Preprint SARS-CoV-2 induces acute neurological signs while CGRP signaling blockade reduces IL-6 release and weight loss in mouse models, 2023, Rahman et al.

[SNT Gatchaman]

SARS-CoV-2 induces acute neurological signs while Calcitonin Gene-Related Peptide CGRP signaling blockade reduces interleukin 6 IL-6 release and weight loss in mouse models
Shafaqat M Rahman; David W Buchholz; Brian Imbiakha; Mason C Jaeger; Justin Leach; Raven M Osborn; Ann O Birmingham; Stephen Dewhurst; Hector C Aguilar; Anne E Luebke

COVID-19 can result in neurological symptoms such as fever, headache, dizziness, and nausea. We evaluated whether the Calcitonin Gene-Related Peptide (CGRP) receptor antagonist, olcegepant, used in migraine treatment could mitigate acute neuroinflammatory and neurological responses to SARS-COV-2 infection.

We infected wildtype C57BL/6J and 129/SvEv mice, and a 129 αCGRP-null mouse line with a mouse-adapted SARS-CoV-2 virus, and evaluated the effect of CGRP receptor antagonism on the outcome of that infection. We determined that CGRP receptor antagonism provided protection from permanent weight loss in older (>12 m) C57BL/6J and 129 SvEv mice. We also observed acute fever and motion-induced dizziness in all older mice, regardless of treatment. However, in both wildtype mouse lines, CGRP antagonism reduced acute interleukin 6 (IL-6) levels by half, with virtually no IL-6 release in mice lacking αCGRP.

These findings suggest that blockage of CGRP signaling protects against acute IL-6 release and subsequent inflammatory events after SARS-CoV-2 infection.


Link | PDF (Preprint: BioRxiv)

 

[SNT Gatchaman]

While CGRP has pleotropic effects on the immune system, CGRP release occurs as a result of SARS-CoV-2 activation of the transient receptor potential (TRP) channels; and is implicated in COVID-19 neurological symptoms such as fever, headache, dizziness, nausea pain, and the subsequent release of interleukin 6 (IL-6).

a recent study with a relatively greater number of patients showed that elevated CGRP plasma levels are correlated with increased disease severity in hospitalized COVID-19 patients [27]. In our study, the migraine drug olcegepant (small molecule CGRP receptor antagonist) reduced IL-6 release at three days post-infection (3 dpi) in two distinct wildtype mouse strains.

In conclusion, in addition to the acute effects studied here, antagonizing CGRP signaling may be therapeutic against long COVID, as long COVID patients also show higher IL-6 plasma levels. As long COVID has been demonstrated in mouse models, future plans include investigating if antagonizing CGRP signaling in preclinical models can mitigate neurological long COVID symptoms.