This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Research
Yu Xu
Department of Otolaryngology–Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, China;
Corresponding Author
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Background: Allergic rhinitis (AR) is a common chronic allergic disease of the upper airway that not only causes peripheral inflammation, but also induces neuroinflammation in the hippocampus, prefrontal cortex, olfactory bulb and other brain areas. Recent studies have suggested that the dopamine D2 receptor acts as a key target in regulating immune functions and neuroinflammatory reaction, which may be a promising target for AR-induced olfactory dysfunction (OD).
Methods: An AR mouse model with OD induced by ovalbumin (OVA) were constructed. A coculture system of olfactory bulb neurons (OBNs) and microglias was established. The buried food pellet test was to evaluate the olfactory function of the mice. Immunofluorescence staining, HE staining, ELISA, Western blotting, and TUNEL staining were also used to investigate the molecular mechanisms underlying the anti-inflammatory effects of the dopamine D2 receptor in AR-induced OD.
Results: We confirmed that AR mice with or without OD had the characteristics of AR, but the expression of the microglial marker CD11b and the related cytokines (TNF-α, IL-1β and IL-6) in the AR mice with OD were significantly increased in the olfactory bulb compared with those of mice without OD. Nasal administration of quinpirole, a dopamine D2 receptor agonist, shortened the time to find the food pellets, inhibited the expression of TLR4/MyD88/NF-κB signalings and the levels of TNF-α, IL-1β and IL-6. In the coculture system of OBNs and microglias, quinpirole inhibited the release of TLR4/MyD88/NF-κB signalings-dependent inflammatory cytokines in the microglias, which was accompanied by decreased AMPA receptor GluR1, increased GluR2 and reduced TUNEL positive cells in the OBNs.
Conclusion: Activation of the dopamine D2 receptor inhibits the release of inflammatory cytokines through the microglia-dependent TLR4/MyD88/NF-κB signalings, alleviates AMPA receptor-mediated damage of the olfactory bulb, and protects olfactory function.
Keywords
Allergic rhinitis, Olfactory dysfunction, Dopamine D2 receptor, Neuroinflammation, AMPA receptor
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This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Research
Yu Xu
Department of Otolaryngology–Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, China;
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 1
Posted 01 Oct, 2020
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Neurobiology of Disease
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background: Allergic rhinitis (AR) is a common chronic allergic disease of the upper airway that not only causes peripheral inflammation, but also induces neuroinflammation in the hippocampus, prefrontal cortex, olfactory bulb and other brain areas. Recent studies have suggested that the dopamine D2 receptor acts as a key target in regulating immune functions and neuroinflammatory reaction, which may be a promising target for AR-induced olfactory dysfunction (OD).
Methods: An AR mouse model with OD induced by ovalbumin (OVA) were constructed. A coculture system of olfactory bulb neurons (OBNs) and microglias was established. The buried food pellet test was to evaluate the olfactory function of the mice. Immunofluorescence staining, HE staining, ELISA, Western blotting, and TUNEL staining were also used to investigate the molecular mechanisms underlying the anti-inflammatory effects of the dopamine D2 receptor in AR-induced OD.
Results: We confirmed that AR mice with or without OD had the characteristics of AR, but the expression of the microglial marker CD11b and the related cytokines (TNF-α, IL-1β and IL-6) in the AR mice with OD were significantly increased in the olfactory bulb compared with those of mice without OD. Nasal administration of quinpirole, a dopamine D2 receptor agonist, shortened the time to find the food pellets, inhibited the expression of TLR4/MyD88/NF-κB signalings and the levels of TNF-α, IL-1β and IL-6. In the coculture system of OBNs and microglias, quinpirole inhibited the release of TLR4/MyD88/NF-κB signalings-dependent inflammatory cytokines in the microglias, which was accompanied by decreased AMPA receptor GluR1, increased GluR2 and reduced TUNEL positive cells in the OBNs.
Conclusion: Activation of the dopamine D2 receptor inhibits the release of inflammatory cytokines through the microglia-dependent TLR4/MyD88/NF-κB signalings, alleviates AMPA receptor-mediated damage of the olfactory bulb, and protects olfactory function.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
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