Amitriptyline Reduces Sepsis-Induced Brain Damage Through TrkA Signaling Pathway
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Amitriptyline Reduces Sepsis-Induced Brain Damage Through TrkA Signaling Pathway Lina Zhang 1,2 & Xiaobei Peng 1 & Yuhang Ai 1 & Li Li 1 & Shuangpin Zhao 1 & Zhiyong Liu 1 & Qianyi Peng 1 & Songyun Deng 1 & Yan Huang 1 & Yunan Mo 1 & Li Huang 1,2 Received: 17 January 2020 / Accepted: 22 May 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Sepsis can induce acute and chronic changes in the central nervous system termed sepsis-associated encephalopathy (SAE). Not only cognitive deficits but also anxiety, depression, and post-traumatic stress disorder are common in severe sepsis survivors. In this study, we demonstrated that amitriptyline, a classic tricyclic antidepressant, reduced sepsis-induced brain damage through the tropomyosin receptor kinase A (TrkA) signaling pathway. Amitriptyline ameliorated neuronal loss assessed by Nissl staining in a mouse cecal ligation and puncture (CLP)–induced sepsis model. Furthermore, amitriptyline reduced early gliosis assessed by immunofluorescence and late cognitive deficits assessed by the Morris water maze (MWM) test. Moreover, amitriptyline treatment attenuated oxidative stress indicated by less superoxide dismutase (SOD) and catalase (CAT) activity consumption and malondialdehyde (MDA) accumulation. Interestingly, those protective effects of amitriptyline could be abolished by GW441756, a TrkA signaling pathway inhibitor. Immunoblot directly showed that TrkA signaling pathway–associated proteins, such as Akt and GSK3β, were involved in the neuroprotective effects of amitriptyline. Thus, amitriptyline appears to be an encouraging candidate to treat cognitive deficits and depression after severe sepsis. Keywords Neuroinflammation . Gliosis . Cognitive deficits . TrkA . Akt . GSK3β
Abbreviations SAE Sepsis-associated encephalopathy CLP Cecal ligation and puncture TrkA Tropomyosin receptor kinase A Akt Serine/threonine-specific protein kinase GSK3β Glycogen synthase kinase 3β GFAP Glial fibrillary acidic protein SOD Superoxide dismutase MDA Malondialdehyde CAT Catalase BBB Blood-brain barrier
* Li Huang [email protected] 1
Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha 410008, China
2
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
Introduction Sepsis is an overwhelming systemic inflammatory course involving multiple organ systems that caused dysregulated host response to infection (Singer et al. 2016). Sepsis can generate acute and chronic changes in the central nervous system called sepsis-associated encephalopathy (SAE), which is clinically characterized by “altered mental status,” from mild inattentiveness and agitation to more severe disruption of consciousness, such as coma (Feng et al. 2017; Nwafor et al. 2019). More than that, rates of anxiety, depression, and posttraumatic stress disorder are higher in intensive care unit survivors than population norms (Calsavara et al. 2018; Davydow et al. 2009; Nikayin e
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