Narrative review reports two important mediators in SARS-CoV-2-induced ischemic stroke recovery

A recent narrative review posted to the International Journal of Molecular Sciences explored neuroinflammation and coronavirus disease 2019 (COVID-19)-induced ischemic stroke recovery.

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been linked to cerebrovascular events, particularly acute ischemic strokes (AIS). However, the etiology of COVID-19-related cerebrovascular events remains unknown and is presumed to be complicated.

Studies report that cerebrovascular events could be connected to a direct viral invasion or an indirect virus-mediated prothrombotic condition in the presence or absence of typical cerebrovascular risk factors.

About the study

In the present review, the researchers evaluated the function of nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome in COVID-19-mediated AIS. The team also evaluated angiotensin-converting enzyme 2 (ACE2)/angiotensin (Ang)-(1-7)/mitochondrial assembly receptor (MasR) axis role in SARS-CoV-2-induced AIS.

The scientists determined the potential of these neuroinflammation mediators in brain repair and secondary preventative measures against AIS in stroke rehabilitation.

The literature search was conducted using keywords like neuroinflammation, COVID-19, and NLRP3 Inflammasome in online databases and search engines. The internet databases used included SCOPUS, PubMed, Google Scholar, and the Institute for Scientific Information (ISI) Web of Knowledge.

Only open access and free full-text articles, such as systematic and narrative reviews, meta-analyses, and original research papers, in the English language, were selected for the current review.

SARS-CoV-2-related ischemic stroke

Recent studies suggest that CoVs are responsible for about 10% of acute respiratory infections, and nearly 15% of β-CoVs-infected individuals experience severe illness, with 6% being critically sick. Further, the acute, subacute, and long-term impacts of COVID-19 might result in respiratory failure or multiple organ dysfunction (MODS).

Published reports have indicated that the human CoVs (HCoVs)-induced cytokine storm is the prime reason for death in people infected by these viruses. The SARS-CoV and Middle Eastern respiratory syndrome CoV (MERS-CoV)-recovered individuals also demonstrated long-term cytokine storm-hyperinflammation and coagulopathy symptoms.

A recent review indicated that post-acute SARS-CoV-2 consists of persistent, delayed, or long-standing complications of COVID-19 more than four weeks after the symptom onset. The hypothesized pathophysiological underpinnings for post-acute SARS-CoV-2 include virus-specific pathophysiological alterations and enhanced thrombo-inflammation.

Several molecular risk elements associated with COVID-19, such as generalized hypercoagulability, endothelial cell (EC) damage, cytokine storm, heightened thrombo-inflammation, ACE2 receptor-mediated cytotoxic impacts on nervous systems, and renin-angiotensin system (RAS) dysfunction, might result in AIS.

Furthermore, a recent meta-analysis found that those who developed AIS after COVID-19 infection were more likely to experience depression and anxiety. Prior research works implied that elevated AIS-induced inflammation was linked to depression following stroke.

Altogether, recent reviews have indicated multiple post-acute to long-SARS-CoV-2 symptoms such as fever, fatigue, chest pain, depression, and neurocognitive difficulties linked to impaired neurological systems.

ACE2/Ang-(1-7)/MasR axis’s role in SARS-CoV-2-induced ischemic stroke

Two proposed routes of SARS-CoV-2 invasion into the brain are 1) hematogenous spread and 2) via olfactory epithelium. In addition, SARS-CoV-2 gains entry to the brain through the ACE2 receptors present in the neuro-glial cells. A hypothesized mechanism of endothelitis and endothelial dysfunction in SARS-CoV-2 patients was RAS disruption, including ACE2 receptor downregulation in vascular ECs.

The attachment of SARS-CoV-2 to the ACE2 receptor causes endocytosis in the receptor, resulting in downregulation or depletion of the protective endothelial ACE2. The interrupted ACE and ACE2 balance also result in heightened proinflammatory disposition and endothelial damage contributing to the pathogenesis of ischemic stroke.

The ACE2 downregulation results in its biological substrate, Des-arg9-bradykinin (DABK), metabolization via the stimulation of DABK/BK receptor B1 (BKB1R) axis signaling. This phenomenon induces inflammation via the release of various proinflammatory mediators.

ACE2/Ang-(1-7)/MasR axis stimulation demonstrated extensive therapeutic capacity in stroke. ACE2/Ang-(1-7)/MasR axis is a well-established angiotensin II counter-regulator, resulting in neuroprotection in stroke. The ACE2 overexpression causes neuroprotective outcomes and might aid in brain repair. Thus, increased MasR activation and modulation of the ACE2/Ang-(1-7)/MasR axis probably enhance neurorehabilitation performance.

NLRP3 inflammasome’s role in SARS-CoV-2-induced ischemic stroke

Overexpression of inflammatory cytokines leads to blood-brain barrier (BBB) damage, allowing SARS-CoV-2 entry into the brain parenchyma. It has been proposed that cytokines and the NLRP3 inflammasome are the key immunological elements mediating the immune response and cytokine storms during the viral invasion. As a result, it is reasonable to assume that the NLRP3 inflammasome is implicated in COVID-19-associated cytokine storms.

Through purinergic 2X7 receptor (P2X7R) activation and elevated extracellular adenosine triphosphate (ATP) levels, SARS-CoV-2 induces NLRP3 inflammasome stimulation. This impact is due to the high expression of P2X7R in neuro-glial cells.

Furthermore, the SARS-CoV-2-associated stimulation of a coagulation cascade through the mannan-binding lectin (MBL)-related serine protease 2 (MASP-2) complex also increases the NLRP3 inflammasome activation. The NLRP3 inflammasome stimulation causes excess release of damage-associated molecular patterns (DAMPs) via gasdermin-D-mediated cell death (GSDMD).

Emerging neurorehabilitation approaches for SARS-CoV-2-mediated ischemic stroke

Several investigations have demonstrated that RAS modulators could enhance functional and structural recovery following stroke. Preclinical investigations have reported that the ACE2/Ang-(1–7)/MasR axis modulation enhances neuroprotection against ischemic stroke. In addition, various studies have depicted that the ACE2/Ang-(1–7)/MasR axis and RAS modulators improve brain repair and neuroplasticity. Thus, RAS and ACE2/Ang-(1–7)/MasR axis modulators could impart anti-oxidative, anti-inflammatory, and neuroprotective potentials against negative impacts of post-ischemic stroke associated with or without SARS-CoV-2. They also enhance brain repair and recovery following a stroke.

Furthermore, the suppression of NLRP3 inflammasome using drugs such as curcumin, parthenolide, and artigenin aid in the recovery of ischemic stroke. NLRP3 inflammasome inhibition should be explored further to gain deeper insights into the molecular processes in post-ischemic stroke brain repair (with or without SARS-CoV-2).

Conclusions

The present narrative review emphasizes the need for a better understanding of the neuroprotection capacity of the NLRP3 inflammasome and the ACE2/Ang-(1-7)/MasR axis, with or without SARS-CoV-2-induced ischemic stroke. Lowered ACE2 expression is crucial to the core neurobiology of stroke recovery in the setting of SARS-CoV-2 infection. Reduction in the expression of ACE2 results in ACE2/Ang-(1–7)/MasR axis suppression and thrombo-inflammation.

Moreover, the AIS-stimulated NLRP3 inflammasome might increase the generation of various proinflammatory cytokines. This results in neuro-glial cell malfunction and nerve cell apoptosis.

Thus, the two aforesaid mediators serve as reasonable speculative molecular targets for possible treatment routes to boost functional recovery and neuroplasticity in stroke rehabilitation and secondary prevention approach in SARS-CoV-2 infection and AIS.