A Peek into Pandora’s Box: COVID-19 and Neurodegeneration
Abstract
:1. Introduction
1.1. Chronology of COVID-19
1.2. Structure of SARS-CoV-2
1.3. Replication of SARS-CoV-2
1.4. Organs Targeted by SARS-CoV-2
S. No. | Drugs/Therapies Tested | Mechanism/Site of Action | State of Success against COVID-19 | References |
---|---|---|---|---|
Antivirals | ||||
1 | Remdesivir | A nucleotide analogue that inhibits the RNA-dependent RNA polymerase (RdRp) of coronaviruses including SARS-CoV-2 | Shortened the time to recovery along with lower incidence of serious adverse events due to respiratory failure; improved survival but did not affect viral clearance | [23,24,25,26] |
2 | Lopinavir–ritonavir | The enzyme 3-chymotrypsin-like protease (3CLpro) plays a crucial role in processing the viral RNA. As a protease inhibitor lopinavir–ritonavir inhibits the action of 3CLpro, thereby disrupting the process of viral replication and release from host cells | No benefits observed | [27] |
3 | Favipiravir | An RdRp inhibitor, the active form of this prodrug acts as a substrate for the RdRp enzyme and gets incorporated in the viral RNA strand, preventing further extension | No benefit. Excessive ferritin forms a complex with favipiravir, thus reducing favipiravir levels in blood in moderate-to-severe disease. On the other hand, high levels of favipiravir and its inactive metabolite M1 inhibit the organic anion transporters in the kidneys resulting in enhanced reabsorption and reduced excretion of uric acid, thus increasing its concentration in blood | [28,29,30,31,32,33] |
4 | Favipiravir in combination with hydroxychloroquine | Inhibition of RdRp and viral binding to host membrane | One trial is underway, while another found efficacy in treatment | [34,35] |
5 | Chloroquine | An antimalarial, inhibits the action of heme polymerase in malarial trophozoites, preventing the conversion of heme to hemozoin. Interferes with virus binding to the host membrane by increasing pH and inhibiting ACE2 receptor | No beneficial effects | [36] |
6 | Hydroxychloroquine | An analogue of chloroquine, used to treat autoimmune diseases in addition to malaria. Mechanism of action similar to chloroquine | Did not affect viral clearance; no beneficial effects | [26,36] |
7 | Hydroxychloroquine in combination with azithromycin | Azithromycin is an antibiotic | Combination of hydroxychloroquine and azithromycin reduced viral load | [37,38,39,40] |
8 | Intravenous immunoglobulin (IVIg immunotherapy) | IVIg is a blood preparation isolated and concentrated from healthy donors mainly consisting of IgG. High-dose IVIg could modulate the activation of cytokine network, neutralize autoantibodies, and regulate proliferation of immune cells | In patients with severe disease, reduction in mortality was seen; in patients with non-severe COVID-19, no benefit was observed | [41,42,43,44] |
9 | Convalescent plasma (immunotherapy) | Passive immunization approach using antibodies from survivors | Effective supplementary treatment if applied early in the disease course | [45,46,47] |
Steroids/anti-inflammatory compounds | ||||
10 | Dexamethasone (9α-fluoro-16α-methylprednisolone) | A glucocorticoid that increases the production of anti-inflammatory compounds | In hospitalized hypoxic COVID-19 patients, lower mortality was observed; another study is ongoing | [48,49] |
11 | Methylprednisolone | A synthetic glucocorticoid, with anti-inflammatory and immunosuppressive effects | Produced better results than dexamethasone; better clinical outcome, i.e., laboratory markers of severity (CRP, D-dimer and LDH), and shorter recovery time, was observed with methylprednisolone, which has been attributed to its higher lung penetration compared to dexamethasone; reduced mortality | [50,51,52,53] |
12 | Anakinra | A recombinant form of human interleukin-1 receptor antagonist (IL1R) | Safe and might be associated with reductions in both mortality and need for mechanical ventilation | [54] |
13 | Anakinra in combination with methylprednisolone | Anti-inflammatory | Risk of death was significantly lower for treated patients | [55,56,57] |
Janus kinase inhibitors | ||||
