key: cord-0929420-dpapsbup
authors: Putilina, M. V.; Grishin, D. V.
title: SARS-CoV-2 (COVID-19) as a Predictor of Neuroinflammation and Neurodegeneration: Potential Treatment Strategies
date: 2021-06-23
journal: Neurosci Behav Physiol
DOI: 10.1007/s11055-021-01108-z
sha: 11a8ee231c61fb3eea5c181b679375d42d6ca0d2
doc_id: 929420
cord_uid: dpapsbup

The SARS-CoV-2 (COVID-19) pandemic has attracted attention to the challenge of neuroinflammation as an unavoidable component of viral infections. Acute neuroinflammatory responses include activation of resident tissue macrophages in the CNS followed by release of a variety of cytokines and chemokines associated with activation of oxidative stress and delayed neuron damage. This makes the search for treatments with indirect anti-inflammatory properties relevant. From this point of view, attention is focused on further study of the treatment of patients with COVID-19 with dipyridamole (Curantil) which, having antiviral and anti-inflammatory effects, can inhibit acute inflammatory activity and progression of fibrosis, is a drug with potential, especially among patients with early increases in the D-dimer concentration and severe signs of microangiopathy.

SARS-CoV-2 coronavirus, discovered in 2019, in contrast to other known coronaviruses inducing atypical pneumonia (SARS-CoV, MERS-CoV), is more contagious and has a greater population transmission rate [1] . The course of the infection it causes, COVID-19, involves more severe clinical manifestations than those seen in acute respiratory infections and infl uenza. Lesions to human organs in COVID-19 are multisystem in nature, involving not only the respiratory system, but also other body systems, including the nervous system [2] . The pandemic caused by SARS-CoV-2 has attracted intense attention to neuroinfl ammation processes as an unavoidable component of viral infection, manifest as synaptic dysfunction, changes in intercellular interactions, degradation of macromolecules, impairments to metabolism, and, as a result, neurodegeneration. Neuroinfl ammation in patients with any pathology is associated with age-dependent increases in the sensitization of the immune system to external and internal stimuli [3] . Processes mediated by neuroinfl ammation lead to neuropsychiatric disorders such as depression and dementia [4, 5] . Thus, there is value in studying potential therapeutic strategies directed at preventing the development and progression of neurodegeneration, especially in elderly COVID-19 patients.

Relationship between Neuroinfl ammation and Neurodegeneration. Neuroinfl ammation is a multilevel molecular-cellular mechanisms which at the fi rst stage supports the compensatory-adaptive responses of the brain, subsequently activating neurodegenerative processes [6] ; it is associated with activation of proinfl ammatory cytokines in response to contact with pathogenic factors (metabolic, toxic, infectious, and traumatic, including chronic stress). Acute neuroinfl ammatory responses include activation of resident tissue macrophages in the central nervous system (CNS) and subsequent release of various cytokines and chemokines, activating oxidative stress and inducing long-term neuron damage and the development of coagulatory cascades inducing endothelial cell damage [7] . Infl ammatory cytokines are a type of signal molecule released from immune cells such as T-helpers (Th) and macrophages. These include not only interleukin (IL)-6, but also IL-1, -8, -12, and -18, tumor necrosis factor α (TNF-α), and γ-interferon (IFN-γ).

tiocytosis [21] . The term cytokine storm (CS) was applied to these processes, referring to uncontrolled infl ammation with elevated synthesis of numerous infl ammation markers (C-reactive protein, IL-6, etc.),leading to multiorgan failure and CNS damage [1] . A CS is initiated by interaction of spike proteins and other protein particles on the coronavirus capsid with cell surface receptors. The interaction of viruses with toll-like receptors triggers the NF-κB infl ammatory signal cascade. Activation of NF-κB stimulates prointerleukin-1 secretion, and this undergoes proteolysis by caspase-1, leading to activation of infl ammasomes and synthesis of active IL-1β. In turn, IL-1β, stimulating the secretion of other proinfl ammatory cytokines, provokes the development of pulmonary fi brosis and fever [21, 22] . Increased proinfl ammatory cytokine secretion and imbalance in the expression of the corresponding receptors and their associated proteins (the main component of the "SARS-CoV-2 phenomenon") result from the ineffective realization of the anti-infl ammatory response with damage to various organs [3, 4] .

