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.
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Data Availability
All datasets generated for this study are included in the manuscript.
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
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This work was supported by the National Natural Science Foundation of China (nos. 81671960, 81873956, and 81974285).
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Lina Zhang, Xiaobei Peng, Yuhang Ai, and Li Huang conceived and designed the research; Li Li, Songyun Deng, Yan Huang, Yunan Mo, and Qianyi Peng performed the experiments; Shuangpin Zhao, Zhiyong Liu, Yunan Mo, and Qianyi Peng analyzed the data; Lina Zhang and Li Huang wrote the paper.
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Zhang, L., Peng, X., Ai, Y. et al. Amitriptyline Reduces Sepsis-Induced Brain Damage Through TrkA Signaling Pathway. J Mol Neurosci 70, 2049–2057 (2020). https://doi.org/10.1007/s12031-020-01611-x
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DOI: https://doi.org/10.1007/s12031-020-01611-x