Login Register Cart 0
Generic placeholder image

Current Neuropharmacology

Editor-in-Chief

ISSN (Print): 1570-159X
ISSN (Online): 1875-6190

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

Estrogens as a Possible Therapeutic Strategy for the Management of Neuroinflammation and Neuroprotection in COVID-19

Author(s): Cindy Bandala*, Noemí Cárdenas-Rodríguez, Samuel Reyes-Long, Alfredo Cortés-Algara, Itzel Jatziri Contreras-García, Teresita Rocío Cruz-Hernández, Alfonso Alfaro-Rodriguez, José Luis Cortes-Altamirano, Martín Perez-Santos, Maricruz Anaya-Ruiz and Eleazar Lara-Padilla*

Volume 21, Issue 10, 2023

Published on: 21 June, 2023

Page: [2110 - 2125] Pages: 16

DOI: 10.2174/1570159X21666230616103850

Price: $65

Abstract

The Coronavirus disease 2019 (COVID-19) affects several tissues, including the central and peripheral nervous system. It has also been related to signs and symptoms that suggest neuroinflammation with possible effects in the short, medium, and long term. Estrogens could have a positive impact on the management of the disease, not only due to its already known immunomodulator effect, but also activating other pathways that may be important in the pathophysiology of COVID-19, such as the regulation of the virus receptor and its metabolites. In addition, they can have a positive effect on neuroinflammation secondary to pathologies other than COVID-19. The aim of this study is to analyze the molecular mechanisms that link estrogens with their possible therapeutic effect for neuroinflammation related to COVID-19. Advanced searches were performed in scientific databases as Pub- Med, ProQuest, EBSCO, the Science Citation index, and clinical trials. Estrogens have been shown to participate in the immune modulation of the response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition to this mechanism, we propose that estrogens can regulate the expression and activity of the Angiotensin-converting enzyme 2 (ACE2), reestablishing its cytoprotective function, which may be limited by its interaction with SARS-CoV-2. In this proposal, estrogens and estrogenic compounds could increase the synthesis of Angiotensin-(1-7) (Ang-(1-7)) that acts through the Mas receptor (MasR) in cells that are being attacked by the virus. Estrogens can be a promising, accessible, and low-cost treatment for neuroprotection and neuroinflammation in patients with COVID-19, due to its direct immunomodulatory capacity in decreasing cytokine storm and increasing cytoprotective capacity of the axis ACE2/Ang (1-7)/MasR.

