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Allergic asthma is characterized by chronic airway inflammation and is constantly associated with anxiety disorder. Recent studies showed bidirectional interaction between the brain and the lung tissue. However, where and how the brain is affected in allergic asthma remains unclear. We aimed to investigate the neuroinflammatory, neurochemical, and neurometabolic alterations that lead to anxiety-like behavior in an experimental model of allergic asthma. Mice were submitted to an allergic asthma model induced by ovalbumin (OVA) and the control group received only Dulbecco’s phosphate-buffered saline (DPBS). Our findings indicate that airway inflammation increases interleukin (IL) -9, IL-13, eotaxin, and IL-1β release and changes acetylcholinesterase (AChE) and Na⁺,K⁺-ATPase activities in the brain of mice. Furthermore, we demonstrate that a higher reactive oxygen species (ROS) formation and antioxidant defense alteration that leads to protein damage and mitochondrial dysfunction. Therefore, airway inflammation promotes a pro-inflammatory environment with an increase of BDNF expression in the brain of allergic asthma mice. These pro-inflammatory environments lead to an increase in glucose uptake in the limbic regions and to anxiety-like behavior that was observed through the elevated plus maze (EPM) test and downregulation of glucocorticoid receptor (GR). In conclusion, the present study revealed for the first time that airway inflammation induces neuroinflammatory, neurochemical, and neurometabolic changes within the brain that leads to anxiety-like behavior. Knowledge about mechanisms that lead to anxiety phenotype in asthma is a beneficial tool that can be used for the complete management and treatment of the disease.
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https://doi.org/10.1007/s11011-022-00907-8
ORIGINAL ARTICLE
Airway inflammation induces anxiety‑like behavior
throughneuroinflammatory, neurochemical, andneurometabolic
changes inanallergic asthma model
GéssicaLuanaAntunes1· JosianeSilvaSilveira1· CarolinaLuft1· SamuelGreggio2· GianinaTeribeleVenturin2·
FelipeSchmitz3· HelenaBiasibetti‑Brendler3· FrancieliVuolo4· FelipeDal‑Pizzol4· JadersonCostadaCosta2·
AngelaT.S.Wyse3· PauloMárcioPitrez5· AlineAndreadaCunha5
Received: 12 April 2021 / Accepted: 6 January 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022
Abstract
Allergic asthma is characterized by chronic airway inflammation and is constantly associated with anxiety disorder. Recent
studies showed bidirectional interaction between the brain and the lung tissue. However, where and how the brain is affected
in allergic asthma remains unclear. We aimed to investigate the neuroinflammatory, neurochemical, and neurometabolic
alterations that lead to anxiety-like behavior in an experimental model of allergic asthma. Mice were submitted to an aller-
gic asthma model induced by ovalbumin (OVA) and the control group received only Dulbecco’s phosphate-buffered saline
(DPBS). Our findings indicate that airway inflammation increases interleukin (IL) -9, IL-13, eotaxin, and IL-1β release and
changes acetylcholinesterase (AChE) and Na+,K+-ATPase activities in the brain of mice. Furthermore, we demonstrate
that a higher reactive oxygen species (ROS) formation and antioxidant defense alteration that leads to protein damage and
mitochondrial dysfunction. Therefore, airway inflammation promotes a pro-inflammatory environment with an increase of
BDNF expression in the brain of allergic asthma mice. These pro-inflammatory environments lead to an increase in glucose
uptake in the limbic regions and to anxiety-like behavior that was observed through the elevated plus maze (EPM) test and
downregulation of glucocorticoid receptor (GR). In conclusion, the present study revealed for the first time that airway inflam-
mation induces neuroinflammatory, neurochemical, and neurometabolic changes within the brain that leads to anxiety-like
behavior. Knowledge about mechanisms that lead to anxiety phenotype in asthma is a beneficial tool that can be used for the
complete management and treatment of the disease.
Keywords Asthma· Neuroinflammation· Mitochondrial dysfunction· Oxidative stress· microPET· Anxiety-like behavior
Introduction
Asthma is a major health problem that currently affects 300
million people worldwide (Dharmage etal. 2019). Allergic
asthma is characterized by bronchial hyperreactivity (BHR),
remodeling, and narrowing of the airway, resulting in wheez-
ing, coughing, and chest tightness. These classic asthma
symptoms are a consequence of chronic airway inflam-
mation, driven by T helper 2 (Th2) cells (Lambrecht etal.
2015). The Th2 lymphocytes classically produce cytokines,
such as interleukin (IL) IL-4, IL-5, and IL-13 which induces
production of immunoglobulin E (IgE), mucus overproduc-
tion, and production of reactive oxygen species (ROS) by
infiltrated leukocytes, especially eosinophils in the airway
(Haspeslagh etal. 2018).
* Géssica Luana Antunes
gessica.antunes@edu.pucrs.br
1 Infant Center, Pontifical Catholic University ofRio Grande
Do Sul (PUCRS), 6690 Ipiranga Ave., PortoAlegre,
RS90619-900, Brazil
2 Preclinical Research Center, Brain Institute - BraIns,
Pontifical Catholic University ofRio Grande Do Sul,
PUCRS, PortoAlegre, RS, Brazil
3 Laboratory ofNeuroprotection andMetabolic Disease,
Department ofBiochemistry, Federal University ofRio
Grande Do Sul, UFRGS, PortoAlegre, RS, Brazil
4 Laboratory ofExperimental Pathophysiology, Graduate
Program inHealth Sciences, Health Sciences Unit,
University ofSouthern Santa Catarina, UNESC, Criciúma,
SC, Brazil
5 Hospital Moinhos de Vento, PortoAlegre, RS, Brazil
/ Published online: 21 January 2022
Metabolic Brain Disease (2022) 37:911–926
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
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