Inhibition of SERPINA3N-dependent neuroinflammation is essential for melatonin to ameliorate trimethyltin chloride–induced neurotoxicity

Yu Xi, Mengyu Liu, Shuzhen Xu, Huihui Hong, Mengyan Chen, Li Tian, Jia Xie, Ping Deng, Chao Zhou, Lei Zhang, Mindi He, Chunhai Chen, Yonghui Lu, Russel J Reiter, Zhengping Yu, Huifeng Pi, Zhou Zhou

Research output: Contribution to journalArticle

Abstract

Trimethyltin chloride (TMT) is a potent neurotoxin that causes neuroinflammation and neuronal cell death. Melatonin is a well-known anti-inflammatory agent with significant neuroprotective activity. Male C57BL/6J mice were intraperitoneally injected with a single dose of melatonin (10 mg/kg) before exposure to TMT (2.8 mg/kg, ip). Thereafter, the mice received melatonin (10 mg/kg, ip) once a day for another three consecutive days. Melatonin dramatically alleviated TMT-induced neurotoxicity in mice by attenuating hippocampal neuron loss, inhibiting epilepsy-like seizures, and ameliorating memory deficits. Moreover, melatonin markedly suppressed TMT-induced neuroinflammatory responses and astrocyte activation, as shown by a decrease in inflammatory cytokine production as well as the downregulation of neurotoxic reactive astrocyte phenotype markers. Mechanistically, serine peptidase inhibitor clade A member 3N (SERPINA3N) was identified as playing a central role in the protective effects of melatonin based on quantitative proteome and bioinformatics analysis. Most importantly, melatonin significantly suppressed TMT-induced SERPINA3N upregulation at both the mRNA and protein levels. The overexpression of Serpina3n in the mouse hippocampus abolished the protective effects of melatonin on TMT-induced neuroinflammation and neurotoxicity. Melatonin protected cells against TMT-induced neurotoxicity by inhibiting SERPINA3N-mediated neuroinflammation. Melatonin may be a promising and practical agent for reducing TMT-induced neurotoxicity in clinical practice.

Original languageEnglish (US)
Article numbere12596
JournalJournal of pineal research
DOIs
StateAccepted/In press - Jan 1 2019

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Melatonin
Protease Inhibitors
Serine
Astrocytes
trimethyltin chloride
trimethyltin
Reducing Agents
Proteome
Computational Biology
Inbred C57BL Mouse
Epilepsy
Hippocampus
Seizures
Cell Death
Anti-Inflammatory Agents
Up-Regulation
Down-Regulation
Cytokines
Phenotype
Neurons

Keywords

  • melatonin
  • neuroinflammation
  • quantitative proteomic analysis
  • reactive astrocytes
  • SERPINA3N
  • trimethyltin

ASJC Scopus subject areas

  • Endocrinology

Cite this

Inhibition of SERPINA3N-dependent neuroinflammation is essential for melatonin to ameliorate trimethyltin chloride–induced neurotoxicity. / Xi, Yu; Liu, Mengyu; Xu, Shuzhen; Hong, Huihui; Chen, Mengyan; Tian, Li; Xie, Jia; Deng, Ping; Zhou, Chao; Zhang, Lei; He, Mindi; Chen, Chunhai; Lu, Yonghui; Reiter, Russel J; Yu, Zhengping; Pi, Huifeng; Zhou, Zhou.

In: Journal of pineal research, 01.01.2019.

Research output: Contribution to journalArticle

Xi, Y, Liu, M, Xu, S, Hong, H, Chen, M, Tian, L, Xie, J, Deng, P, Zhou, C, Zhang, L, He, M, Chen, C, Lu, Y, Reiter, RJ, Yu, Z, Pi, H & Zhou, Z 2019, 'Inhibition of SERPINA3N-dependent neuroinflammation is essential for melatonin to ameliorate trimethyltin chloride–induced neurotoxicity', Journal of pineal research. https://doi.org/10.1111/jpi.12596
Xi, Yu ; Liu, Mengyu ; Xu, Shuzhen ; Hong, Huihui ; Chen, Mengyan ; Tian, Li ; Xie, Jia ; Deng, Ping ; Zhou, Chao ; Zhang, Lei ; He, Mindi ; Chen, Chunhai ; Lu, Yonghui ; Reiter, Russel J ; Yu, Zhengping ; Pi, Huifeng ; Zhou, Zhou. / Inhibition of SERPINA3N-dependent neuroinflammation is essential for melatonin to ameliorate trimethyltin chloride–induced neurotoxicity. In: Journal of pineal research. 2019.
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abstract = "Trimethyltin chloride (TMT) is a potent neurotoxin that causes neuroinflammation and neuronal cell death. Melatonin is a well-known anti-inflammatory agent with significant neuroprotective activity. Male C57BL/6J mice were intraperitoneally injected with a single dose of melatonin (10 mg/kg) before exposure to TMT (2.8 mg/kg, ip). Thereafter, the mice received melatonin (10 mg/kg, ip) once a day for another three consecutive days. Melatonin dramatically alleviated TMT-induced neurotoxicity in mice by attenuating hippocampal neuron loss, inhibiting epilepsy-like seizures, and ameliorating memory deficits. Moreover, melatonin markedly suppressed TMT-induced neuroinflammatory responses and astrocyte activation, as shown by a decrease in inflammatory cytokine production as well as the downregulation of neurotoxic reactive astrocyte phenotype markers. Mechanistically, serine peptidase inhibitor clade A member 3N (SERPINA3N) was identified as playing a central role in the protective effects of melatonin based on quantitative proteome and bioinformatics analysis. Most importantly, melatonin significantly suppressed TMT-induced SERPINA3N upregulation at both the mRNA and protein levels. The overexpression of Serpina3n in the mouse hippocampus abolished the protective effects of melatonin on TMT-induced neuroinflammation and neurotoxicity. Melatonin protected cells against TMT-induced neurotoxicity by inhibiting SERPINA3N-mediated neuroinflammation. Melatonin may be a promising and practical agent for reducing TMT-induced neurotoxicity in clinical practice.",
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author = "Yu Xi and Mengyu Liu and Shuzhen Xu and Huihui Hong and Mengyan Chen and Li Tian and Jia Xie and Ping Deng and Chao Zhou and Lei Zhang and Mindi He and Chunhai Chen and Yonghui Lu and Reiter, {Russel J} and Zhengping Yu and Huifeng Pi and Zhou Zhou",
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T1 - Inhibition of SERPINA3N-dependent neuroinflammation is essential for melatonin to ameliorate trimethyltin chloride–induced neurotoxicity

