COVID-19: "The Phantom Menace" to Brain Health?

A Brief Introduction into SARS-CoV-2, The Virus that Causes COVID-19

               A new infectious disease, the coronavirus disease 2019 (COVID-19), has changed the order of global life, the life of the Indonesian people is no exception. Around the middle of the first quarter of 2020, the world was shocked by the announcement from WHO regarding the escalation of COVID-19 status, from epidemic to pandemic (Q. Li et al., 2020). Pandemic, based on the definition of the World Health Organization (2020), is a condition of public health emergencies characterized by the presence of new disease that are rapidly spreading globally, crossing the geographical boundaries of countries. This disease was first reported in the city of Wuhan, Hubei province, China at the end of 2019 (Guo et al., 2020). The new virus, which is similar to the virus that caused the previous SARS outbreak, was successfully identified and later classified as β-coronavirus (novel coronavirus / nCoV), based on research involving the use of special antibodies against SARS coronavirus (Tian et al., 2020). The virus that causes COVID-19 is subsequently known worldwide as SARS-Coronavirus-2 or abbreviated as SARS-CoV-2.

               SARS-CoV-2 has a protein on the surface of its viral particles called S (spike) protein, in the form of protrusions that make the shape of this virus look like a crown (Latin: corona). The structure of SARS-CoV-2 has recently been comprehensively reviewed by Astuti & Ysrafil (2020). This spike protein binds strongly to targets on the surface of human cells known as ACE-2. ACE-2 protein is abundant in the human respiratory tract, with more ACE-2 levels found in the lung tissue of smokers (G. Li et al., 2020). ACE-2 is the main entry point for the virus that causes COVID-19 to attack infected individuals, which in turn will cause various effects, from asymptomatic infections to death.

               Lately there have been several scientific reports that show that COVID-19 can damage the brain health of sufferers, in addition to impacting the health of the respiratory tract. Considering the dangers posed by COVID-19, it is worthwhile to identify together more deeply about the potential impact that this disease can have on health or brain function, and to what extent the development of treatment for COVID-19 exists to date, specifically related to its effects on the brain.

COVID-19 as a “Phantom Menace” to Brain Health

Disturbances in the respiratory system as as a result of COVID-19 is a health problem that is relatively well-known by ordinary people. Not infrequently we read or hear about COVID-19 cases that require sufferers to get intensive care with respiratory aids (in medical circles known as mechanical ventilators). This condition has several other impacts, which are not insignificant health financing. The availability of mechanical ventilators is also relatively limited. The effect of COVID-19 on the health of the human respiratory system has been widely reported in various media, but did you know that COVID-19 can also manifest itself in other forms, such as disorders of brain function? Recently there have been reports by experts that COVID-19 can cause several clinical manifestations that indicate the occurrence of brain disorders. In fact, in mid-May 2020 a number of experts mentioned that SARS-CoV2 as a cause of COVID-19 could potentially be determined to be a new virus that can cause disease in the brain or known as neuropathogen (Montalvan et al., 2020).

Various studies conducted during the COVID-19 pandemic revealed an additional issue that had not received much attention from all people related to COVID-19, namely its impact on the central nervous system, especially the brain. Borrowing the title of one of the sequels to the Star Wars film by George Lucas, namely "The Phantom Menace", the author would like to suggest that COVID-19 is "The Phantom Menace" which is a vague or unclear enemy (menace) like a ghost (phantom) , which in the context of this writing is a scourge for health, both individual health and public health. "Phantom" itself is a metaphor that the authors propose because it wants to show how difficult it is in real terms we observe the virus that causes it because it is so tiny and many things that are not yet known about this virus, especially in organs other than the lungs, namely the brain, as difficult as we explain the phenomena of ghosts scientifically with the current technology.

Based on a study conducted by Chen et al. (2020), published in the journal BioRxiv, it is known that ACE-2 is also found in the human brain, especially in an area known as substantia nigra (the part of the brain responsible for motoric coordination) and ventricles of the brain (the part where a lot of brain fluid is found). This finding is very important, because it can be a foothold for further research related to the effect of COVID-19 on the brain, given the role of ACE-2 as a target of the SARS-CoV-2 virus to enter human cells. This finding might explain why in the COVID-19 case series in Wuhan, China, there were also neurological (brain) disorders in the form of new onset strokes and awareness disorders. What is striking and interesting is the fact that this impairment of brain function is related to the age of older patients, the presence of underlying disease (often in the form of hypertension), the degree of severe pain and the characteristics of patients who show fewer common symptoms and signs of COVID- 19, namely fever and cough (Mao et al., 2020). Regarding why brain disorders in the COVID-19 case in Wuhan are less common in cases of mild infection (non-severe infection), it is likely related to a patient's immune condition better than patients with severe infection.