« Previous Next »
Graphical Abstract

[1]
WHO. Coronavirus (COVID-19) dashboard. Available from: https://covid19.who.int/
[2]
Ryder, S.P.; Morgan, B.R.; Massi, F. Analysis of rapidly emerging variants in structured regions of the SARS-CoV-2 Genome. bioRxiv, 2020.
[http://dx.doi.org/10.1101/2020.05.27.120105]
[3]
Zhang, J.; Wang, M.; Zhao, M.; Guo, S.; Xu, Y.; Ye, J.; Ding, W.; Wang, Z.; Ye, D.; Pan, W.; Liu, M.; Li, D.; Luo, Z.; Liu, J.; Wan, J. The Clinical Characteristics and Prognosis Factors of Mild-Moderate Patients With COVID-19 in a Mobile Cabin Hospital: A Retrospective, Single-Center Study. Front. Public Health, 2020, 8(264), 264.
[http://dx.doi.org/10.3389/fpubh.2020.00264] [PMID: 32582615]
[4]
Chen, K.H.; Wang, S.F.; Wang, S.Y.; Yang, Y.P.; Wang, M.L.; Chiou, S.H.; Chang, Y.L. Pharmacological development of the potential adjuvant therapeutic agents against coronavirus disease 2019. J. Chin. Med. Assoc., 2020, 83(9), 817-821.
[http://dx.doi.org/10.1097/JCMA.0000000000000375] [PMID: 32568969]
[5]
Grandi, G.; Facchinetti, F.; Bitzer, J. The gendered impact of coronavirus disease (COVID-19): do estrogens play a role? Eur. J. Contracept. Reprod. Health Care, 2020, 25(3), 233-234.
[http://dx.doi.org/10.1080/13625187.2020.1766017] [PMID: 32469251]
[6]
Jin, J.M.; Bai, P.; He, W.; Wu, F.; Liu, X.F.; Han, D.M.; Liu, S.; Yang, J.K. Gender differences in patients with COVID-19: focus on severity and mortality. Front. Public Health, 2020, 8(152), 152.
[http://dx.doi.org/10.3389/fpubh.2020.00152] [PMID: 32411652]
[7]
Shi, Y.; Yu, X.; Zhao, H.; Wang, H.; Zhao, R.; Sheng, J. Host susceptibility to severe COVID-19 and establishment of a host risk score: findings of 487 cases outside Wuhan. Crit. Care, 2020, 24(1), 108.
[http://dx.doi.org/10.1186/s13054-020-2833-7] [PMID: 32188484]
[8]
Qin, L.; Li, X.; Shi, J.; Yu, M.; Wang, K.; Tao, Y.; Zhou, Y.; Zhou, M.; Xu, S.; Wu, B.; Yang, Z.; Zhang, C.; Yue, J.; Cheng, C.; Liu, X.; Xie, M. Gendered effects on inflammation reaction and outcome of COVID-19 patients in Wuhan. J. Med. Virol., 2020, 92(11), 2684-2692.
[http://dx.doi.org/10.1002/jmv.26137] [PMID: 32497297]
[9]
Lan, J.; Ge, J.; Yu, J.; Shan, S.; Zhou, H.; Fan, S.; Zhang, Q.; Shi, X.; Wang, Q.; Zhang, L.; Wang, X. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature, 2020, 581(7807), 215-220.
[http://dx.doi.org/10.1038/s41586-020-2180-5] [PMID: 32225176]
[10]
Chen, J.; Jiang, Q.; Xia, X.; Liu, K.; Yu, Z.; Tao, W.; Gong, W.; Han, J.D.J. Individual variation of the SARS-CoV-2 receptor ACE2 gene expression and regulation. Aging Cell, 2020, 19(7), e13168.
[http://dx.doi.org/10.1111/acel.13168] [PMID: 32558150]
[11]
Collantes, M.E.V.; Espiritu, A.I.; Sy, M.C.C.; Anlacan, V.M.M.; Jamora, R.D.G. Neurological manifestations in COVID-19 infection: a systematic review and meta-analysis. Can. J. Neurol. Sci., 2021, 48(1), 66-76.
[http://dx.doi.org/10.1017/cjn.2020.146] [PMID: 32665054]
[12]
Mao, L.J.H.; Wang, M.; Chen, S.; He, Q.; Chang, J.; Hong, C.; Zhou, Y.; Wang, D.; Miao, X.; Li, Y.; Hu, Bo. Neurological manifestations of hospitalized patients with COVID-19 in Wuhan, China. JAMA Neurol., 2020, 77(6), 683-690.
[http://dx.doi.org/10.1001/jamaneurol.2020.1127] [PMID: 32275288]
[13]
Ahmed, J.O.; Ahmad, S.A.; Hassan, M.N.; Kakamad, F.H.; Salih, R.Q.; Abdulla, B.A.; Rahim Fattah, F.H.; Mohammed, S.H.; Ali, R.K.; Salih, A.M. Post COVID-19 neurological complications; a meta-analysis. Ann. Med. Surg. (Lond.), 2022, 76, 103440.
[http://dx.doi.org/10.1016/j.amsu.2022.103440] [PMID: 35261766]
[14]
Wei, H.; Yin, H.; Huang, M.; Guo, Z. The 2019 novel cornoavirus pneumonia with onset of oculomotor nerve palsy: a case study. J. Neurol., 2020, 267(5), 1550-1553.
[http://dx.doi.org/10.1007/s00415-020-09773-9] [PMID: 32100124]
[15]
Fotuhi, M.; Mian, A.; Meysami, S.; Raji, C.A. Neurobiology of COVID-19. J. Alzheimers Dis., 2020, 76(1), 3-19.
[http://dx.doi.org/10.3233/JAD-200581] [PMID: 32538857]
[16]
Chen, X.; Laurent, S.; Onur, O.A.; Kleineberg, N.N.; Fink, G.R.; Schweitzer, F.; Warnke, C. A systematic review of neurological symptoms and complications of COVID-19. J. Neurol., 2021, 268(2), 392-402.
[http://dx.doi.org/10.1007/s00415-020-10067-3] [PMID: 32691236]
[17]
Li, Y.; Li, M.; Wang, M.; Zhou, Y.; Chang, J.; Xian, Y.; Wang, D.; Mao, L.; Jin, H.; Hu, B. Acute cerebrovascular disease following COVID-19: a single center, retrospective, observational study. Stroke Vasc. Neurol., 2020, 5(3), 279-284.
[http://dx.doi.org/10.1136/svn-2020-000431] [PMID: 32616524]
[18]
