Substance P and Prokineticin-2 are overexpressed in olfactory neurons and play differential roles in persons with persistent post-COVID-19 olfactory dysfunction.

Persistent olfactory dysfunction (OD) is one of the most complaining and worrying complications of long COVID-19 because of the potential long-term neurological consequences. While causes of OD in the acute phases of the SARS-CoV-2 infection have been figured out, reasons for persistent OD are still unclear. Here we investigated the activity of two inflammatory pathways tightly linked with olfaction pathophysiology, namely Substance P (SP) and Prokineticin-2 (PK2), directly within the olfactory neurons (ONs) of patients to understand mechanisms of persistent post-COVID-19 OD. ONs were collected by non-invasive brushing from ten patients with persistent post-COVID-19 OD and ten healthy controls. Gene expression levels of SP, Neurokinin receptor 1, Interleukin-1ß (IL-1ß), PK2, PK2 receptors type 1 and 2, and Prokineticin-2-long peptide were measured in ONs by Real Time-PCR in both the groups, and correlated with residual olfaction. Immunofluorescence staining was also performed to quantify SP and PK2 proteins. OD patients, compared to controls, exhibited increased levels of both SP and PK2 in ONs, the latter proportional to residual olfaction. This work provided unprecedented, preliminary evidence that both SP and PK2 pathways may have a role in persistent post-COVID-19 OD. Namely, if the sustained activation of SP, lasting months after infection's resolution, might foster chronic inflammation and contribute to hyposmia, the PK2 expression could instead support the smell recovery.

Investigational drugs for the treatment of olfactory dysfunction.

INTRODUCTION: Olfactory dysfunction could be the sign of acquired or degenerative diseases. The loss of the sense can be caused by a damage in the nasal structure (olfactory epithelium) or a neuro inflammation/degeneration in the superior olfactory pathway. The understanding of the origin of the smell alteration would be desirable for appropriate management of the problem. Unfortunately, clinical investigations do not always allow to define the exact cause. AREAS COVERED: This review discusses the treatments available and their mechanism of action based on the administration methods; in fact, just looking at the results obtained by the researcher using topic versus systemic treatment, might be possible to speculate about the peripheral or central origin of the olfactory disorder. EXPERT OPINION: Because COVID-19 causes olfactory loss and several treatments (topical and systemic) have been tested in this disease, we have decided to use this model of acquired olfactory loss to discuss the different therapeutical option. The authors believe these treatments might be an option also for treating olfactory disease related to neurodegeneration.