Papaverine inhibits lipopolysaccharide-induced microglial activation by suppressing NF-κB signaling pathway

Drug Design, Development and Therapy, Feb 2016

Papaverine inhibits lipopolysaccharide-induced microglial activation by suppressing NF-κB signaling pathway Yalong Dang,1 Yalin Mu,2 Kun Wang,3 Ke Xu,2 Jing Yang,1 Yu Zhu,1 Bin Luo2,3 1Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China; 2Department of Ophthalmology, Yellow-River Hospital, Sanmenxia City, People’s Republic of China; 3Clinical Laboratory, Yellow-River Hospital, Sanmenxia City, People’s Republic of China Objective: To investigate the effects of papaverine (PAP) on lipopolysaccharide (LPS)-induced microglial activation and its possible mechanisms. Materials and methods: BV2 microglial cells were first pretreated with PAP (0, 0.4, 2, 10, and 50 µg/mL) and then received LPS stimulation. Transcription and production of proinflammatory factors (IL1β, TNFα, iNOS, and COX-2) were used to evaluate microglial activation. The transcriptional changes undergone by M1/M2a/M2b markers were used to evaluate phenotype transformation of BV2 cells. Immunofluorescent staining and Western blot were used to detect the location and expression of P65 and p-IKK in the presence or absence of PAP pretreatment. Results: Pretreatment with PAP significantly inhibited the expression of IL1β and TNFα, and suppressed the transcription of M1/M2b markers Il1rn, Socs3, Nos2 and Ptgs2, but upregulated the transcription of M2a markers (Arg1 and Mrc1) in a dose-dependent manner. In addition, PAP pretreatment significantly decreased the expression of p-IKK and inhibited the nuclear translocation of P65 after LPS stimulation. Conclusion: PAP not only suppressed the LPS-induced microglial activity by inhibiting transcription/production of proinflammatory factors, but also promoted the transformation of activated BV2 cells from cytotoxic phenotypes (M1/M2b) to a neuroprotective phenotype (M2a). These effects were probably mediated by NF-κB signaling pathway. Thus, it would be a promising candidate for the treatment of neurodegenerative diseases. Keywords: papaverine, microglia, neuroprotection, neuroinflammation

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Papaverine inhibits lipopolysaccharide-induced microglial activation by suppressing NF-κB signaling pathway

Drug Design, Development and Therapy Papaverine inhibits lipopolysaccharide-induced microglial activation by suppressing nF- kB signaling pathway Yalong Dang 1 3 Yalin Mu 1 2 Kun Wang 0 1 Ke Xu 1 2 Jing Yang 1 3 Yu Zhu 1 3 0 clinical laboratory, Yellowriver hospital , sanmenxia city, People's republic of china 1 Bin luo Department of Ophthalmology, Yellowriver hospital , West heping road, hubin District, 472000 sanmenxia city, People's republic of china 2 Department of Ophthalmology, Yellow-river hospital, s anmenxia c ity, People's r epublic of china 3 Department of Ophthalmology, The First a ffiliated h ospital of Zhengzhou University , Zhengzhou, People's republic of china dead roF PowerdbyTCPDF(ww.tcpdf.org) Objective: To investigate the effects of papaverine (PAP) on lipopolysaccharide (LPS)-induced microglial activation and its possible mechanisms. Materials and methods: BV2 microglial cells were first pretreated with PAP (0, 0.4, 2, 10, and 50 μg/mL) and then received LPS stimulation. Transcription and production of proinflammatory factors (IL1β, TNFα, iNOS, and COX-2) were used to evaluate microglial activation. The transcriptional changes undergone by M1/M2a/M2b markers were used to evaluate phenotype transformation of BV2 cells. Immunofluorescent staining and Western blot were used to detect the location and expression of P65 and p-IKK in the presence or absence of PAP pretreatment. Results: Pretreatment with PAP significantly inhibited the expression of IL1β and TNFα, and suppressed the transcription of M1/M2b markers Il1rn, Socs3, Nos2 and Ptgs2, but upregulated the transcription of M2a markers (Arg1 and Mrc1) in a dose-dependent manner. In addition, PAP pretreatment significantly decreased the expression of p-IKK and inhibited the nuclear translocation of P65 after LPS stimulation. Conclusion: PAP not only suppressed the LPS-induced microglial activity by inhibiting transcription/production of proinflammatory factors, but also promoted the transformation of activated BV2 cells from cytotoxic phenotypes (M1/M2b) to a neuroprotective phenotype (M2a). These effects were probably mediated by NF-kB signaling pathway. Thus, it would be a promising candidate for the treatment of neurodegenerative diseases. papaverine; microglia; neuroprotection; neuroinflammation - open access to scientific and medical research O r i g i n a l r e s e a r c h Introduction Microglial cells, representing 10%–20% of the total glial cells in the central nervous system (CNS), are the prime innate immunocytes responding against inflammatory, infectious, and other pathophysiological stimuli.1 Under “rest” conditions, they show highly ramified shapes and actively supervise the microenvironment of CNS.2 In case of acute insults, they quickly transform into highly activated ameboid-like shapes, phagocytize the injured neurons, release inflammatory factors, and thus restore the homeostasis of CNS.3 However, if the insults cannot be controlled effectively, a chronic, self-propagating microglial response characterized by sustained release of cytotoxic molecules (cytokines, chemokines, and radical species) will be incurred,4,5 which usually results in chronic neuroinflammation and secondary neuronal injury. This is a common phenomenon also observed in many acute/chronic retinal degenerative diseases, such as glaucoma,6 age-related macular degeneration,7 and ocular traumatic injury.8 Therefore, inhibiting overactivated microglial responses and alleviating the release of neurotoxic molecules are promising therapeutic approaches for these diseases. To date, great efforts in screening new drugs capable of inhibiting overactivated microglial responses have achieved many progresses. Our team identified a set of drugs that exhibited anti-neuroinflammatory effects. We found that 081 minocycline not only significantly decreased the number of l-Ju2 activated microglia in the subretinal space and outer nuclear -13 layer, but also remarkably alleviated the loss of photoreceptors 8on in light-induced retinal degeneration.9 Additionally, we also ..72413 iannvdesnteiguarateldstuhrevievfafel.ctWsoefftoeturnadnd1rinμeMonomftiectrroagnldiarlinaectsivigantiiofin.831 cantly inhibited the production of TNFα and IL1β in mouse y5b microglial cells10, and alleviated the death of retinal ganglion /om cells in an acute ocular hypertension model.11 However, since .ssc the working concentration of tetrandrine in vitro is much reep higher than that in the blood, it is hard to be used as an antivo neuroinflammatory drug in clinical practice. .//:sdwww l.yseonu alkaloid extracted from Papaver somniferum L, not only Recently, we found papaverine (PAP), an isoquinoline ttph lan suppressed the lipopolysaccharide (LPS)-induced microglial o rom rse activity by inhibiting transcription/production of proinflamf p dead roF matory factors, but also promoted the transformation of lno activated BV2 cells from cytotoxic phenotypes (M1/M2b) to odw a neuroprotective (...truncated)


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Yalong Dang, Yalin Mu, Kun Wang, Ke Xu, Jing Yang, Yu Zhu, Bin Luo. Papaverine inhibits lipopolysaccharide-induced microglial activation by suppressing NF-κB signaling pathway, Drug Design, Development and Therapy, 2016, pp. 851-859, DOI: 10.2147/DDDT.S97380