In the CNS, the immune response is produced by cells of endogenous origin -microglia and endothelial cells, as well as exogenous cells, i.e., dendritic cells, T-and B-lymphocytes, and cells of the mononuclear phagocyte system. Entry of virus into the CNS occurs immediately after infection. Evidence has been obtained showing similarity between CNS lesions in COVID-19 and those induced by herpes simplex virus and HIV, as all infect neurons via fast retrograde axonal transport [19] . SARS-CoV-2 is simultaneously neurotropic and neurovirulent. It is able to penetrate into the CNS by neuronal dissemination, in which the virus initially infects peripheral neurons, and then, using the host cell apparatus, infects CNS neurons, inducing a set of consequences related to the disease, including neurodegenerative. This mechanism of propagation is termed the "Trojan horse" mechanism [23] . The CoV spike glycoprotein used by SARS-CoV-2 to bind to cell membranes induces ACE2 receptor expression in neurons and endothelial cells and determines the neuroinvasive potential of the virus. Cells bearing CD4 receptors become targets of the virus -macrophages, neuroglia, and capillary endothelia. After crossing the BBB, the virus can replicate in microglia and neurons, producing corresponding damage to the BBB. Infected microglial cells produce low molecular weight peptides with toxic actions on astrocytes, leading to excessive accumulation of glutamate in the extracellular space and development of glutamate excitotoxicity. These processes occur on the background of impairments to brain blood fl ow autoregulation, vasospasm, increased platelet aggregation, and formation of intravascular stasis, impaired microcirculation, and endothelial dysfunction.

Impairments to endothelial function result in sharp changes in the spectrum of active substances produced by them [7] . The endothelium starts to secrete aggregants, coagulants, and vasoconstrictors, some of which (the renin-angiotensin system) affect the whole cardiovascular Endothelial cells are a key component in the bloodbrain barrier (BBB), so endothelial dysfunction is always associated with damage to the BBB. Impairments to the integrity of the BBB allow various types of cells to enter the damaged part of the brain [8] . Migrating immunocompetent cells (along with damaged cells) produce infl ammatory mediators, accelerating neuron death [9] . Endogenous danger-associated molecular pattern (DAMP) molecules are released from the intracellular space of dead or damaged cells, and these are believed to be activators of the microglia and brain tissue-infi ltrating peripheral immunocompetent cells [10] [11] [12] [13] [14] . Microglia activated by high-mobility group box 1 (HMGB1) secrete TNF-α, IL-1β, reactive oxygen species (ROS), and numerous proinfl ammatory cytokines [11, 12] , which initiate infl ammatory reactions in the brain in response to harmful stimuli [13, 14] . Increases in the number of activated glial cells and the concentrations of a number of cytokines (such as TNF-α) in the hippocampus, cerebral cortex, substantia nigra, and striatum are associated with decreases in hippocampal volume and cognitive dysfunction due to the neurodegenerative process [15] .

Apart from microglia, damaged astrocytes and pericytes can produce proinfl ammatory cytokines [15] . Activated astrocytes form a glial scar, limiting the potential for recovery of damaged axons. Pericytes located along capillary walls provide density to the BBB. Damage (hypoxia, ischemia, infection) impairs BBB density, leading to impairment of intercellular circulation in the perivascular spaces with activation of macrophages via development of local infl ammation [16] . Apart from the local immune response, damage to neurovascular units can produce the phenomenon of systemic suppression of immunity, which is clinically apparent as increases in susceptibility to viral and bacterial infections, including pneumonia or lower urinary tract infections [17, 18] . Cytokine reactions make a signifi cant contribution to the mechanism of CNS damage leading to neuron degeneration in Alzheimer's disease, Parkinson's disease, stroke, etc. [4] .

