Abstract
Cerebrovascular events, notably acute ischemic strokes (AIS), have been reported in the setting of novel coronavirus disease (COVID-19) infection. Commonly regarded as cryptogenic, to date, the etiology is thought to be multifactorial and remains obscure; it is linked either to a direct viral invasion or to an indirect virus-induced prothrombotic state, with or without the presence of conventional cerebrovascular risk factors. In addition, patients are at a greater risk of developing long-term negative sequelae, i.e., long-COVID-related neurological problems, when compared to non-COVID-19 stroke patients. Central to the underlying neurobiology of stroke recovery in the context of COVID-19 infection is reduced angiotensin-converting enzyme 2 (ACE2) expression, which is known to lead to thrombo-inflammation and ACE2/angiotensin-(1–7)/mitochondrial assembly receptor (MasR) (ACE2/Ang-(1-7)/MasR) axis inhibition. Moreover, after AIS, the activated nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome may heighten the production of numerous proinflammatory cytokines, mediating neuro-glial cell dysfunction, ultimately leading to nerve-cell death. Therefore, potential neuroprotective therapies targeting the molecular mechanisms of the aforementioned mediators may help to inform rehabilitation strategies to improve brain reorganization (i.e., neuro-gliogenesis and synaptogenesis) and secondary prevention among AIS patients with or without COVID-19. Therefore, this narrative review aims to evaluate the mediating role of the ACE2/Ang- (1-7)/MasR axis and NLRP3 inflammasome in COVID-19-mediated AIS, as well as the prospects of these neuroinflammation mediators for brain repair and in secondary prevention strategies against AIS in stroke rehabilitation.
Highlights
The current pandemic of the highly contagious novel coronavirus disease (COVID-19)is continuing to impose a significant public health challenge worldwide
This narrative review aims to evaluate the mediating role of the angiotensin-converting enzyme 2 (ACE2)/Ang- (1-7)/mitochondrial assembly receptor (MasR) axis and NLRP3 inflammasome in COVID-19-mediated acute ischemic strokes (AIS), as well as the prospects of these neuroinflammation mediators for brain repair and in secondary prevention strategies against AIS in stroke rehabilitation
Multiple molecular risk factors related to SARS-CoV-2 and the occurrence of COVID-19 could mediate extreme surges and the untimely onset of AIS [31,32]. These risk factors include generalized hypercoagulability, poorly regulated immune response leading to cytokine storm, endothelial cell (EC) damage leading to elevated levels of microthrombogenic extracellular-derived circulating microparticles, increased thrombo-inflammation, renin-angiotensin system (RAS) dysregulation, and direct cytotoxic effects on the nervous system related to the ACE2 receptor uptake of SARS-CoV-2 viruses [33,34]
Summary
The current pandemic of the highly contagious novel coronavirus disease (COVID-19). is continuing to impose a significant public health challenge worldwide. There is the ongoing production of pro-inflammatory agents (i.e., cytokines such as interleukins (IL-10, -8, -6, and -17), chemokines, granulocytes colony stimulating factors (G-CSF), and tumor necrosis factor-α (TNF-α)) due to viral infection and the activation of transcription factors, such as inflammatory complex, nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome, and nuclear factor kappa B (NF-κB), which activate the release of pathogen-associated molecular patterns [5] In the brain, these responses subsequently heighten the production of numerous pro-inflammatory cytokines, mediating neuro-glial cell dysfunction, leading to nerve-cell death [3]. This narrative review aims to evaluate the mediating role of the ACE2/Ang-(1-7)/MasR axis and NLRP3 inflammasome in COVID-19-mediated AIS and to highlight the prospects of these neuroinflammation mediators for brain repair and in secondary prevention strategies against AIS in stroke rehabilitation
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