Papaverine exerts neuroprotective effect by inhibiting nlrp3 inflammasome activation in an mptp-induced microglial priming mouse model challenged with lps

Yea Hyun Leem, Jin Sun Park, Jung Eun Park, Do Yeon Kim, Hee Sun Kim

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Microglial priming is the process of microglial proliferation and activation in response to neurodegeneration and abnormal protein accumulation. Priming makes microglia susceptible to secondary inflammatory stimuli and causes exaggerated inflammatory responses. In the present study, we established a microglial priming model in mice by administering a single injection of 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 20 mg/kg). MPTP induced microglial activation without dopaminergic degeneration; however, subsequent treatment with a sub-toxic dose of lipopolysaccharides (LPS) induced an amplified inflammatory response and caused nigrostriatal dopaminergic degeneration. These pathological and inflammatory changes, including microglial activation and dopaminergic cell loss in the substantia nigra (SN) area were reversed by papaverine (PAP) administration. In addition, MPTP/LPS enhanced interleukin-1β (IL-1β) expression and processing via nod-like receptor protein 3 (NLRP3) inflammasome activation in the SN region of mice. However, PAP treatment suppressed inflammasome activation and subsequent IL-1β maturation. Moreover, PAP inhibited nuclear factor-κB (NF-κB) and enhanced cAMP-response element binding protein (CREB) activity in the SN of MPTP/LPS mice. These results suggest that PAP inhibits the activation of NLRP3 inflammasome by modulating NF-κB and CREB signaling pathways, which results in reduced microglial activation and neuronal cell death. Thus, PAP may be a potential candidate for the treatment of Parkinsons’s disease, which is aggravated by systemic inflammation.

Original languageEnglish
Pages (from-to)295-302
Number of pages8
JournalBiomolecules and Therapeutics
Volume29
Issue number3
DOIs
StatePublished - 2021

Bibliographical note

Funding Information:
This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2016R1A6A3A11930120, 2018R1A2B6003074 and 2020R1I1A1A01057922).

Publisher Copyright:
© 2021 The Korean Society of Applied Pharmacology.

Keywords

  • Microglial priming
  • NLRP3 inflammasome
  • Neuronal cell death
  • Papaverine
  • Parkinson’s disease
  • Systemic inflammation

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