The Role of Neuroinfl ammation in the Pathogenesis of COVID-19. Thus far, the pathogenesis of damage associated with SARS-CoV-2 has received insuffi cient study. SARS-CoV-2 is known to have a genome sequence close to that of SARS-CoV-1 [1] . Both viruses use protein spikes on their surfaces to bind the angiotensin converting enzyme 2 (ACE-2) receptor in mammalian cells, after which membrane-bound serine protease 2 activates the spikes [19] . Unlike other viruses of this group, the rate of entry of SARS-CoV-2 into cells is linked with preliminary preactivation of the peplomer (spike) by furin. After infection, the virus spreads through the respiratory tract, inducing release of proinfl ammatory cytokines. A feature of this infection is the presence of extramedullary megakaryocytes which actively produce platelets [20] . There is a simultaneous reduction in the blood lymphocyte count, particularly T-lymphocytes, and suppression of endogenous immune system mechanism with development of secondary hemophagocyte lymphohis-current information (especially when living alone) can have the result that the early symptoms of the disease will not be recognized, leading to the risk of progression of infection and the development of complications [32] . The early neurological manifestations of COVID-19 can be general weakness, apathy, loss of appetite, asthenia, and perhaps episodic memory loss at the initial stages, with diffi culty committing information to memory. The later stages can be linked with total amnesia, progression of cognitive impairments, disorientation, confusion, hallucinations, delusions, and depression [33, 34] . Severe depression can lead to impairments to cognitive functions and can even simulate dementia.

The neurological signs of COVID-19 usually appear immediately after infection, though they can also develop at later stages of the disease or after recovery [27] . Patients with COVID-19 have also been found to develop neurological symptoms such as headache, vertigo, myalgia, and anosmia, and cases of encephalitis, necrotizing hemorrhagic encephalopathy, stroke, epileptic seizures, delirium, rhabdomyolysis, and Guillain-Barré syndrome have also been recorded [28, 29] .

Asthenic disorders are dominant among patients with virus infection. The most frequent are oscillations in arterial blood pressure, tachycardia, and pulse rate lability, a diversity of pains or simply unpleasant sensations, erythema or pallor of the skin, feelings of heat at normal body temperature, or, conversely, elevated chilliness, and local (palms, feet, armpits) or generalized hyperhidrosis. Patients rarely complain of melancholy or low mood; more typical is painful fi xation on unpleasant somatic sensations, which cannot be fully explained in terms of the ongoing diseases. Typical complaints are headache, pain in the back, joints, and internal organs, vertigo, and noises and sounds in the head [34, 35] .

Possible Therapeutic Strategies in COVID-19: A Focus on Neuroinfl ammation. The current therapeutic strategy for the treatment of neurodegenerative diseases is based mainly on correction of clinical symptoms, though its effi cacy in some patients is minimal, as it does not always take account of the complex pathogenetic mechanisms, including neuroinfl ammation, etiological factors, and the features of the clinical picture. Selection of medication requires consideration of the fact that cognitive impairments in patients with COVIS-19 may be a manifestation not of the direct neurodegenerative process, but can be indirectly associated with the development of hypoxic encephalopathy [36] . Impairments to neurotransmitter functions (insuffi cient or, conversely, excessive reactivity) causes disorganization of synaptic processes and is always synergistic with hypoxia in ischemia or virus infection, so selection of fi rst-line drugs is always diffi cult.

In the current absence of guideline documents for the treatment of COVID-19, it is diffi cult to say whether any strategy has advantages, so drugs fi tting with the majority of therapeutic approaches should be chosen. Primary is the need to correct comorbid states [37] . system. Increases in blood coagulability are linked with a high risk of death from COVID-19 [23] . Increased blood plasmin and plasminogen concentrations are biomarkers for increased susceptibility to SARS-CoV-2, as plasmin protease can cleave the corresponding site on SARS-CoV-2 S protein, increasing its virulence [24] .

