Journal of the Neurological Sciences 427 (2021) 117554

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Journal of the Neurological Sciences
journal homepage: www.elsevier.com/locate/jns

Letter to the Editor
Potentials to alleviate coagulopathy and enhance microglial function of beta (β)- glucans, making
them worth a clinical study for COVID-19’s neurological sequalae
A R T I C L E I N F O
Keywords
COVID-19
Neurological sequalae
Microglia
Beta glucan
Nutritional supplement

Dear Editor,
Widespread neurological and psychiatric sequalae of COVID-19 havebeen reported affecting all age groups [1] with presence of low-grade
chronic inflammation and down-regulated ACE-2 levels making the in­dividual more vulnerable for severe neurological effects of COVID-19[2] as there will be greater disruption of the blood-brain barrier andhyper inflammation. Systemic immune inflammation index (SII)
including neutrophil, platelet and lymphocyte counts serve as potential
biomarkers to find an individual’s risk of neurological effects of COVID19 [2]. SARS-CoV2 has been shown to affect the immune pathways
associated with the central nervous system (CNS) and the peripheral
nervous system (PNS) leading to long-term neurological sequelae [3].
Intracranial hemorrhage, ischemic stroke, parkinsonism, dementia,
anxiety disorders and psychotic disorders have been reported as
sequalae of COVID-19 [4]. A recently published retrospective cohort
study on the neurological and psychiatric sequalae of COVID-19 in
236,379 patients [5] has shown that the incidence of ischemic stroke inabout 10% of patients, majority with COVID-19 associated encepha­lopathy which is alarming and necessitates steps to prevent or manage inthose already affected. Werner et al. [6] have reported yet anotherneurological sequala, incidence of transient global amnesia during theCOVID-19 hypothesizing the mechanism to be an encephalitic autoim­
mune pathology by the SARS CoV2 virus. Neurological manifestations of
COVID-19 are thus postulated to be due to the binding of SARS-CoV-2 toACE-2 activating intracellular pattern recognition receptors (PRRs)
which sense the pathogen associated molecular patterns (PAMPs)
setting off maladapted immune responses leading to inflammatory andimmune activities disrupting the coagulation-embolism pathways in theCNS and PNS [7]. The different types of cells in the CNS and PNS
including the glial cells, neurons, endothelial and arterial smooth muscle
cells are all affected leading to the neurological manifestations of
COVID-19 [8]. However, the effects of SARS-CoV2 on human astrocytes,
especially the microglia being the key-players in neural inflammation[6] makes us specifically focus on microglia in the context of conditions
that involve neural- inflammation such as stroke, Parkinson’s disease,
Alzheimer’s etc. For recovery, optimal functioning of the neuroglia isessential for synaptic organization, neurotrophic support, phagocytosis
of apoptotic cells, debris removal, myelin turnover, control of neuronal

excitability besides brain protection and repair. Microglia during
COVID-19 are postulated to be in a primed state due to a previous
encounter of inflammatory stimuli, when challenged with SARS-CoV-2
infection, in those with co-morbidities including psychological stress,
gut dysbiosis, metabolic disorders, obesity and ageing lead to severe
neurological sequalae [7]. Therefore, strategies towards beneficial
reprogramming of microglia, apart from management of co-morbidities
gain critical importance to prevent and manage COVID-19 associatedneurological sequalae. Some of the vaccines themselves associated withpossible coagulation risk apart from not widely available and lack ofdefinitive therapies for COVID-19, divert our attention to supportive
strategies such as biological response modifying beta glucans which aresafe food supplements, yet with potentials for a long-term prophylaxis.
Especially, an AFO-202 beta (β)- glucan possessing potentials as a vac­cine adjuvant COVID-19, exerting beneficial influence on all arms of
immunity, on blood glucose and lipid levels while modulating immunedysfunction associated coagulopathy [9] is worth considering for clin­
ical trials. Beta (β)- glucan -mediated microglial activation elicits aunique immune response that doesn’t result in significant production ofcytokines or chemokines via its major receptor, the Dectin-1 mediatedsignaling pathway [10]. Reports have documented that β-Glucans havethe potential to prevent or treat excessive microglial activation during
chronic inflammatory conditions [11] and their triggering of neuro­
inflammation has been shown to actually enable CNS axon regeneration[12]. Above all, β-Glucans have been shown to have neuroprotective
effects after transient retinal ischemia and reperfusion [13] besidehaving been proven to exert antioxidant effects on the brain [14] in adiabetic neuropathy model. Their direct antiplatelet, antioxidative,
anticoagulant and antithrombotic actions on the systemic hematologicalcomponents support the beneficial effects to prevent COVID-19associated coagulopathy [9]. These positive effects of β-Glucans alongwith capabilities to improve elements of cognition and brain function
via the gut-brain axis in an obese mouse model [15] adds to their merit
as a prophylactic agent in the fight against COVID-19 and its neuro­
logical sequalae.

https://doi.org/10.1016/j.jns.2021.117554
Received 27 April 2021; Received in revised form 14 June 2021; Accepted 21 June 2021
Available online 22 June 2021
0022-510X/© 2021 Elsevier B.V. All rights reserved.

Letter to the Editor

Journal of the Neurological Sciences 427 (2021) 117554

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Consent for publication
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Availability of data and materials
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Funding
No external funding was obtained for preparing the manuscript
Authors’ contributions
NI, and SA contributed to conception and design. SA drafted themanuscript. KR, RK and MI performed critical revision of the manu­
script. All authors contributed to manuscript revision, read, andapproved the submitted version.
Declaration of Competing InterestAuthor Samuel Abraham is a shareholder in GN Corporation, Japan
which in turn is a shareholder in the manufacturing company of the AFO
202 Beta Glucan.

Kadalraja Raghavana, Ramesh Shankar Kandaswamyb,Nobunao Ikewakic,d, Masaru Iwasakie, Samuel J.K. Abrahame,f,g,*a
Department of Paediatric Neurology, Sarvee Integra Private Limited,Chennai, Indiab
Consultant Psychiatrist & Clinical Director, Lincolnshire Partnership NHSFoundation Trust, United KingdomcDept. of Medical Life Science, Kyushu University of Health and Welfare,JapandInstitute of Immunology, Junsei Educational Institute, Nobeoka, Miyazaki,
JapaneCentre for Advancing Clinical Research (CACR), University of Yamanashi- School of Medicine, Chuo, JapanfMary-Yoshio Translational Hexagon (MYTH), Nichi-In Centre forRegenerative Medicine (NCRM), Chennai, Indiag
Antony- Xavier Interdisciplinary Scholastics (AXIS), GN Corporation Co.
Ltd., Kofu, Japan

Acknowledgements
The authors thank Mr. Takashi Onaka, Mr. Yasunori Ikeue, Mr.
Mitsuru Nagataki (Sophy Inc., Kochi, Japan), for necessary technicalclarifications and Loyola-ICAM College of Engineering and Technology(LICET), India for their support to our research.
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*2Corresponding author at: 3-8, Wakamatsu, Kofu, Yamanashi 4000866, Japan.
E-mail addresses: drkraghavan27@gmail.com (K. Raghavan),drsam@nichimail.jp, drspp@nichimail.jp (S.J.K. Abraham).