Impact of histaminergic H3 receptor antagonist on hypoglossal nucleus in chronic intermittent hypoxia conditions
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ORIGINAL INVESTIGATION
Impact of histaminergic H3 receptor antagonist on hypoglossal nucleus in chronic intermittent hypoxia conditions Liang Xie 1,2 & Qinhan Wu 1,2 & Weiping Hu 1,2 & Xu Wu 1,2 & Guiling Xiang 1,2 & Shengyu Hao 1,2 & Han Guo 1,2 & Shanqun Li 1,2 Received: 1 June 2020 / Accepted: 10 September 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Rationale The hypoglossal nucleus (HN) controls the movement of the genioglossus (GG) muscle whose dysfunction leads to airway occlusion and occurrence of obstructive sleep apnea (OSA). Histamine produced by the tuberomammillary nucleus (TMN) has a potent excitatory action on GG muscle activity. Objectives The aim of the study was to investigate the role histaminergic neurons play in the regulation of the genioglossus. Methods C57BL/6 mice were exposed to chronic intermittent hypoxia (CIH) for 3 weeks to resemble OSA. The histamine H3 receptor (H3R) antagonist ciproxifan was applied to increase histamine in the brain. Histamine levels and GG activity were measured by liquid chromatography–tandem mass spectrometry (LC-MS/MS) and electromyogram (EMG) separately. Neuronal activity and repair ability of the HN and TMN and key proteins of histamine were analyzed by immunohistochemistry and western blots. Results Significant decline of histamine level and GG activity of the HN and TMN induced by CIH exposure could be ameliorated by ciproxifan. Application of ciproxifan could also partly reverse the decline of the histidine decarboxylase (HDC) by CIH. Conclusions This investigation studied the impacts of ciproxifan on the HN and TMN in CIH conditions and revealed that the negative effects on the HN and TMN caused by CIH could be partly ameliorated by ciproxifan, which might open new perspectives for the development of pharmacological treatment for OSA. Keywords Hypoglossal nucleus . Tuberomammillary nucleus . Histamine . Ciproxifan . Chronic intermittent hypoxia
Introduction Obstructive sleep apnea (OSA) is a common and increasingly prevalent sleep disorder characterized by repetitive wakefulness and recurrent episodes of decreased (hypopnea) or absent (apnea) inspiratory airflow during sleep, resulting from the narrowing and closure of the upper airway along with intermittent oxygen desaturations (Dempsey et al. 2010). The Liang Xie, Qinhan Wu and Weiping Hu contributed equally to this work. * Han Guo [email protected] * Shanqun Li [email protected]; [email protected] 1
Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Rd., Shanghai 200032, China
2
Clinical Centre for Sleep Breathing Disorders and Snoring, Zhongshan Hospital, Fudan University, Shanghai, China
genioglossus (GG) muscle of the tongue is one of the pharyngeal dilator muscles. Its contraction promotes the anterior tongue movement and enlarges the pharyngeal airway, which increases the airflow in the upper way and prevents the occurrence of OSA in humans (Jordan and White 2008). A previous study proved that GG atony result
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