14 | Ruxolitinib | Inhibitor of Janus kinases (JAK) 1 and 2, anti-inflammatory | Decreased the time on mechanical ventilation, hospitalization time, the need for vasopressor support, and decreased mortality and improved lung congestion. Phase III trial conducted by Novartis did not observe these beneficial effects | [58,59,60] |
15 | Baricitinib | Inhibitor of JAK, anti-inflammatory, and reduces receptor-mediated viral endocytosis | A phase I/II clinical trial is under way | [61] |
16 | Baricitinib (in combination with Tocilizumab and Corticosteroids) | JAK inhibitor | The addition of baricitinib did not substantially reduce mortality in hospitalized patients with COVID-19. Combination of baricitinib with corticosteroids was associated with greater improvement in pulmonary function | [62,63] |
17 | Baricitinib, ruxolitinib, tofacitinib | JAK/STAT inhibitor | Reduce excessive inflammation | [64,65] |
Monoclonal antibodies against SARS-CoV-2 | ||||
18 | Bamlanivimab | Monoclonal antibody treatment providing immediate, passive immunity | Accelerated the natural decline in viral load over time | [66] |
19 | Bamlanivimab in combination with etesevimab | These antibodies attach to the spike protein of SARS-CoV-2 at two different sites, preventing its entry into the cells | Statistically significant reduction in SARS-CoV-2 viral load | [67,68] |
20 | Casirivimab in combination with imdevimab | Bind to different sites on the receptor binding domain of the spike protein of SARS-CoV-2, blocking its attachment to the human ACE2 receptor | In high-risk patients, this treatment significantly reduced rate of hospitalization | [69,70,71] |
Therapeutic antibodies targeting inflammatory cytokines | ||||
21 | Tocilizumab | Monoclonal antibody against interleukin-6 (IL-6) receptor | Reduction in mortality, intubation | [72,73] |
22 | Clazakizumab, olokizumab, siltuximab | Monoclonal antibody against IL-6, IL-8 | Similar effects in diminishing leukocyte | [74,75,76,77] |
23 | Levilimab, sarilumab | Monoclonal antibody against IL-6R/gp130 | Sustained clinical improvement | [78,79,80] |
24 | Canakinumab | Monoclonal antibody against IL-1β | Favorable prognosis compared to standard of care | [81,82] |
25 | Guselkumab, risankizumab, ustekinumab | Monoclonal antibody against IL-12/IL-23 | Protects against COVID-19 in rheumatological patients | [83,84,85] |
26 | Ixekizumab, secukinumab | Monoclonal antibody against IL-17A | Beneficial effects of inhibiting IL-17 | [86,87,88] |
27 | Emapalumab | Monoclonal antibody antagonist of interferon IFN-γ | Protects against cytokine storm resistant to anakinra, tocilizumab, and JAK inhibitors | [89] |
28 | Infliximab, adalimumab | Monoclonal antibody against tumor necrosis factor (TNF-α) | Facilitated clinical recovery in severe and critical cases | [90,91] |
29 | Gimsilumab, lenzilumab, otilimab, TJ003234 | Granulocyte-macrophage colony-stimulating factor (GM-CSF) neutralization | Safe and associated with faster improvement in clinical outcomes | [92,93,94,95] |
30 | Namilumab | Monoclonal antibody against GM-CSF | Reduction in inflammation | [96] |
31 | Mavrilimumab | Monoclonal antibody against GM-CSF receptor | Improved clinical outcomes | [97,98] |
Other compounds | ||||
32 | Dapansutrile | Selective and orally active NLRP3 inflammasome inhibitor | Clinical trials ongoing | [99] |
33 | Etanercept | Tumor necrosis factor receptor (TNFR) inhibitor | Protects against evolution to more severe disease | [100,101] |
34 | Melatonin | Blocks the activity of cluster differentiation 147 (CD147) | Has anti-inflammatory, anti-oxidant activities | [102,103,104] |
2. SARS-CoV-2 and the Nervous System
2.1. ACE2 Expression in Brain
2.2. Cytokine Storm and Leaky BBB
3. COVID-19 and Neurodegeneration
3.1. Oxidative Stress, Dysregulation of Iron Homeostasis, and Mitochondrial Dysfunction
3.2. Therapeutic Prospects
3.3. Biomarker Identification and Development
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Chandra, A.; Johri, A. A Peek into Pandora’s Box: COVID-19 and Neurodegeneration. Brain Sci. 2022, 12, 190. https://doi.org/10.3390/brainsci12020190
Chandra A, Johri A. A Peek into Pandora’s Box: COVID-19 and Neurodegeneration. Brain Sciences. 2022; 12(2):190. https://doi.org/10.3390/brainsci12020190
Chicago/Turabian StyleChandra, Abhishek, and Ashu Johri. 2022. "A Peek into Pandora’s Box: COVID-19 and Neurodegeneration" Brain Sciences 12, no. 2: 190. https://doi.org/10.3390/brainsci12020190