Beghi, E.; Feigin, V.; Caso, V.; Santalucia, P.; Logroscino, G. COVID-19 infection and neurological complications: present findings and future predictions. Neuroepidemiology, 2020, 54(5), 364-369.
[http://dx.doi.org/10.1159/000508991] [PMID: 32610334]
[19]
Bautista-Vargas, M.; Bonilla-Abadía, F.; Cañas, C.A. Potential role for tissue factor in the pathogenesis of hypercoagulability associated with in COVID-19. J. Thromb. Thrombolysis, 2020, 50(3), 479-483.
[http://dx.doi.org/10.1007/s11239-020-02172-x] [PMID: 32519164]
[20]
Yan, R.; Zhang, Y.; Li, Y.; Xia, L.; Guo, Y.; Zhou, Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science, 2020, 367(6485), 1444-1448.
[http://dx.doi.org/10.1126/science.abb2762] [PMID: 32132184]
[21]
Hoffmann, M.; Kleine-Weber, H.; Schroeder, S.; Krüger, N.; Herrler, T.; Erichsen, S.; Schiergens, T.S.; Herrler, G.; Wu, N.H.; Nitsche, A.; Müller, M.A.; Drosten, C.; Pöhlmann, S. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell, 2020, 181(2), 271-280.e8.
[http://dx.doi.org/10.1016/j.cell.2020.02.052] [PMID: 32142651]
[22]
Belouzard, S.; Chu, V.C.; Whittaker, G.R. Activation of the SARS coronavirus spike protein via sequential proteolytic cleavage at two distinct sites. Proc. Natl. Acad. Sci. USA, 2009, 106(14), 5871-5876.
[http://dx.doi.org/10.1073/pnas.0809524106] [PMID: 19321428]
[23]
Rico-Mesa, J.S.; White, A.; Anderson, A.S. Outcomes in patients with COVID-19 infection taking ACEI/ARB. Curr. Cardiol. Rep., 2020, 22(5), 31.
[http://dx.doi.org/10.1007/s11886-020-01291-4] [PMID: 32291526]
[24]
Touyz, R.M.; Li, H.; Delles, C. ACE2 the Janus-faced protein - from cardiovascular protection to severe acute respiratory syndrome-coronavirus and COVID-19. Clin. Sci. (Lond.), 2020, 134(7), 747-750.
[http://dx.doi.org/10.1042/CS20200363] [PMID: 32255491]
[25]
Lanza, K.; Perez, L.G.; Costa, L.B.; Cordeiro, T.M.; Palmeira, V.A.; Ribeiro, V.T.; Simões e Silva, A.C. Covid-19: the renin-angiotensin system imbalance hypothesis. Clin. Sci. (Lond.), 2020, 134(11), 1259-1264.
[http://dx.doi.org/10.1042/CS20200492] [PMID: 32507883]
[26]
Rodrigues Prestes, T.R.; Rocha, N.P.; Miranda, A.S.; Teixeira, A.L.; Simoes-e-Silva, A.C. The anti-inflammatory potential of ACE2/angiotensin-(1-7)/mas receptor axis: evidence from basic and clinical research. Curr. Drug Targets, 2017, 18(11), 1301-1313.
[http://dx.doi.org/10.2174/1389450117666160727142401] [PMID: 27469342]
[27]
Zhang, H.; Baker, A. Recombinant human ACE2: acing out angiotensin II in ARDS therapy. Crit. Care, 2017, 21(1), 305.
[http://dx.doi.org/10.1186/s13054-017-1882-z] [PMID: 29237475]
[28]
Rey-Parra, G.J.; Vadivel, A.; Coltan, L.; Hall, A.; Eaton, F.; Schuster, M.; Loibner, H.; Penninger, J.M.; Kassiri, Z.; Oudit, G.Y.; Thébaud, B. Angiotensin converting enzyme 2 abrogates bleomycin-induced lung injury. J. Mol. Med. (Berl.), 2012, 90(6), 637-647.
[http://dx.doi.org/10.1007/s00109-012-0859-2] [PMID: 22246130]
[29]
Samavati, L.; Uhal, B.D. ACE2, much more than just a receptor for SARS-COV-2. Front. Cell. Infect. Microbiol., 2020, 10, 317.
[http://dx.doi.org/10.3389/fcimb.2020.00317] [PMID: 32582574]
[30]
Misra, S.; Kolappa, K.; Prasad, M.; Radhakrishnan, D.; Thakur, K.T.; Solomon, T.; Michael, B.D.; Winkler, A.S.; Beghi, E.; Guekht, A.; Pardo, C.A.; Wood, G.K.; Hsiang-Yi Chou, S.; Fink, E.L.; Schmutzhard, E.; Kheradmand, A.; Hoo, F.K.; Kumar, A.; Das, A.; Srivastava, A.K.; Agarwal, A.; Dua, T.; Prasad, K. Frequency of neurologic manifestations in COVID-19. Neurology, 2021, 97(23), e2269-e2281.
[http://dx.doi.org/10.1212/WNL.0000000000012930] [PMID: 34635561]
[31]
Baig, A.M. Counting the neurological cost of COVID-19. Nat. Rev. Neurol., 2022, 18(1), 5-6.
[http://dx.doi.org/10.1038/s41582-021-00593-7] [PMID: 34795449]
[32]
Nikbakht, F.; Mohammadkhanizadeh, A.; Mohammadi, E. How does the COVID-19 cause seizure and epilepsy in patients? The potential mechanisms. Mult. Scler. Relat. Disord., 2020, 46, 102535.
[http://dx.doi.org/10.1016/j.msard.2020.102535] [PMID: 33010584]
[33]
Roved, J.; Westerdahl, H.; Hasselquist, D. Sex differences in immune responses: Hormonal effects, antagonistic selection, and evolutionary consequences. Horm. Behav., 2017, 88, 95-105.
[http://dx.doi.org/10.1016/j.yhbeh.2016.11.017] [PMID: 27956226]
[34]
Li, F.; Boon, A.C.M.; Michelson, A.P.; Foraker, R.E.; Zhan, M.; Payne, P.R.O. Estrogen hormone is an essential sex factor inhibiting inflammation and immune response in COVID-19. Sci. Rep., 2022, 12(1), 9462.
[http://dx.doi.org/10.1038/s41598-022-13585-4] [PMID: 35676404]
[35]
