Amitriptyline Reduces Sepsis-Induced Brain Damage Through TrkA Signaling Pathway

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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Funding

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.

Corresponding author

Correspondence to Li Huang.

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All protocols were conducted in accordance with the Institutional Animal Care and Use Committee of Central South University.

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The authors declare that they have no competing interests.

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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 (2020). https://doi.org/10.1007/s12031-020-01611-x

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Keywords

  • Neuroinflammation
  • Gliosis
  • Cognitive deficits
  • TrkA
  • Akt
  • GSK3β