western blot. e results highlighted that there was no significant difference at 4 hours. e protein expression gradually increased after 4 hours, and the expression was at its highest at 72 hours (Figure 1(b)). ese results indicate that the expression of ADAM8 is abnormal in mice with cerebral ischemiareperfusion injury, which may play an unknown functional role. e optimal treatment time is within 4 hours after stroke, after which irreversible damage will occur, and the inflammatory response gradually worsens from 4 hours to 3 days after stroke
Due to the greater damage to the brain caused by MCAO, the mortality rate of the mice was higher after 3 days. erefore, we selected the study subjects at 24-hour time point after ischemia-reperfusion injury
Summary
Stroke can cause disability and death of patients, and it has become one of the public safety issues affecting human health around the world, and ischemic stroke accounts for more than 71% of the cases[1]. In the 1970s, it was discovered that the initial clinical manifestations of stroke patients were mainly hypoperfusion of blood in the penumbra of cerebral ischemia and defects in physiological electrical function. Over time, this area gradually transforms into irreversibly damaged tissue (called the ischemic core), but its transformation rate varies from person to person [2]. Current stroke treatment methods are mainly intravenous thrombolysis and rapid reperfusion of intravascular thrombus removal within 4.5 hours after stroke. Both methods can reduce the risk of death and disability. What is more frightening is that this is an irreversible injury, usually accompanied by large areas of cerebral edema, cerebral infarction, or hemorrhagic transformation, which eventually leads to neurological deficits and impaired consciousness, mostly manifested as necrosis of nerve cells in the core area of cerebral infarction [4]. erefore, there is a dire need to find a broader and safer treatment and it is necessary to establish other treatment strategies
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