Rowland, S.P.; O’Brien, B.E. Screening for low testosterone is needed for early identification and treatment of men at high risk of mortality from Covid-19. Crit. Care, 2020, 24(1), 367.
[http://dx.doi.org/10.1186/s13054-020-03086-z]
[36]
Giagulli, V.A.; Guastamacchia, E.; Magrone, T.; Jirillo, E.; Lisco, G.; De Pergola, G.; Triggiani, V. Worse progression of COVID-19 in men: Is testosterone a key factor? Andrology, 2021, 9(1), 53-64.
[http://dx.doi.org/10.1111/andr.12836] [PMID: 32524732]
[37]
Morales, T. Recent findings on neuroprotection against excitotoxicity in the hippocampus of female rats. J. Neuroendocrinol., 2011, 23(11), 994-1001.
[http://dx.doi.org/10.1111/j.1365-2826.2011.02141.x] [PMID: 21507086]
[38]
Tilbrook, A.J.; Clarke, I.J. Neuroendocrine mechanisms of innate states of attenuated responsiveness of the hypothalamo-pituitary adrenal axis to stress. Front. Neuroendocrinol., 2006, 27(3), 285-307.
[http://dx.doi.org/10.1016/j.yfrne.2006.06.002] [PMID: 16930683]
[39]
Kinsley, C.H.; Lambert, K.G. Reproduction-induced neuroplasticity: natural behavioural and neuronal alterations associated with the production and care of offspring. J. Neuroendocrinol., 2008, 20(4), 515-525.
[http://dx.doi.org/10.1111/j.1365-2826.2008.01667.x] [PMID: 18266940]
[40]
Jaedicke, K.M.; Fuhrmann, M.D.; Stefanski, V. Lactation modifies stress-induced immune changes in laboratory rats. Brain Behav. Immun., 2009, 23(5), 700-708.
[http://dx.doi.org/10.1016/j.bbi.2009.02.005] [PMID: 19232537]
[41]
Yang, F.; Zheng, Q.; Jin, L. Dynamic function and composition changes of immune cells during normal and pathological pregnancy at the maternal-fetal interface. Front. Immunol., 2019, 10, 2317.
[http://dx.doi.org/10.3389/fimmu.2019.02317] [PMID: 31681264]
[42]
Voskuhl, R.; Momtazee, C. Pregnancy: effect on multiple sclerosis, treatment considerations, and breastfeeding. Neurotherapeutics, 2017, 14(4), 974-984.
[http://dx.doi.org/10.1007/s13311-017-0562-7] [PMID: 28766273]
[43]
Spence, R.D.; Voskuhl, R.R. Neuroprotective effects of estrogens and androgens in CNS inflammation and neurodegeneration. Front. Neuroendocrinol., 2012, 33(1), 105-115.
[http://dx.doi.org/10.1016/j.yfrne.2011.12.001] [PMID: 22209870]
[44]
Rossi, C.; Cicalini, I.; Zucchelli, M.; di Ioia, M.; Onofrj, M.; Federici, L.; Del Boccio, P.; Pieragostino, D. Metabolomic signature in sera of multiple sclerosis patients during pregnancy. Int. J. Mol. Sci., 2018, 19(11), 3589.
[http://dx.doi.org/10.3390/ijms19113589] [PMID: 30441762]
[45]
Wang, Z.; Wang, Z.; Xiong, G. Clinical characteristics and laboratory results of pregnant women with COVID-19 in Wuhan, China. Int. J. Gynaecol. Obstet., 2020, 150(3), 312-317.
[http://dx.doi.org/10.1002/ijgo.13265] [PMID: 32510581]
[46]
Yang, Z.; Wang, M.; Zhu, Z.; Liu, Y. Coronavirus disease 2019 (COVID-19) and pregnancy: a systematic review. J. Matern. Fetal Neonatal Med., 2022, 35(8), 1619-1622.
[http://dx.doi.org/10.1080/14767058.2020.1759541] [PMID: 32354293]
[47]
Breslin, N.; Baptiste, C.; Gyamfi-Bannerman, C.; Miller, R.; Martinez, R.; Bernstein, K.; Ring, L.; Landau, R.; Purisch, S.; Friedman, A.M.; Fuchs, K.; Sutton, D.; Andrikopoulou, M.; Rupley, D.; Sheen, J.J.; Aubey, J.; Zork, N.; Moroz, L.; Mourad, M.; Wapner, R.; Simpson, L.L.; D’Alton, M.E.; Goffman, D. Coronavirus disease 2019 infection among asymptomatic and symptomatic pregnant women: two weeks of confirmed presentations to an affiliated pair of New York City hospitals. Am. J. Obstet. Gynecol. MFM, 2020, 2(2), 100118.
[http://dx.doi.org/10.1016/j.ajogmf.2020.100118] [PMID: 32292903]
[48]
Allotey, J.; Stallings, E.; Bonet, M.; Yap, M.; Chatterjee, S.; Kew, T.; Debenham, L.; Llavall, A.C.; Dixit, A.; Zhou, D.; Balaji, R.; Lee, S.I.; Qiu, X.; Yuan, M.; Coomar, D.; Sheikh, J.; Lawson, H.; Ansari, K.; van Wely, M.; van Leeuwen, E.; Kostova, E.; Kunst, H.; Khalil, A.; Tiberi, S.; Brizuela, V.; Broutet, N.; Kara, E.; Kim, C.R.; Thorson, A.; Oladapo, O.T.; Mofenson, L.; Zamora, J.; Thangaratinam, S. PregCOV-19 Living Systematic Review Consortium. Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis. BMJ, 2020, 1, 370-m3320.
[http://dx.doi.org/10.1136/bmj.m3320]
[49]
Lokken, E.M.; Walker, C.L.; Delaney, S.; Kachikis, A.; Kretzer, N.M.; Erickson, A.; Resnick, R.; Vanderhoeven, J.; Hwang, J.K.; Barnhart, N.; Rah, J.; McCartney, S.A.; Ma, K.K.; Huebner, E.M.; Thomas, C.; Sheng, J.S.; Paek, B.W.; Retzlaff, K.; Kline, C.R.; Munson, J.; Blain, M.; LaCourse, S.M.; Deutsch, G.; Adams Waldorf, K.M. Clinical characteristics of 46 pregnant women with a severe acute respiratory syndrome coronavirus 2 infection in Washington State. Am. J. Obstet. Gynecol., 2020, 223(6), 911.e1-911.e14.