The exact mechanism of how SARS-CoV-2 can enter the brain is not yet known, but there are several studies that help us answer this. SARS-CoV-2 is thought to be able to enter the brain through several mechanisms. The first mechanism, namely hematogenous virus entry (entering from the bloodstream). Viruses can enter through blood circulation into nerve cells of the brain, through components of blood vessel walls known as brain capillary endothelium. The relatively slow flow of blood in the brain's capillaries allows the virus spike protein to bind more optimally with ACE2 on the surface of the brain's capillary endothelium. This is thought to trigger the rupture of blood vessels in the brain which can trigger signs and symptoms of stroke, as happened in a number of COVID-19 cases that have been reported by Mao et al. (2020). After entering through the blood vessels of the brain, the virus can then enter the nerve cells (neurons) of the brain, multiply, and damage neurons, because brain neurons also have ACE2 on their surface. The second mechanism proposed is the mechanism of spreading of the virus from the structure of the skull that is close to the nasal cavity. SARS-CoV-2 is also thought to be able to enter the brain through the cribriform plate of the ethmoid bone, which is a component of the base of our skull bones. This cribriform plate is close to one of the important structures in the human respiratory tract, the olfactory bulb (Baig et al., 2020). The olfactory bulb plays an important role as a relay station for information from the nerve nerve receptors in the nose (Kosaka & Kosaka, 2009). Disturbance in smell (smell or smell) that appears suddenly has been reported in early July 2020 as one of the most common symptoms experienced by COVID-19 patients with mild symptoms of infection (Boscolo-Rizzo et al., 2020). These findings can be used as a reference to strengthen the alleged mechanism of the entry of the virus that causes COVID-19 into the brain through the respiratory tract, because it is not impossible that the symptoms in the form of interference in haunting have to do with the entry of the virus through the olfactory bulb. Further research is important to ascertain the mechanism of the spread of the virus in the human body, as well as how the outcome is on the brain health of sufferers of COVID-19, which initially comes with complaints of upper respiratory tract disorders or disorders in the sense of smell.

After the patient is recovered from COVID-19, does the brain function disorder also heal? Logically, of course we can expect this to happen, but unfortunately after infection, other brain disorders can also arise. Brain function disorders after COVID-19 infection that are often reported are cognitive dysfunction such as memory disorders (Ritchie et al., 2020). Memory function in humans is regulated by a part of the brain called the hippocampus. This brain structure also plays an important role in determining our mental health, because it also functions to regulate memory for traumatic events. Mental disorders associated with traumatic events, one of which is posttraumatic stress disorder (PTSD). Anxiety and PTSD are often found in patients who experience respiratory distress, especially acute respiratory distress syndrome (ARDS). ARDS is a common problem found in COVID-19 patients, especially in those who need a mechanical ventilator (Arentz et al., 2020). Based on experimental studies in PTSD mouse models that the authors have worked on, part of the hippocampus (CA1 area) may also play a role in disorders that occur in PTSD sufferers, but these findings have not been clinically confirmed (Mahendra et al., 2017). The author has also conducted a review of the mechanisms that might be involved in this hippocampus disorder, a type of stress on the nerve cells of the brain known as endoplasmic reticulum stress / RE stress (Mahendra & Putra, 2018). Therefore, studies of impaired memory function, hippocampus and stress RE, both in experimental animals exposed to SARS-CoV-2 and in patients with COVID-19, are important and interesting to do so that COVID-19 traits such as " The Phantom Menace" can be understood better.

Selected Trial Drug for COVID-19 with the Potential to Protect the Brain

The number of cases and death rates due to COVID-19 is increasing globally, so experts around the world are now racing against the time to examine drugs that are potentially used to treat COVID-19. Among the many drugs investigated for their efficacy against COVID-19, there are several drugs that are predicted to have bright prospects for development into drugs for COVID-19 therapy. Some of these drugs are remdesivir and chloroquine.

