Preprint Article Version 2 Preserved in Portico This version is not peer-reviewed

Daily Low Dose of Erythropoietin in Neuroinflammation; EPO Might Be Hazardous in COVID-19

Version 1 : Received: 5 June 2020 / Approved: 7 June 2020 / Online: 7 June 2020 (16:21:35 CEST)
Version 2 : Received: 16 August 2020 / Approved: 20 August 2020 / Online: 20 August 2020 (09:06:38 CEST)

How to cite: Nejat, R.; Sadr, A.S.; Ebrahimi, A.; Nabati, A.; Eshaghi, E. Daily Low Dose of Erythropoietin in Neuroinflammation; EPO Might Be Hazardous in COVID-19. Preprints 2020, 2020060107. Nejat, R.; Sadr, A.S.; Ebrahimi, A.; Nabati, A.; Eshaghi, E. Daily Low Dose of Erythropoietin in Neuroinflammation; EPO Might Be Hazardous in COVID-19. Preprints 2020, 2020060107.


Neuroinflammation, defined as inflammatory reactions mediated by cytokines, chemokines, reactive oxygen species, and secondary messengers in the central nervous system (CNS) including the brain and spinal cord is the basis of many neurological disorders. Recently, erythropoietin (EPO) has been considered and studied as a modulator of neuroinflammation. On this article minireview of pathophysiology of neuroinflammation and the neuroprotective effects of EPO is discussed and a case of subacute huge subdural hematoma with double mydriasis operated urgently, treated with low daily dose (vs high dose once or twice a month in the literature) of EPO and recovered fully and discharged home with good consciousness is reported. In addition, the probable unfavorable outcome of erythropoietin administration in patients with neuroinflammation in COVID-19 is considered.


Ang II; COVID19; erythropoietin; EPO-R; neuroinflammation: AT1R; SARS-CoV2; angiotensin(1-7); COVID-19 encephalopathy


Medicine and Pharmacology, Pharmacology and Toxicology

Comments (1)

Comment 1
Received: 20 August 2020
Commenter: Reza Nejat
Commenter's Conflict of Interests: Author
Comment: 1- Title has changed to: "Daily Low Dose of Erythropoietin in Neuroinflammation;EPO might be hazardous in COVID-19"
2- "Summary" is replaced with "Abstract".
3- Citations in the abstract are removed.
4- the last sentence in the abstract is changed to "In addition, the probable unfavorable outcome of erythropoietin administration in patients with neuroinflammation in COVID19 is considered." 
5- the 2nd and 3rd paragraphs on page8 section "EPO and Neuroinflammation in Brain Involvement in COVID-19" have changed to:
"According to some clinical evidence showing that erythropoietin might be supportive in patients with COVID-19 a randomized clinical trial has recently been designed [105, 106] However, neuroinflammation involving the brain in COVID-19 needs special consideration. SARS-CoV2 follows the track of ACE2 in the brain. As to the proposed novel theory that is supported by a great amount of literature in which the pathophysiology of cytokine storm and acute inflammatory reactions in COVID-19 are attributed to downregulation of ACE2 and subsequent hyperacute excess of angiotensin II (Ang II) relative to angiotensin(1-7) with supra-activation of angiotensin receptor type 1 (AT1R)[107] , EPO should be administered in these patients cautiously because of the positive feedback interactions  EPO and Ang II might exert.[108, 109]It has been reported that Ang II blood level in patients with COVID-19 is higher than that in non-infected healthy people.[110] AT1R located in brain circumventricular area and cerebrovascular endothelial cells is activated by circulating Ang II with the ability to impair neurovascular coupling and reduce cerebral blood flow (low dose of 0.1 pmol/min of Ang II  results in a 23% reduction in CBF).[111, 112]"
6- all COVID19 are replaced with COVID-19
7- At the end of "conclusion" the sentence "However, EPO due to its positive reciprocal feedback effect on angiotensin II, the hyperacute excess of which seems to be the culprit of inducing the deadly cytokine storm in COVID-19, should be used cautiously in this disease." was added.
8-The number of references has increased to 119.
9-The order of the references changed due to omission of citations in the abstract. References 2-4 are displaced to 24-26.
10- References 105 and 106 are newly added.
11- DOI of reference 107 is added.
12- Acknowledgement is changed to: "The authors would like to express their greatest thanks and gratitude to physicians including intensivists, anesthesiologists, radiologists, emergency medicine and infectious disease specialists and other healthcare workers who sacrifice the lives with dignity in CORONA pandemic and to all the anesthesiologists and personnel of Bazarganan Hospital ICU, Tehran, Iran, especially to adorable nurses who always take care of the patients meticulously and to the radiologists and personnel of imaging department of this hospital."
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