[http://dx.doi.org/10.1016/j.ajog.2020.05.031] [PMID: 32439389]
[50]
Collin, J.; Byström, E.; Carnahan, A.; Ahrne, M. Public Health Agency of Sweden’s Brief Report: Pregnant and postpartum women with severe acute respiratory syndrome coronavirus 2 infection in intensive care in Sweden. Acta Obstet. Gynecol. Scand., 2020, 99(7), 819-822.
[http://dx.doi.org/10.1111/aogs.13901] [PMID: 32386441]
[51]
Torres-Torres, J.; Martinez-Portilla, R.J.; Espino-y-Sosa, S.; Estrada-Gutierrez, G.; Solis-Paredes, J.M.; Villafan-Bernal, J.R.; Medina-Jimenez, V.; Rodriguez-Morales, A.J.; Rojas-Zepeda, L.; Poon, L.C. Comorbidity, poverty and social vulnerability as risk factors for mortality in pregnant women with confirmed SARS-CoV-2 infection: analysis of 13 062 positive pregnancies including 176 maternal deaths in Mexico. Ultrasound Obstet. Gynecol., 2022, 59(1), 76-82.
[http://dx.doi.org/10.1002/uog.24797] [PMID: 34672382]
[52]
Stewart, S.; Newson, L.; Briggs, T.A.; Grammatopoulos, D.; Young, L.; Gill, P. Long COVID risk - a signal to address sex hormones and women’s health. Lancet Reg. Health Eur., 2021, 11, 100242.
[http://dx.doi.org/10.1016/j.lanepe.2021.100242] [PMID: 34746909]
[53]
Bucciarelli, V.; Nasi, M.; Bianco, F.; Seferovic, J.; Ivkovic, V.; Gallina, S.; Mattioli, A.V. Depression pandemic and cardiovascular risk in the COVID-19 era and long COVID syndrome: Gender makes a difference. Trends Cardiovasc. Med., 2022, 32(1), 12-17.
[http://dx.doi.org/10.1016/j.tcm.2021.09.009] [PMID: 34619336]
[54]
Newson, L.; Lewis, R.; O’Hara, M. Long Covid and menopause - the important role of hormones in Long Covid must be considered. Maturitas, 2021, 152, 74.
[http://dx.doi.org/10.1016/j.maturitas.2021.08.026]
[55]
Rudroff, T.; Workman, C.D.; Bryant, A.D. Potential factors that contribute to post-COVID-19 fatigue in women. Brain Sci., 2022, 12(5), 556.
[http://dx.doi.org/10.3390/brainsci12050556] [PMID: 35624943]
[56]
Pelà, G.; Goldoni, M.; Solinas, E.; Cavalli, C.; Tagliaferri, S.; Ranzieri, S.; Frizzelli, A.; Marchi, L.; Mori, P.A.; Majori, M.; Aiello, M.; Corradi, M.; Chetta, A. Sex-related differences in long-COVID-19 syndrome. J. Womens Health (Larchmt.), 2022, 31(5), 620-630.
[http://dx.doi.org/10.1089/jwh.2021.0411] [PMID: 35333613]
[57]
Marchenkova, L.A.; Makarova, E.V. Characteristics of COVID-19 in peri- and postmenopausal women. Role of hormone replacement therapy. Vopr. ginekol. akus. perinatol. Gynecol. Obstet. and Perinatol., 2022, 21(1), 85-90.
[http://dx.doi.org/10.20953/1726-1678-2022-1-85-90]
[58]
Szukiewicz, D.; Wojdasiewicz, P.; Watroba, M.; Szewczyk, G. Mast cell activation syndrome in COVID-19 and female reproductive function: theoretical background vs. J. Immunol. Res., 2022, 2022, 1-22.
[http://dx.doi.org/10.1155/2022/9534163] [PMID: 35785029]
[59]
Ortona, E.; Buonsenso, D.; Carfi, A.; Malorni, W.; Munblit, D.; De Rose, C.; Sinatti, D.; Ricchiuto, A.; Valentini, P. Long COVID: an estrogen-associated autoimmune disease? Cell Death Discov., 2021, 7(1), 77.
[http://dx.doi.org/10.1038/s41420-021-00464-6] [PMID: 33850105]
[60]
Micevych, P.; Dominguez, R. Membrane estradiol signaling in the brain. Front. Neuroendocrinol., 2009, 30(3), 315-327.
[http://dx.doi.org/10.1016/j.yfrne.2009.04.011] [PMID: 19416735]
[61]
Crespo-Castrillo, A.; Arevalo, M.A. Microglial and astrocytic function in physiological and pathological conditions: estrogenic modulation. Int. J. Mol. Sci., 2020, 21(9), 3219.
[http://dx.doi.org/10.3390/ijms21093219] [PMID: 32370112]
[62]
Cersosimo, M.G.; Benarroch, E.E. Estrogen actions in the nervous system. Neurology, 2015, 85(3), 263-273.
[http://dx.doi.org/10.1212/WNL.0000000000001776] [PMID: 26109716]
[63]
Giraud, S.N.; Caron, C.M.; Pham-Dinh, D.; Kitabgi, P.; Nicot, A.B. Estradiol inhibits ongoing autoimmune neuroinflammation and NFκB-dependent CCL2 expression in reactive astrocytes. Proc. Natl. Acad. Sci. USA, 2010, 107(18), 8416-8421.
[http://dx.doi.org/10.1073/pnas.0910627107] [PMID: 20404154]
[64]
Novella, S.; Dantas, A.P.; Segarra, G.; Medina, P.; Hermenegildo, C. Vascular aging in women: is estrogen the fountain of youth? Front. Physiol., 2012, 3, 165.
[http://dx.doi.org/10.3389/fphys.2012.00165] [PMID: 22685434]
[65]
de Morais, S.D.B.; Shanks, J.; Zucker, I.H. Integrative physiological aspects of brain RAS in hypertension. Curr. Hypertens. Rep., 2018, 20(2), 10.
[http://dx.doi.org/10.1007/s11906-018-0810-1] [PMID: 29480460]
[66]
Brown, N.J.; Vaughan, D.E. Role of angiotensin II in coagulation and fibrinolysis. Heart Fail. Rev., 1999, 3(3), 193-198.