Remdesivir

Remdesivir is predicted as a good drug candidate for anti-COVID-19 therapy. This drug works to inhibit the multiplication (replication) of the virus, through inhibition of a component of coronavirus called RNA-dependent RNA polymerase (RdRp). The effectiveness of remdesivir against SARS and MERS (which is also caused by coronavirus) has been previously studied (Cao et al., 2020), while research on its effects on the Ebola virus which also damages the brain is in process (Mulangu et al., 2019). Research into the effects of drugs on humans often involves experimental animals that resemble humans, namely primates such as monkeys. In the prestigious scientific journal Nature among international scientists, it was reported that the Remdesivir molecule quickly circulated (distributed) into the brain of rhesus monkeys, as soon as the drug was administered into the body of these experimental animals (Warren et al., 2016). A study using human respiratory epithelial cells conducted in Wuhan showed that remdesivir is the drug with the strongest and most immediate inhibitory properties against the viruses that cause SARS and MERS, among a number of drugs studied (Wang et al., 2020). In summary it can be said if this drug has potential as an anti-multicoronavirus and is well spread into brain tissue. Based on the findings so far, it would not be an exaggeration to suppose that remdesivir is very feasible to study its efficacy in COVID-19 cases with impaired brain function.

Chloroquine

Chloroquine is a relatively well-known drug as an antimalarial drug. This drug has also been studied for safety and efficacy in dealing with COVID-19. Chloroquine is reported as one of the drugs that effectively inhibits the entry of SARS-CoV-2 into the target cell and inhibits the replication and release of virus particles from the host cell (Wang et al., 2020). After a systematic review, this drug was concluded to have several advantages, namely relatively inexpensive and safe given, based on pre-clinical studies of cells and animals that have been conducted (Cortegiani et al., 2020). Studies in mice with traumatic brain injury show that chloroquine can suppress inflammation (inflammation) and nerve cell death in the brain, in addition to protecting the brain from other diseases such as Alzheimer's disease which is characterized by cognitive impairment (Cui et al., 2015). Chloroquine can reach high levels in the brain, and has a long half-life (Telgt et al., 2005). Half-life can simply be interpreted as the time needed for the amount of drug in the blood to be reduced to half of the previous amount. This on the one hand supports the alleged positive effect of chloroquine in dealing with brain disorders related to COVID-19, but on the other hand there are case reports of mental disorders related to chloroquine administration in human subjects with experimental malaria infections. Mental disorders that occur are reported to occur after administration of the drug for 10 days and recover completely within a few months. Chloroquine level in the bloodstream in this subject was reported to be in the range of therapeutic level (Telgt et al., 2005). This indicates that this drug can accumulate significantly in the brain in less than 2 weeks, and occurs as a side effect of the drug. Although these side effects are relatively rare, in-depth studies are needed in order to obtain the maximum therapeutic effect of chloroquine with minimal side effects for selected COVID-19 cases.

What Can We Learn?

Based on the results of existing studies related to COVID-19 and brain health, we can take some important take home messages. Some of these important things, namely:

(1) SARS-CoV-2 is most likely to enter and damage brain cells through blood vessels or parts of the skull that are close to the nasal cavity, although the exact mechanism is not yet known.

(2) Clinicians should also pay more attention to the manifestations of brain disorders in the case of COVID-19, so that optimal preventive measures can be made to prevent brain damage and death.

(3) In the current pandemic era of COVID-19, if cases of brain disorders are found, especially in elderly patients, who are not accompanied by fever or cough and a history of high blood pressure, it is necessary to at least screen tests such as rapid diagnostic tests for detection the possibility of COVID-19.

(4) Drugs with fast action, strong antiviral effects, and good ability to penetrate deep into the brain are some of the main features that promise to be developed as a therapy for brain disorders related to COVID-19.

In addition to increasing knowledge through information about COVID-19 which is like "The Phantom Menace", we certainly hope that effective prevention and treatment efforts in managing human cases of COVID-19 (especially with impaired brain function) can be accomplished immediately. So, while waiting for encouraging results from various studies on COVID-19, let's protect our health and our brains from the dangers of COVID-19 by continuing to adopt clean and healthy living behaviors.

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