LongCovid

Abstract

30% of COVID-19 patients suffers from long-term olfactory dysfunction (anosmia and hyposmia respectively)[1, 2]. However, limited treatments are currently available for patients diagnosed with persistent post-COVID infection involving persistent olfactory problems. Purpose: The purpose of this draft is to review the capacity of (endo)cannabinoids and phytocannabinoids to neuromodulate, repair, and promote olfactory function in patients affected with olfactory dysfunction following a COVID-19 infection.

Background

The Pax6-Tbr2 transcription factor has been reported to be a critical pathway for promoting neurogenesis and maintenance of olfactory sensory neurons (OSNs)[3]. Furthermore, this transcription factor can be activated via cannabinoids receptors (CB1/2) activity[4]. Interestingly, increased endocannabinoid-mediated Pax6-Tbr2 expression in olfactory bulb mitral cells correlates with production of GABAergic OB interneurons.

Summary

1. Disinhibition of GABAergic interneurons in the olfactory bulb is implicated in the etiology of post-COVID-19 infection. Complementary evidences suggests that GABA receptors may potentially limit COVID-19 disease severity, lung viral load and death in SARS-CoV-2 infected mice[5]. Furthermore, reduced inhibition of GABAergic interneurons within the primary motor cortex (M1) of post-COVID-19 patients suggest that olfactory dysfunction is partially caused by dopamine (D2) dysregulation.[6][7]

2. Pax6-Tbr2 expression may enhances olfactory training (OT) by promoting growth and regeneration of new GABAergic neurons in the olfactory bulb.

Important findings

1. Endocannabinoids signaling controls olfactory processing including olfactory learning and memory.

2. The SARS-CoV-2 virus can enter the nervous system by invading the neural-mucosal interface in the olfactory mucosa.

3. SARS-CoV-2 infection can impairs olfactory function and disrupt GABAergic interneurons in the olfactory bulb.

4. Pax6-Tbr2 expression plays a critical role in the generation of GABAergic OB interneurons.

Conclusion

More research is warranted to assess the role of endocannabinoids in controlling neural repair and regeneration of GABAergic OB interneurons in patients with chronic olfactory dysfunction after COVID-19 infection. Future directions: Focus on MAO-B inhibitors (ie: rasagiline) for treatment of olfactory dysfunction in long-COVID. [8]

References

1. https://www.mdpi.com/2077-0383/11/12/3275/htm

   Olfactory Training in Post-COVID-19 Persistent Olfactory Disorders: Value Normalization for Threshold but Not Identification

2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9377782/

   COVID-19 and olfactory dysfunction: a looming wave of dementia?

3. https://www.sciencedirect.com/science/article/abs/pii/S1044743113000146

   Pax6 regulates Tbr1 and Tbr2 expressions in olfactory bulb mitral cells

4. https://academic.oup.com/cercor/article/25/9/2395/2926052

   CB1 Cannabinoid Receptor-Dependent Activation of mTORC1/Pax6 Signaling Drives Tbr2 Expression and Basal Progenitor Expansion in the Developing Mouse Cortex

5. https://www.biorxiv.org/content/10.1101/2022.06.07.494579v1

   GABA-receptors are a new druggable target for limiting disease severity, lung viral load, and death in SARS-CoV-2 infected mice

6. https://www.sciencedirect.com/science/article/pii/S1388245721000808

   Intracortical GABAergic dysfunction in patients with fatigue and dysexecutive syndrome after COVID-19

7. https://www.pnas.org/doi/10.1073/pnas.2118570119

   Olfactory regulation by dopamine and DRD2 receptor in the nose

8. https://www.nature.com/articles/s12276-021-00646-3

   Redefining differential roles of MAO-A in dopamine degradation and MAO-B in tonic GABA synthesis

9. https://www.cell.com/cell-reports/fulltext/S2211-1247(18)31797-2

   Single-Cell RNA-Seq of Mouse Olfactory Bulb Reveals Cellular Heterogeneity and Activity-Dependent Molecular Census of Adult-Born Neurons

10. https://www.jneurosci.org/content/36/31/8210

    A Subtype of Olfactory Bulb Interneurons Is Required for Odor Detection and Discrimination Behaviors

11. https://www.jneurosci.org/content/28/25/6439

    A Dlx2- and Pax6-Dependent Transcriptional Code for Periglomerular Neuron Specification in the Adult Olfactory Bulb

12. https://link.springer.com/article/10.1007/s00702-021-02326-y

    Endocannabinoid and dopaminergic system: the pas de deux underlying human motivation and behaviors