[http://dx.doi.org/10.1023/A:1009757416302]
[67]
Fabbri, V.P.; Riefolo, M.; Lazzarotto, T.; Gabrielli, L.; Cenacchi, G.; Gallo, C.; Aspide, R.; Frascaroli, G.; Liguori, R.; Lodi, R.; Tonon, C.; D’Errico, A.; Foschini, M.P. COVID-19 and the brain: the neuropathological italian experience on 33 adult autopsies. Biomolecules, 2022, 12(5), 629.
[http://dx.doi.org/10.3390/biom12050629] [PMID: 35625558]
[68]
Zhang, L.; Zetter, M.A.; Guerra, E.C.; Hernández, V.S.; Mahata, S.K.; Eiden, L.E. ACE2 in the second act of COVID-19 syndrome: peptide dysregulation and possible correction with oestrogen. J. Neuroendocrinol., 2021, 33(2), e12935.
[http://dx.doi.org/10.1111/jne.12935] [PMID: 33462852]
[69]
Dudzinski, D.; Michel, T. Life history of eNOS: Partners and pathways. Cardiovasc. Res., 2007, 75(2), 247-260.
[http://dx.doi.org/10.1016/j.cardiores.2007.03.023] [PMID: 17466957]
[70]
Hilliard, L.M.; Sampson, A.K.; Brown, R.D.; Denton, K.M. The “his and hers” of the renin-angiotensin system. Curr. Hypertens. Rep., 2013, 15(1), 71-79.
[http://dx.doi.org/10.1007/s11906-012-0319-y] [PMID: 23180053]
[71]
Philippens, I.H.C.H.M.; Böszörményi, K.P.; Wubben, J.A.M.; Fagrouch, Z.C.; van Driel, N.; Mayenburg, A.Q.; Lozovagia, D.; Roos, E.; Schurink, B.; Bugiani, M.; Bontrop, R.E.; Middeldorp, J.; Bogers, W.M.; de Geus-Oei, L.F.; Langermans, J.A.M.; Verschoor, E.J.; Stammes, M.A.; Verstrepen, B.E. Brain inflammation and intracellular α-synuclein aggregates in macaques after SARS-CoV-2 Infection. Viruses, 2022, 14(4), 776.
[http://dx.doi.org/10.3390/v14040776]
[72]
Kramer, P.R.; Kramer, S.F.; Guan, G. 17β-estradiol regulates cytokine release through modulation of CD16 expression in monocytes and monocyte-derived macrophages. Arthritis Rheum., 2004, 50(6), 1967-1975.
[http://dx.doi.org/10.1002/art.20309] [PMID: 15188374]
[73]
Nadkarni, S.; Cooper, D.; Brancaleone, V.; Bena, S.; Perretti, M. Activation of the annexin A1 pathway underlies the protective effects exerted by estrogen in polymorphonuclear leukocytes. Arterioscler. Thromb. Vasc. Biol., 2011, 31(11), 2749-2759.
[http://dx.doi.org/10.1161/ATVBAHA.111.235176] [PMID: 21836070]
[74]
Vermillion, M.S.; Ursin, R.L.; Attreed, S.E.; Klein, S.L. Estriol reduces pulmonary immune cell recruitment and inflammation to protect female mice from severe influenza. Endocrinology, 2018, 159(9), 3306-3320.
[http://dx.doi.org/10.1210/en.2018-00486] [PMID: 30032246]
[75]
Ghisletti, S.; Meda, C.; Maggi, A.; Vegeto, E. 17beta-estradiol inhibits inflammatory gene expression by controlling NF-kappaB intracellular localization. Mol. Cell. Biol., 2005, 25(8), 2957-2968.
[http://dx.doi.org/10.1128/MCB.25.8.2957-2968.2005] [PMID: 15798185]
[76]
Matschke, J.; Lütgehetmann, M.; Hagel, C.; Sperhake, J.P.; Schröder, A.S.; Edler, C.; Mushumba, H.; Fitzek, A.; Allweiss, L.; Dandri, M.; Dottermusch, M.; Heinemann, A.; Pfefferle, S.; Schwabenland, M.; Sumner Magruder, D.; Bonn, S.; Prinz, M.; Gerloff, C.; Püschel, K.; Krasemann, S.; Aepfelbacher, M.; Glatzel, M. Neuropathology of patients with COVID-19 in Germany: a post-mortem case series. Lancet Neurol., 2020, 19(11), 919-929.
[http://dx.doi.org/10.1016/S1474-4422(20)30308-2] [PMID: 33031735]
[77]
Kanberg, N.; Simrén, J.; Edén, A.; Andersson, L.M.; Nilsson, S.; Ashton, N.J.; Sundvall, P.D.; Nellgård, B.; Blennow, K.; Zetterberg, H.; Gisslén, M. Neurochemical signs of astrocytic and neuronal injury in acute COVID-19 normalizes during long-term follow-up. EBioMedicine, 2021, 70, 103512.
[http://dx.doi.org/10.1016/j.ebiom.2021.103512] [PMID: 34333238]
[78]
Savelieff, M.G.; Feldman, E.L.; Stino, A.M. Neurological sequela and disruption of neuron-glia homeostasis in SARS-CoV-2 infection. Neurobiol. Dis., 2022, 168, 105715.
[http://dx.doi.org/10.1016/j.nbd.2022.105715] [PMID: 35364273]
[79]
Santos-Galindo, M.; Acaz-Fonseca, E.; Bellini, M.J.; Garcia-Segura, L.M. Sex differences in the inflammatory response of primary astrocytes to lipopolysaccharide. Biol. Sex Differ., 2011, 2(1), 7.
[http://dx.doi.org/10.1186/2042-6410-2-7] [PMID: 21745355]
[80]
Sivritas, D.; Becher, M.U.; Ebrahimian, T.; Arfa, O.; Rapp, S.; Bohner, A.; Mueller, C.F.; Umemura, T.; Wassmann, S.; Nickenig, G.; Wassmann, K. Antiproliferative effect of estrogen in vascular smooth muscle cells is mediated by Kruppel-like factor-4 and manganese superoxide dismutase. Basic Res. Cardiol., 2011, 106(4), 563-575.
[http://dx.doi.org/10.1007/s00395-011-0174-z] [PMID: 21484412]
[81]
