The role of inflammasomes in ischemic stroke - from pathophysiology to treatments

Abstract

Stroke is the second leading cause of mortality worldwide and a major cause of long-term disability. Clinically, stroke can be classified as either ischemic or haemorrhagic. Ischemic stroke is the most common type of stroke and accounts for approximately 80% of all stroke cases. The pathophysiological processes following stroke are complex and extensive, and include bioenergetic failure, excitotoxicity, oxidative stress and inflammation, which leads to necrotic and apoptotic cell death. Recent findings have provided insight into a newly described inflammatory mechanism that may contribute to neuronal and glial cell death during cerebral ischemia known as sterile inflammation involving intracellular multi-protein complexes termed inflammasomes. Despite neuroprotective agents decreasing neuronal cell death and infarct size under in vitro and in vivo stroke models, respectively, all such agents tested in stroke patients have failed in clinical trials. Novel potential therapies envisaged to target multiple cell injury mechanisms in the brain following cerebral ischemia include-intravenous immunoglobulin (IVIg) and intermittent fasting (IF). IVIg is a purified polyclonal immunoglobulin preparation obtained from the plasma of several thousand healthy donors. Numerous experimental studies by our laboratory demonstrated that administration of IVIg was able to significantly attenuate brain injury in mice subjected to experimental stroke. Moreover, IF is a form of dietary energy restriction and encompasses alternate periods of ad libitum feeding and fasting, which have been proven to decrease the development of age-related diseases. Previous experimental studies demonstrated that IF was able to significantly attenuate brain injury outcome in mice subjected to experimental stroke. However, the precise mechanism(s) in how IVIg and IF directly protect neurons and cerebral tissue from inflammasome-mediated sterile inflammation following ischemic stroke remains to be determined and is a major focus of this research thesis. In the first study of this research thesis, we performed a comprehensive investigation into the expression patterns of NLRP1 and NLRP3 inflammasome proteins and both IL-1β and IL-18 in mouse primary cortical neurons subjected to simulated ischemia and in a model of focal ischemic stroke in C57BL/6J mice. In addition, determined whether the NLRP1 and NLRP3 inflammasome could be targeted with a Caspase-1 inhibitor and IVIg for therapeutic intervention. The study demonstrated that ischemia-like conditions increased the levels of NLRP1 and NLRP3 inflammasome proteins and both IL-1β and IL-18 in neurons and brain tissues. Moreover, Caspase-1 II inhibitor and IVIg treatment protected neurons and brain tissue by a mechanism(s) involving Caspase-1 inhibition and suppression of NLRP1 and NLRP3 inflammasome activity, respectively, under in vitro and in vivo ischemic conditions. In the second study of this research thesis, we provide evidence that the NF-κB and MAPK(s) signaling pathways are involved in regulating the ...

Analysis of Controlled Mechanism With Significant Nonlinearities

“…To insert an ANN controller, the opensource library FANN [12] have been implemented through CCustomBlock. The library was chosen because it is programmed in C language (Activate supports neither C++ nor C#) and it provides tools for complex usage of ANN.…”