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

Schirinzi, Tommaso; Lattanzi, Roberta; Maftei, Daniela; Grillo, Piergiorgio; Zenuni, Henri; Boffa, Laura; Albanese, Maria; Simonetta, Clara; Bovenzi, Roberta; Maurizi, Riccardo; Loccisano, Laura; Vincenzi, Martina; Greco, Antonio; Girolamo, Stefano Di; Mercuri, Nicola Biagio; Passàli, Francesco Maria; Severini, Cinzia

doi:10.1016/j.bbi.2022.12.017

Cited by 14 publications

(7 citation statements)

References 47 publications

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“…Olfactory dysfunction (OD), comprehending loss (anosmia) or reduction of the sense of smell, is one of the long-term effects of COVID-19. The expression of PK2 in olfactory neurons (ONs) of patients with post-COVID-19 OD has been significantly increased and correlated with the data obtained by odor tests to their residual odor, suggesting a contribution of PK2 in OD recovery ( Schirinzi et al, 2023 ). Since efficient mitochondria in ONs are critical for proper olfactory signaling ( Fluegge et al, 2012 ) and PK2 enhances mitochondrial bioenergetics ( Neal et al, 2018 ), the authors hypothesize that PK2 may improve olfaction by stimulating mitochondrial activity or directly or counteracting the deleterious effects of chronic inflammation, which impairs mitochondrial activity exacerbating oxidative stress.…”

Section: The Prokineticin Signaling In Inflammation and Infectionmentioning

confidence: 65%

Therapeutic Potential of Targeting Prokineticin Receptors in Diseases

Vincenzi,

Kremić,

Jouve

et al. 2023

Pharmacol Rev

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The prokineticins (PKs) were discovered approximately 20 years ago as small peptides inducing gut contractility. Today, they are established as angiogenic, anorectic, and proinflammatory cytokines, chemokines, hormones, and neuropeptides involved in variety of physiologic and pathophysiological pathways. Their altered expression or mutations implicated in several diseases make them a potential biomarker. Their G-protein coupled receptors, PKR1 and PKR2, have divergent roles that can be therapeutic target for treatment of cardiovascular, metabolic, and neural diseases as well as pain and cancer. This article reviews and summarizes our current knowledge of PK family functions from development of heart and brain to regulation of homeostasis in health and diseases. Finally, the review summarizes the established roles of the endogenous peptides, synthetic peptides and the selective ligands of PKR1 and PKR2, and nonpeptide orthostatic and allosteric modulator of the receptors in preclinical disease models. The present review emphasizes the ambiguous aspects and gaps in our knowledge of functions of PKR ligands and elucidates future perspectives for PK research. Significance Statement This review provides an in-depth view of the prokineticin family and PK receptors that can be active without their endogenous ligand and exhibits “constitutive” activity in diseases. Their non- peptide ligands display promising effects in several preclinical disease models. PKs can be the diagnostic biomarker of several diseases. A thorough understanding of the role of prokineticin family and their receptor types in health and diseases is critical to develop novel therapeutic strategies with safety concerns.

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Section: The Prokineticin Signaling In Inflammation and Infectionmentioning

confidence: 65%

Therapeutic Potential of Targeting Prokineticin Receptors in Diseases

Vincenzi,

Kremić,

Jouve

et al. 2023

Pharmacol Rev

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“…In addition, cytokines, which are released during infection, reduce the expression of monoamino‐2 vesicular carriers [32], suggesting that SARS‐CoV‐2 infection, per se, may play a role in dopaminergic dysregulation. Moreover, recent studies show that the olfactory system exhibits inflammatory signatures, which might spread to the CNS and trigger degenerative processes [33].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, recent studies show that the olfactory system exhibits inflammatory signatures, which might spread to the CNS and trigger degenerative processes [33].…”

Section: Discussionmentioning

confidence: 99%

Parkinson disease following COVID‐19: Report of six cases

Calculli

Bocci

Porcino

et al. 2023

Euro J of Neurology

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Background and purpose Core clinical manifestations of COVID‐19 include influenza‐like and respiratory symptoms. However, it is now evident that neurological involvement may occur during SARS‐CoV‐2 infection, covering an extensive spectrum of phenotypical manifestations. A major challenge arising from this pandemic is represented by detecting emerging neurological complications following recovery from SARS‐CoV‐2 infection. To date, a few post‐COVID‐19‐infected subjects diagnosed with Parkinson disease (PD) have been described, raising the possibility of a connection between the infection and neurodegenerative processes. Here, we describe a case series of six subjects who developed PD after COVID‐19. Methods Patients were observed at Scientific Institute for Research and Health Care Mondino Foundation Hospital, Pavia (Italy), and San Paolo University Hospital of Milan (Italy) between March 2021 and June 2022. In all subjects, SARS‐CoV‐2 infection was confirmed by means of reverse transcriptase polymerase chain reaction from a nasopharyngeal swab. Subjects underwent an accurate neurological evaluation, and neuroimaging studies were performed. Results We describe six subjects who developed PD with an average time window after SARS‐CoV‐2 infection of 4–7 weeks. Apparently, no relationship with COVID‐19 severity emerged, and no overt structural brain abnormalities were found. All subjects experienced unilateral resting tremor at onset and showed a satisfactory response to dopaminergic treatment. Conclusions Immune responses to SARS‐CoV‐2 infection have been shown to shape the individual susceptibility to develop long‐term consequences. We hypothesize that, in these subjects, COVID‐19 has unmasked a latent neurodegenerative process. Characterization of the neuroinflammatory signatures in larger cohorts is warranted, which might provide novel insights into the pathogenesis of PD.

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“…The findings suggest that persistent T cell‐mediated inflammation may be associated with olfactory dysfunction in long‐COVID patients. In addition to IFN, other inflammatory cytokines such as substance P and prokineticin‐2 may also have a role in COVID‐related olfactory dysfunction [71].…”

Section: Olfactory Receptor Neuron Dysfunction Despite Not Being Infe...mentioning

confidence: 99%

Mechanisms of COVID‐19‐associated olfactory dysfunction

Chang,

Zaikos,

Kilner‐Pontone

et al. 2024

Neuropathology Appl Neurobio

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Olfactory dysfunction is one of the most common symptoms of COVID‐19. In the first 2 years of the pandemic, it was frequently reported, although its incidence has significantly decreased with the emergence of the Omicron variant, which has since become the dominant viral strain. Nevertheless, many patients continue to suffer from persistent dysosmia and dysgeusia, making COVID‐19‐associated olfactory dysfunction an ongoing health concern. The proposed pathogenic mechanisms of COVID‐19‐associated olfactory dysfunction are complex and likely multifactorial. While evidence suggests that infection of sustentacular cells and associated mucosal inflammation may be the culprit of acute, transient smell loss, alterations in other components of the olfactory system (e.g., olfactory receptor neuron dysfunction, olfactory bulb injury and alterations in the olfactory cortex) may lead to persistent, long‐term olfactory dysfunction. This review aims to provide a comprehensive summary of the epidemiology, clinical manifestations and current understanding of the pathogenic mechanisms of COVID‐19‐associated olfactory dysfunction.

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

Cited by 14 publications

References 47 publications

Therapeutic Potential of Targeting Prokineticin Receptors in Diseases

Therapeutic Potential of Targeting Prokineticin Receptors in Diseases

Parkinson disease following COVID‐19: Report of six cases

Mechanisms of COVID‐19‐associated olfactory dysfunction

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