Stelzig, K.E.; Canepa-Escaro, F.; Schiliro, M.; Berdnikovs, S.; Prakash, Y.S.; Chiarella, S.E. Estrogen regulates the expression of SARS-CoV-2 receptor ACE2 in differentiated airway epithelial cells. Am. J. Physiol. Lung Cell. Mol. Physiol., 2020, 318(6), L1280-L1281.
[http://dx.doi.org/10.1152/ajplung.00153.2020] [PMID: 32432918]
[82]
Shimada, K.; Kitazato, K.T.; Kinouchi, T.; Yagi, K.; Tada, Y.; Satomi, J.; Kageji, T.; Nagahiro, S. Activation of estrogen receptor-α and of angiotensin-converting enzyme 2 suppresses ischemic brain damage in oophorectomized rats. Hypertension, 2011, 57(6), 1161-1166.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.110.167650] [PMID: 21536991]
[83]
Abdelkader, N.F.; Abd El-Latif, A.M.; Khattab, M.M. Telmisartan/17β-estradiol mitigated cognitive deficit in an ovariectomized rat model of Alzheimer’s disease: Modulation of ACE1/ACE2 and AT1/AT2 ratio. Life Sci., 2020, 245, 117388.
[http://dx.doi.org/10.1016/j.lfs.2020.117388] [PMID: 32007576]
[84]
Miranda, M.; Morici, J.F.; Zanoni, M.B.; Bekinschtein, P. Brain-derived neurotrophic factor: a key molecule for memory in the healthy and the pathological brain. Front. Cell. Neurosci., 2019, 13, 363.
[http://dx.doi.org/10.3389/fncel.2019.00363] [PMID: 31440144]
[85]
Shete, A. Urgent need for evaluating agonists of angiotensin-(1-7)/Mas receptor axis for treating patients with COVID-19. Int. J. Infect. Dis., 2020, 96, 348-351.
[http://dx.doi.org/10.1016/j.ijid.2020.05.002] [PMID: 32389847]
[86]
Malek Mahdavi, A. A brief review of interplay between vitamin D and angiotensin-converting enzyme 2: Implications for a potential treatment for COVID-19. Rev. Med. Virol., 2020, 30(5), e2119.
[http://dx.doi.org/10.1002/rmv.2119] [PMID: 32584474]
[87]
Zhang, H.; Liu, Y.; Rao, L.; Cen, Y.; Cheng, K. Effects of the combination of Herba Epimedii and Semen Plentaginis on the aortic ACE2/Angiotensin-(1-7)/Mas receptor axis and blood pressure in spontaneously hypertensive rats. Int. J. Clin. Exp. Med., 2019, 12(4), 3376-3386.
[88]
Ghasemnejad-Berenji, M.; Pashapour, S.; Ghasemnejad-Berenji, H. Therapeutic potential for clomiphene, a selective estrogen receptor modulator, in the treatment of COVID-19. Med. Hypotheses, 2020, 145, 110354.
[http://dx.doi.org/10.1016/j.mehy.2020.110354] [PMID: 33129007]
[89]
Allegretti, M.; Cesta, M.C.; Zippoli, M.; Beccari, A.; Talarico, C.; Mantelli, F.; Bucci, E.M.; Scorzolini, L.; Nicastri, E. Repurposing the estrogen receptor modulator raloxifene to treat SARS-CoV-2 infection. Cell Death Differ., 2022, 29(1), 156-166.
[http://dx.doi.org/10.1038/s41418-021-00844-6] [PMID: 34404919]
[90]
Lemes, R.M.R.; Costa, A.J.; Bartolomeo, C.S.; Bassani, T.B.; Nishino, M.S.; Pereira, G.J.S.; Smaili, S.S.; Maciel, R.M.B.; Braconi, C.T.; da Cruz, E.F.; Ramirez, A.L.; Maricatto, J.T.; Janini, L.M.R.; Prado, C.M.; Stilhano, R.S.; Ureshino, R.P. 17β-estradiol reduces SARS-CoV-2 infection in vitro. Physiol. Rep., 2021, 9(2), e14707.
[http://dx.doi.org/10.14814/phy2.14707] [PMID: 33463909]
[91]
Seth, S.; Sharma, R.; Mishra, P.; Solanki, H.; Singh, M.; Singh, M. Role of short-term estradiol supplementation in symptomatic postmenopausal COVID-19 females: A randomized controlled trial. J Midlife Health, 2021, 12(3), 211-218.
[http://dx.doi.org/10.4103/jmh.JMH_57_21] [PMID: 34759703]
[92]
U.S. National Library of Medicine. Clinical Trials Page., Available on-line: www.clinicaltrials.gov (accessed on April 20, 2022) Identifier: NCT04539626.
[93]
U.S. National Library of Medicine. Clinical Trials Page., Available on-line: www.clinicaltrials.gov (accessed on April 20, 2022) Identifier: NCT04359329.
[94]
U.S. National Library of Medicine. Clinical Trials Page., Available on-line: www.clinicaltrials.gov (accessed on April 20, 2022) Identifier: NCT04853069.
[95]
U.S. National Library of Medicine. Clinical Trials Page., Available on-line: www.clinicaltrials.gov (accessed on April 20, 2022) Identifier: NCT04865029.
[96]
U.S. National Library of Medicine. Clinical Trials Page., Available on-line: www.clinicaltrials.gov (accessed on April 20, 2022) Identifier: NCT04801836.
[97]
U.S. National Library of Medicine. Clinical Trials Page., Available on-line: www.clinicaltrials.gov (accessed on April 20, 2022) Identifier: NCT05172050.
[98]
Estera, L.A.; Walsh, S.P.; Headen, J.A.; Williamson, R.E.; Kalinski, A.L. Neuroinflammation: Breaking barriers and bridging gaps. Neurosci. Res., 2021, S0168-0102(21), 00222-4.
[http://dx.doi.org/10.1016/j.neures.2021.11.001]
[99]
Muzio, L.; Viotti, A.; Martino, G. Microglia in neuroinflammation and neurodegeneration: from understanding to therapy. Front. Neurosci., 2021, 15, 742065.