The precise mechanism of development of coagulopathy and microangiopathy in COVID-19 is unknown. This is probably linked with diffuse infl ammation or damage to endothelial cells [25] . The most widespread damage liked with thrombotic microangiopathy are thrombotic thrombocytopenic purpura and hemolytic uremia syndrome. Patients probably develop so-called small vessel disease. This term is used to describe a series of syndromes, whose pathogenesis is quite unclear and may be linked with damage to the perforant cerebral arterioles, capillaries, and venules [26] . The clinical signs of small vessel disease are beyond the framework of clear acute syndromes and can be apparent as changes in mood and depression, balance problems, falls in the elderly, reversible amnesia, and autonomic dysfunction [5] ; furthermore, small vessel disease itself is the commonest cause of silent strokes.

The most vulnerable patients in COVID-19 are the elderly, with comorbid states such as heart disease, kidney disease, arterial hypertension, diabetes mellitus, obesity, and atherosclerosis [27] [28] [29] . Development of viral infection in these patients is associated with increased levels of markers for liver dysfunction (aspartate aminotransferase, alanine aminotransferase, albumin, bilirubin), along with severe impairments to coagulation. As a rule, these fi ndings are prognostically unfavorable indicators and provide evidence of a more severe course of pneumonia and progression of gastrointestinal tract damage [30] . The presence of chronic comorbid diseases in these patients explains the more severe course of COVID-19 in the elderly. A multicenter Chinese trial (n = 280) showed that severe disease was more commonly seen in patients more than 65 years old, 85.5% of patients with severe diseasing having diabetes mellitus, arterial hypertension, or angina, which were encountered at frequencies 7-10 times greater (p = 0.042) than in patients with mild COVID-19 [30] . Decompensation of any somatic or infectious disease has signifi cant infl uences on the state of cognitive functions in elderly patients because of the large number of pathogenic factors.

Patients with other diseases and new virus infection are in a "vicious circle": on the one hand, arterial hypertension, especially when poorly controlled, and diabetes mellitus are known to be directly linked with small vessel damage in the brain and cognitive changes [31] . On the other hand, patients with impaired cognitive functions are at elevated risk of COVID-19 infection, as they are often unable to obtain or understand the required information on the importance of the problem and methods of preventing disease. Such patients are not aware of the need for prophylaxis of disease or strict observation of self-isolation regimes. Their limited access to al treatment with dipyridamole led to increases in the numbers of circulating lymphocytes and platelets, decreases in the D-dimer level, and a notable improvement in clinical outcomes. Dipyridamole inhibits the expression of proinfl ammatory cytokines (IL-1, -2) and TNF-α, largely slowing the translocation of the p65 subunit of nuclear factor κB NF-κB, which increases the activation, differentiation, and effector functions of T-cells and infl ammasomes [46] [47] [48] .

Dipyridamole has systemic and local anti-infl ammatory effects, signifi cantly reducing the level of matrix metalloproteinase-9 in monocytes [48] . As a pyrimidine derivative, dipyridamole is an interferon inducer and has a modulatory action on the functional activity of the interferon system; it reverses decreased IFN-α and IFN-γ production by in vitro blood leukocytes; it increases nonspecifi c antiviral resistance to viral infections [47] . The drug has powerful antiviral effects in relation to single-stranded RNA viruses in vitro and in an in vivo model of VSV-induced viral pneumonia; it displays an interferon-modulating action in recurrent opportunistic viral infections on the background of chronic emotional stress.

Dipyridamole suppresses SARS-CoV-2 replication, suggesting that the therapeutic dose of the drug may potentiate the antiviral reactions of infected patients [44] . Furthermore, as a phosphodiesterase inhibitor, dipyridamole has additional advantages in patients with new viral infections, as it has a vasodilating action, increasing the adenosine level, inhibits phosphodiesterase in vascular smooth muscle cells, and is a classical endothelioprotector [49] . In addition to the antithrombotic and vasodilating effects, the antioxidant and endothelioprotector actions of dipyridamole may slow neurodegenerative processes, improving cognitive functions [50] .