AU - Xi, Yu

AU - Liu, Mengyu

AU - Xu, Shuzhen

AU - Hong, Huihui

AU - Chen, Mengyan

AU - Tian, Li

AU - Xie, Jia

AU - Deng, Ping

AU - Zhou, Chao

AU - Zhang, Lei

AU - He, Mindi

AU - Chen, Chunhai

AU - Lu, Yonghui

AU - Reiter, Russel J

AU - Yu, Zhengping

AU - Pi, Huifeng

AU - Zhou, Zhou

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Trimethyltin chloride (TMT) is a potent neurotoxin that causes neuroinflammation and neuronal cell death. Melatonin is a well-known anti-inflammatory agent with significant neuroprotective activity. Male C57BL/6J mice were intraperitoneally injected with a single dose of melatonin (10 mg/kg) before exposure to TMT (2.8 mg/kg, ip). Thereafter, the mice received melatonin (10 mg/kg, ip) once a day for another three consecutive days. Melatonin dramatically alleviated TMT-induced neurotoxicity in mice by attenuating hippocampal neuron loss, inhibiting epilepsy-like seizures, and ameliorating memory deficits. Moreover, melatonin markedly suppressed TMT-induced neuroinflammatory responses and astrocyte activation, as shown by a decrease in inflammatory cytokine production as well as the downregulation of neurotoxic reactive astrocyte phenotype markers. Mechanistically, serine peptidase inhibitor clade A member 3N (SERPINA3N) was identified as playing a central role in the protective effects of melatonin based on quantitative proteome and bioinformatics analysis. Most importantly, melatonin significantly suppressed TMT-induced SERPINA3N upregulation at both the mRNA and protein levels. The overexpression of Serpina3n in the mouse hippocampus abolished the protective effects of melatonin on TMT-induced neuroinflammation and neurotoxicity. Melatonin protected cells against TMT-induced neurotoxicity by inhibiting SERPINA3N-mediated neuroinflammation. Melatonin may be a promising and practical agent for reducing TMT-induced neurotoxicity in clinical practice.

AB - Trimethyltin chloride (TMT) is a potent neurotoxin that causes neuroinflammation and neuronal cell death. Melatonin is a well-known anti-inflammatory agent with significant neuroprotective activity. Male C57BL/6J mice were intraperitoneally injected with a single dose of melatonin (10 mg/kg) before exposure to TMT (2.8 mg/kg, ip). Thereafter, the mice received melatonin (10 mg/kg, ip) once a day for another three consecutive days. Melatonin dramatically alleviated TMT-induced neurotoxicity in mice by attenuating hippocampal neuron loss, inhibiting epilepsy-like seizures, and ameliorating memory deficits. Moreover, melatonin markedly suppressed TMT-induced neuroinflammatory responses and astrocyte activation, as shown by a decrease in inflammatory cytokine production as well as the downregulation of neurotoxic reactive astrocyte phenotype markers. Mechanistically, serine peptidase inhibitor clade A member 3N (SERPINA3N) was identified as playing a central role in the protective effects of melatonin based on quantitative proteome and bioinformatics analysis. Most importantly, melatonin significantly suppressed TMT-induced SERPINA3N upregulation at both the mRNA and protein levels. The overexpression of Serpina3n in the mouse hippocampus abolished the protective effects of melatonin on TMT-induced neuroinflammation and neurotoxicity. Melatonin protected cells against TMT-induced neurotoxicity by inhibiting SERPINA3N-mediated neuroinflammation. Melatonin may be a promising and practical agent for reducing TMT-induced neurotoxicity in clinical practice.

KW - melatonin

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KW - SERPINA3N

KW - trimethyltin

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