[http://dx.doi.org/10.3389/fnins.2021.742065] [PMID: 34630027]
[100]
Kölliker-Frers, R.; Udovin, L.; Otero-Losada, M.; Kobiec, T.; Herrera, M.I.; Palacios, J.; Razzitte, G.; Capani, F. Neuroinflammation: an integrating overview of reactive-neuroimmune cell interactions in health and disease. Mediators Inflamm., 2021, 2021, 1-20.
[http://dx.doi.org/10.1155/2021/9999146] [PMID: 34158806]
[101]
Almey, A.; Milner, T.A.; Brake, W.G. Estrogen receptors in the central nervous system and their implication for dopamine-dependent cognition in females. Horm. Behav., 2015, 74, 125-138.
[http://dx.doi.org/10.1016/j.yhbeh.2015.06.010] [PMID: 26122294]
[102]
Marin, R.; Casañas, V.; Pérez, J.A.; Fabelo, N.; Fernandez, C.E.; Diaz, M. Oestrogens as modulators of neuronal signalosomes and brain lipid homeostasis related to protection against neurodegeneration. J. Neuroendocrinol., 2013, 25(11), 1104-1115.
[http://dx.doi.org/10.1111/jne.12068] [PMID: 23795744]
[103]
Yang, S.H.; Liu, R.; Perez, E.J.; Wen, Y.; Stevens, S.M., Jr; Valencia, T.; Brun-Zinkernagel, A.M.; Prokai, L.; Will, Y.; Dykens, J.; Koulen, P.; Simpkins, J.W. Mitochondrial localization of estrogen receptor β. Proc. Natl. Acad. Sci. USA, 2004, 101(12), 4130-4135.
[http://dx.doi.org/10.1073/pnas.0306948101] [PMID: 15024130]
[104]
Ascenzi, P.; di Masi, A.; Leboffe, L.; Fiocchetti, M.; Nuzzo, M.T.; Brunori, M.; Marino, M. Neuroglobin: From structure to function in health and disease. Mol. Aspects Med., 2016, 52, 1-48.
[http://dx.doi.org/10.1016/j.mam.2016.10.004] [PMID: 27825818]
[105]
Lan, W.B.; Lin, J.H.; Chen, X.W.; Wu, C.Y.; Zhong, G.X.; Zhang, L.Q.; Lin, W.P.; Liu, W.N.; Li, X.; Lin, J.L. Overexpressing neuroglobin improves functional recovery by inhibiting neuronal apoptosis after spinal cord injury. Brain Res., 2014, 1562, 100-108.
[http://dx.doi.org/10.1016/j.brainres.2014.03.020] [PMID: 24675030]
[106]
Raychaudhuri, S.; Skommer, J.; Henty, K.; Birch, N.; Brittain, T. Neuroglobin protects nerve cells from apoptosis by inhibiting the intrinsic pathway of cell death. Apoptosis, 2010, 15(4), 401-411.
[http://dx.doi.org/10.1007/s10495-009-0436-5] [PMID: 20091232]
[107]
Xiong, X.X.; Pan, F.; Chen, R.Q.; Hu, D.X.; Qiu, X.Y.; Li, C.Y.; Xie, X.Q.; Tian, B.; Chen, X.Q. Neuroglobin boosts axon regeneration during ischemic reperfusion via p38 binding and activation depending on oxygen signal. Cell Death Dis., 2018, 9(2), 163.
[http://dx.doi.org/10.1038/s41419-017-0260-8] [PMID: 29416029]
[108]
Voskuhl, R.R. Estrogen therapy for brain gray matter atrophy and associated disability. U.S. Patent, 2021,213,033, 2021.
[109]
Donaldson, W.A.; Sem, D.S.; Frick, K.M. Substituted (4-Hydroxyphenyl) cycloalkane and (4-Hydroxyphenyl) cycloalkene compounds and uses thereof as selective agonists of the estrogen receptor beta isoform for enhanced memory consolidation. U.S. Patent, 2021,340155, 2021.
[110]
Katzenellenbogen, J.A.; Tiwari-Woodruff, S.K.; Kim, S.H.; Katzenellenbogen, B. Estrogen receptor beta ligands for the prevention and treatment of multiple sclerosisi and other demyelinating, inflammatory and neurodegenerative diseases. U.S. Patent, 2021,230,121, 2021.
[111]
Voskuhl, R. Estrogen receptor ligand treatment for neurodegenerative diseases. U.S. Patent, 2021,008,002, 2021.
[112]
Voskuhl, R.R.; Wang, H.; Wu, T.C.J.; Sicotte, N.L.; Nakamura, K.; Kurth, F.; Itoh, N.; Bardens, J.; Bernard, J.T.; Corboy, J.R.; Cross, A.H.; Dhib-Jalbut, S.; Ford, C.C.; Frohman, E.M.; Giesser, B.; Jacobs, D.; Kasper, L.H.; Lynch, S.; Parry, G.; Racke, M.K.; Reder, A.T.; Rose, J.; Wingerchuk, D.M.; MacKenzie-Graham, A.J.; Arnold, D.L.; Tseng, C.H.; Elashoff, R. Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol., 2016, 15(1), 35-46.
[http://dx.doi.org/10.1016/S1474-4422(15)00322-1] [PMID: 26621682]
[113]
Jung, M.E.; Voskuhl, R.R. Estrogen receptor ligands compositions and methods related thereto. U.S. Patent, 2021,196,667, 2021.
[114]
Voskuhl, R.R. Estriol therapy for autoimmune and neurodegenerative diseases and disorders. U.S. Patent 2015,051,178, 2015.
[115]
Olsson, R. Compounds and compositions for treating neurodegenerative diseases. WIPO Patent, 2014(125), 12, 2014.
[116]
Diaz-Brinton, R.; Zhao, L. Phytoestrogenic formulations for alleviation or prevention of neurodegenerative diseases. U.S. Patent 2012,164,122, 2012.
[117]
Piu, F.; Gil, D.W.; Olsson, R.; Gustafsson, M.; Hyldtoft, L.; Siemasko, K.; Stern, M.E. Compounds with activity at estrogen receptors. WIPO Patent 2008(033), 894, 2008.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy