Topical Dexamethasone Administration Impairs Protein Synthesis and Neuronal Regeneration in the Olfactory Epithelium

Author(s)

Crisafulli, Umberto ^{[1, 2]} ; Xavier, Andre M. ^[2] ; dos Santos, Fabiana B. ^[2] ; Cambiaghi, Tavane D. ^[3] ; Chang, Seo Y. ^[2] ; Porcionatto, Marimelia ^[2] ; Castilho, Beatriz A. ^[3] ; Malnic, Bettina ^[1] ; Glezer, Isaias ^[2]

Affiliation

^[1] Univ Sao Paulo, Inst Quim, Dept Biochem, Sao Paulo - Brazil

^[2] Univ Fed Sao Paulo, Dept Biochem, Escola Paulista Med, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Escola Paulista Med, Dept Microbiol Immunol & Parasitol, Sao Paulo - Brazil

• Document type: Journal article
• Source: FRONTIERS IN MOLECULAR NEUROSCIENCE; v. 11, MAR 6 2018.
• Web of Science Citations: 2

Abstract

Chronic inflammatory process in the nasal mucosa is correlated with poor smell perception. Over-activation of immune cells in the olfactory epithelium (OE) is generally associated with loss of olfactory function, and topical steroidal anti-inflammatory drugs have been largely used for treating such condition. Whether this therapeutic strategy could directly affect the regenerative process in the OE remains unclear. In this study, we show that nasal topical application of dexamethasone (DEX; 200 or 800 ng/nostril), a potent synthetic anti-inflammatory steroid, attenuates OE lesion caused by Gram-negative bacteria lipopolysaccharide (LPS) intranasal infusion. In contrast, repeated DEX (400 ng/nostril) local application after lesion establishment limited the regeneration of olfactory sensory neurons after injury promoted by LPS or methimazole. Remarkably, DEX effects were observed when the drug was infused as 3 consecutive days regimen. The anti-inflammatory drug does not induce OE progenitor cell death, however, disturbance in mammalian target of rapamycin downstream signaling pathway and impairment of protein synthesis were observed during the course of DEX treatment. In addition, in vitro studies conducted with OE neurospheres in the absence of an inflammatory environment showed that glucocorticoid receptor engagement directly reduces OE progenitor cells proliferation. Our results suggest that DEX can interfere with the intrinsic regenerative cellular mechanisms of the OE, raising concerns on the use of topical anti-inflammatory steroids as a risk factor for progressive olfactory function impairment. (AU)

• FAPESP's process: 09/52047-5 - Translational regulation mediated by elF2 in eukaryotes
• Grantee: Beatriz Amaral de Castilho
• Support type: Research Projects - Thematic Grants
• FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
• Grantee: Ohara Augusto
• Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 07/53732-8 - Post-lesion cell regeneration in the nervous system and functional aspects of genes linked to innate immune response
• Grantee: Isaias Glezer
• Support type: Research Grants - Young Investigators Grants
• FAPESP's process: 09/04437-9 - The role of innate immune response in the course of neuroregeneration: a gene expression profile study
• Grantee: Umberto Crisafulli
• Support type: Scholarships in Brazil - Master
• FAPESP's process: 16/24471-0 - Odorant receptors: mechanisms of gene expression and signal transduction
• Grantee: Bettina Malnic
• Support type: Research Projects - Thematic Grants
• FAPESP's process: 11/13134-0 - Study of the influence of signaling Toll-Like Receptors (TLRs) and the gene MyD88 on olfactry epithelium neuronal regeneration
• Grantee: Umberto Crisafulli
• Support type: Scholarships in Brazil - Doctorate (Direct)