Excessive quantities of proinfl ammatory cytokines, especially IL-1, lead to expression of brain-derived neurotrophic factor [40] , so restoration of neurotrophics is directly associated with the extent of reductions in the severity of CS. A potential direction for treatment is provided by use of neurotrophic drugs [51] .

Conclusions. The medical community continues to lack full information on the pathogenic actions of COVID-19 virus and its possible consequences for the nervous system. However, existing data lead to the view that the virus activates infl ammation processes and neurodegeneration with subsequent manifestation of cognitive impairments. This confi rms the need for seeking drugs acting on the whole neurovascular unit with indirect or direct anti-infl ammatory effects with demonstrated effi cacy. From this point of view, further study of the treatment of COVID-19 patients with dipyridamole, whose antiviral and anti-infl ammatory actions inhibit acute infl ammation and the progression of fi brosis, is a potentially valuable drug, especially in patients with the early signs of increased D-dimer concentrations and signs of microangiopathy.

The authors have no confl icts of interests.

Antihypertensive drugs and statins are medications whose infl uences on the functional state of the endothelium have received the most study [38, 39] . There are as yet no experimental or clinical data evidencing favorable or unfavorable infl uences of treatment with angiotensin converting enzyme inhibitors, renin-angiotensin-aldosterone system blockers, and other antihypertensive drugs on the prognosis and course of illness in patients with COVID-19 or patients with COVID-19 with cardiovascular disease and receiving treatment with these drugs.

The role of systemic infl ammation provides grounds for using anti-infl ammatory drugs. At the same time, the incidence of side effects when these are used in the long term (hypertension, hyperglycemia, osteoporosis, increased risk of cardiovascular events, gastrointestinal tract pathology) makes their prescription inadvisable. Many other drugs also have anti-infl ammatory actions, with reductions in the activity of the cellular components of infl ammation (activation of neutrophils and monocytes, as well as leukocyte-platelet conjugates) and/or soluble biomarkers (such as C-reactive protein, cytokines, and interleukins). A series of pilot studies with drugs inhibiting IL-1 and IL-6β have shown that their use in addition to standard treatment improves disease outcomes, though they have a number of contraindications; in particular, there is a lack of data on infl uences on cognitive functions, especially in the long-term phase of COVID-19 [40] .

As a result of the decrease in the arachidonic acid level, the signs of CS, and other factors, the use of antiplatelet drugs is currently regarded as having potential in the treatment of COVID-19 [41] [42] [43] . These can increase the level of adaptation of neurons to damage, increasing their viability in unfavorable conditions and thus providing optimum restoration of blood fl ow in damaged vessels [44] . Recent years have seen many reports confi rming the role of platelets as key signal and effector cells in overcoming the hemostatic, infl ammatory, and immune continuums in infectious and viral diseases [45] . These cells, binding virus via Fc receptors or plasma proteins, activate the release of "microbial" proteins and peptides by platelets, including platelet factor PF-4, T-cells, recombinant human protein (RANTES), and fi brinopeptide B. RANTES operates as a chemoattractant for blood monocytes, T-helpers, and eosinophils; the protein induces histamine release from basophils and activates eosinophils. Acting via a diverse set of mechanisms, activated platelets can isolate and kill pathogens or promote their elimination from the body via macrophage and neutrophil activation, enhancing the generation of neutrophil extracellular traps and the formation of platelet aggregates and microthrombi.

Published clinical studies run in China have shown that the antiplatelet drug dipyridamole has anti-HCoV-19 effects [44] . In a model of viral pneumonia, it activated antiviral immunity and signifi cantly improved survival, displaying marked antiaggregant actions. In clinical practice, addition-

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