Biomol Ther.  2021 May;29(3):295-302. 10.4062/biomolther.2021.039.

Papaverine Exerts Neuroprotective Effect by Inhibiting NLRP3 Inflammasome Activation in an MPTP-Induced Microglial Priming Mouse Model Challenged with LPS

• Leem YH
• Park JS
• Park JE
• Kim DY
• Kim HS

• KMID: 2515278
• DOI: http://doi.org/10.4062/biomolther.2021.039

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-methyl-4-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.

Keyword

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