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Dipyridamole Attenuates Experimental Periodontitis by Regulating M1 Macrophage Polarization via PKA/PKG Pathways

Jiaying Song,Xingyi Li,Kailibinuer Abuduwaili,Yue Sun,Jiangbo Li,Danying Chen,Zhuofan Chen,Zhipeng Li,Baoxin Huang

Aim Periodontitis is a chronic inflammatory disease initiated by dysbiosis of the local microbial community. As a non-specific phosphodiesterase inhibitor, dipyridamole features anti-oxidant and anti-inflammatory properties. This study aimed to investigate the effects of dipyridamole in an experimental rat model of periodontitis. Methods Thirty rats were divided randomly into three groups ( n = 10): non-ligature group (NL), ligature-induced periodontitis group (L), and ligature-induced periodontitis with dipyridamole administered group (L + D). All rats were euthanized on Day 14. Alveolar bone resorption was analyzed by microcomputed tomography. The mRNA levels of Il1b , Il6 , tumor necrosis factor alpha ( Tnfa ), and inducible nitric oxide synthase ( iNos ) in gingival tissue were assessed by real-time quantitative polymerase chain reaction (qRT-PCR). Inflammation level, osteoclasts, and macrophages infiltration were analyzed histologically. RAW264.7 macrophages were stimulated with Porphyromonas gingivalis lipopolysaccharide ( P.g. LPS) to induce M1 polarization. Different concentration of dipyridamole (0/2/10 μM) was added simultaneously. To explore the role of PKA/PKG pathways, RAW 264.7 macrophages were pretreated with 10 μM H-89 (PKA inhibitor) or 1 μM KT-5823 (PKG inhibitor), respectively. Expression of pro-inflammatory cytokines and M1 markers were detected by qRT-PCR, ELISA, and flow cytometry. Results Dipyridamole administration reduced alveolar bone loss, protein levels of inflammatory cytokines, and osteoclastogenesis in rats with experimental periodontitis. It also showed a tendency to decrease mRNA levels of Il1b , Il6 , and Tnfa but without significant differences in gingival tissues. Moreover, the infiltration of macrophage and M1 macrophage polarization in gingival tissue of periodontitis rats were inhibited by dipyridamole administration. In addition, dipyridamole could downregulate the gene expression of Il1b and Tnfa , as well as the protein level of TNF-α, CD86, and iNOS in RAW264.7 treated with P.g. LPS. When PKA/PKG pathways were blocked, the suppression of TNF-α, CD86, and iNOS was reversed significantly. Conclusion Dipyridamole alleviated experimental periodontitis in rat models by regulating M1 polarization via activation of PKA/PKG pathways and emerges as a hopeful remedy for periodontitis. Graphical As non-specific phosphodiesterase inhibitor, dipyridamole reduced alveolar bone loss, expression level of inflammatory cytokines, and osteoclast genesis in ligature-induced periodontitis of rats by regulating M1 macrophage polarization via activation of PKA/PKG pathways, emerging as a hopeful treatment for periodontal disease.