Cross-Talk Between Key Players in Patients with COVID-19 and Ischemic Stroke: A Review on Neurobiological Insight of the Pandemic

Abstract

The global pandemic of novel coronavirus disease 2019 (COVID-19) has taken the entire human race by surprise and led to an unprecedented number of mortalities worldwide so far. Current clinical studies have interpreted that angiotensin-converting enzyme 2 (ACE2) is the host receptor for severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). In addition, ACE2 is the major component of the renin-angiotensin system. ACE2 deteriorates angiotensin II, a peptide that is responsible for the promotion of stroke. The downregulation of ACE2 further activates an immunological cascade. Thus, researchers need to explore and examine the possible links between COVID-19 and ischemic stroke (IS). Human ACE2 expression level and pattern in various tissues might be decisive for the vulnerability, symptoms, and treatment outcomes of the SARS-CoV-2 infection. The swift increase in the knowledge of SARS-CoV-2 has given creditable evidence that SARS-CoV-2 infected patients also encounter neurological deficits. As the SARS-CoV-2 binds to ACE2, it will hamper the activity of ACE2 in providing neuroprotection, especially in the case of stroke patients. Due to the downregulation of ACE2, the inflammatory response is activated in the ischemic penumbra. The COVID-19 pandemic has affected people with various pre-existing diseases, including IS, in such a way that these patients need special care and attention for their survival. Several clinical trials are currently ongoing worldwide as well as many other projects are in different stages of conceptualization and planning to facilitate the effective management of stroke patients with COVID-19 infection.

Keywords: Angiotensin-converting enzyme 2; COVID-19; Inflammatory response; Ischemic stroke; Renin-angiotensin system.

Fig. 1

Mechanistic overview of replication and pathophysiology of COVID-19. SARS-CoV-2 gets transmitted via faecal or droplet infection. Left panel: SARS-CoV-2 replicate in type II alveoli where it binds to the ACE2 receptor. By the process of transcription and translation, the single-stranded RNA of the SARS-CoV2 virus makes multiple copies with the help of host genetic material. Right panel: multiple copies of SARS-CoV2 deteriorate the alveoli initializing the inflammatory cascades comprising interleukins and neutrophils. Activated interleukins act upon hypothalamus in the brain, affecting prostaglandins release, which is responsible for fever. Overactivation of interleukins increases the capillary permeability of alveoli, resulting in alveolar edema. Consequently, hypoxemia occurs with shortness of breath, affecting lung output. In this sequel, the partial pressure of oxygen decreases, affecting the heart rate and respiratory rate. When the infection remains unchecked, further inflammation severely affects the heart, which influences the blood supply to kidneys and liver distressing their functioning. Excessive inflammation generates an imprudent amount of reactive oxygen species that rigorously affect the gastric cavity. Collectively, the SARS-CoV-2 infection leads to multi-organ failure that may even lead to death. SIRS-systemic inflammatory response syndrome; RDRP-RNA-dependent RNA polymerase; Rib-Ribosome; BUN-Blood Urea Nitrogen; ALT-Alanine Transaminase; AST-Aspartate Aminotransferase; CRP-C-Reactive Protein; ROS-Reactive Oxygen Species; ↓ decrease; ↑ increase

Fig. 2

Schematic diagram illustrating the role of RAS in cross-talk between ischemic stroke and SARS-CoV-2 infection. The brain RAS is regulator of physiological homeostasis and cerebrovascular disorders such as IS. Classical RAS elements include ACE, Ang II, and AT₁R. Angiotensinogen is hydrolyzed to Ang I by the aspartyl protease renin enzyme. Furthermore, ACE hydrolyzes the Ang I into Ang II. The interaction of newly formed Ang II with AT₁R increases the risk of ischemic stroke as it results in an enhanced risk of thrombosis. On the other hand, the newly found RAS pathway exhibits the hydrolysis of Ang II in the presence of ACE2 to Ang-(1–7), which acts as a ligand for the Mas receptor. This new axis has anti-oxidative, anti-inflammatory, and antithrombotic activity, thus decreasing the risk of ischemic stroke. The binding of SARS-CoV-2 with ACE2 receptor in lungs leads to the downregulation of ACE2 expression, which further results in accumulation in Ang II, thus activating the AT₁R pathway and increased risk of IS. AT₁R pathway activation leads to excitotoxicity, immunosuppression, neuroinflammation, and oxidative stress, finally resulting in acute lung injury. A secondary cascade is also activated due to excitotoxicity which results in the release of stored glutamate in brain cells, thus disrupting the BBB and allowing easy access of SARS-CoV-2 in brain. Breakdown of BBB also increases the intracranial pressure resulting in activation of SNS, hypoxia, capillary leakage, neurogenic pulmonary edema, and finally acute lung injury. Excitotoxicity is a crucial link between COVID-19 and IS, as incidence of IS also results in excitotoxicity and breakdown of BBB, resulting in higher risk of comorbidity. ↓ Decrease; ↑ Increase