Novel antioxidative nanotherapeutics in a rat periodontitis model: Reactive oxygen species scavenging by redox injectable gel suppresses alveolar bone resorption.

The excessive production of reactive oxygen species (ROS) has been implicated in a variety of disorders, but to date, ROS scavengers have not been widely used for local treatment of inflammation, because they are rapidly eliminated from the inflamed site. We have designed a novel redox injectable gel (RIG) that is formed at 37 °C after disintegration of nano-assembled flower micelles allowing nitroxide radicals to act locally as specific ROS scavengers for the treatment of periodontitis. In the present study, we have confirmed retention of the RIG in the periodontal region, along with its antioxidant-related anti-inflammatory effects, and we have subsequently evaluated the inhibitory effect of the RIG against Porphyromonas gingivalis (P. gingivalis)-induced alveolar bone loss attributed to ROS. Alveolar bone loss was estimated by morphometry, gingival blood flow was measured using laser Doppler flowmetry, and osteoclast differentiation was evaluated by tartrate-resistant acid phosphatase staining. The results show that the RIG can inhibit P. gingivalis-induced bone loss by antioxidant-related anti-inflammatory actions, and this suggests that the RIG is a promising novel therapeutic agent for the treatment of P. gingivalis-induced periodontitis.

[1]  Y. Nagasaki,et al.  The ROS scavenging and renal protective effects of pH-responsive nitroxide radical-containing nanoparticles. , 2011, Biomaterials.

[2]  Newell W Johnson,et al.  Periodontal diseases. , 2005, Lancet.

[3]  Y. Matsumoto,et al.  Design of high-performance anti-adhesion agent using injectable gel with an anti-oxidative stress function. , 2015, Biomaterials.

[4]  T. Maruyama,et al.  Periodontitis-induced lipid peroxidation in rat descending aorta is involved in the initiation of atherosclerosis. , 2009, Journal of periodontal research.

[5]  T. Yoneda,et al.  Effects of hydrogen-rich water on aging periodontal tissues in rats , 2014, Scientific Reports.

[6]  D. Leibfritz,et al.  Free radicals and antioxidants in normal physiological functions and human disease. , 2007, The international journal of biochemistry & cell biology.

[7]  K. Sasaguri,et al.  Ameliorating effects of Juzentaihoto on restraint stress and P. gingivalis-induced alveolar bone loss. , 2014, Archives of oral biology.

[8]  K. Tsukinoki,et al.  Restraint stress enhances alveolar bone loss in an experimental rat model. , 2006, Journal of periodontal research.

[9]  Masaichi-chang-il Lee,et al.  Inhibitory effects of Jixueteng on P. gingivalis-induced bone loss and osteoclast differentiation. , 2012, Archives of oral biology.

[10]  H. Amano,et al.  Tea Polyphenols Inhibit Rat Osteoclast Formation and Differentiation. , 2012, Journal of pharmacological sciences.

[11]  Toru Yoshitomi,et al.  An orally administered redox nanoparticle that accumulates in the colonic mucosa and reduces colitis in mice. , 2012, Gastroenterology.

[12]  J. Jones,et al.  Meta-analysis of periodontal disease and risk of coronary heart disease and stroke. , 2003, Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics.

[13]  D. Kinane,et al.  Generation of inflammatory stimuli: how bacteria set up inflammatory responses in the gingiva. , 2005, Journal of clinical periodontology.

[14]  R. Page,et al.  Chronic inflammatory gingival and periodontal disease. , 1978, JAMA.

[15]  T. Tomofuji,et al.  Initial apical migration of junctional epithelium in rats following application of lipopolysaccharide and proteases. , 2005, Journal of periodontology.

[16]  Y. Nagasaki,et al.  Design of core--shell-type nanoparticles carrying stable radicals in the core. , 2009, Biomacromolecules.

[17]  Yi Yan Yang,et al.  Injectable Hydrogels from Triblock Copolymers of Vitamin E‐Functionalized Polycarbonate and Poly(ethylene glycol) for Subcutaneous Delivery of Antibodies for Cancer Therapy , 2014 .

[18]  D. Graves,et al.  Soluble antagonists to interleukin-1 (IL-1) and tumor necrosis factor (TNF) inhibits loss of tissue attachment in experimental periodontitis. , 2001, Journal of clinical periodontology.

[19]  C. Cao,et al.  Polymorphonuclear neutrophils and their mediators in gingival tissues from generalized aggressive periodontitis. , 2001, Journal of periodontology.

[20]  T. Ohnishi,et al.  Oxidative stress causes alveolar bone loss in metabolic syndrome model mice with type 2 diabetes. , 2009, Journal of periodontal research.

[21]  Y. Nagasaki,et al.  Redox nanoparticle therapeutics to cancer--increase in therapeutic effect of doxorubicin, suppressing its adverse effect. , 2013, Journal of controlled release : official journal of the Controlled Release Society.

[22]  Y. Nagasaki,et al.  The behavior of ROS-scavenging nanoparticles in blood , 2014, Journal of clinical biochemistry and nutrition.

[23]  N. Tani-Ishii,et al.  Peptidoglycan of Actinomyces naeslundii induces inflammatory cytokine production and stimulates osteoclastogenesis in alveolar bone resorption. , 2012, Archives of oral biology.

[24]  Y. Nagasaki,et al.  Dual Stimuli-Responsive Redox-Active Injectable Gel by Polyion Complex Based Flower Micelles for Biomedical Applications , 2015 .

[25]  T. Nakajima,et al.  A bacterial glycan core linked to surface (S)-layer proteins modulates host immunity through Th17 suppression , 2012, Mucosal Immunology.

[26]  E. Vichinsky,et al.  Oxidative stress and inflammation in iron‐overloaded patients with β‐thalassaemia or sickle cell disease , 2006 .

[27]  T. Maruyama,et al.  Effects of vitamin C intake on gingival oxidative stress in rat periodontitis. , 2009, Free radical biology & medicine.

[28]  Y. Nagasaki,et al.  Redox-active injectable gel using thermo-responsive nanoscale polyion complex flower micelle for noninvasive treatment of local inflammation. , 2013, Journal of controlled release : official journal of the Controlled Release Society.

[29]  D. Oda,et al.  Neutrophil-mediated damage to human gingival epithelial cells. , 1992, Journal of periodontal research.

[30]  G. G. Stokes "J." , 1890, The New Yale Book of Quotations.

[31]  R. Page,et al.  The pathogenesis of human periodontitis: an introduction. , 1997, Periodontology 2000.

[32]  Masaichi-chang-il Lee,et al.  Gingival vascular functions are altered in type 2 diabetes mellitus model and/or periodontitis model , 2012, Journal of clinical biochemistry and nutrition.

[33]  Toru Yoshitomi,et al.  Development of an oral nanotherapeutics using redox nanoparticles for treatment of colitis-associated colon cancer. , 2015, Biomaterials.

[34]  D. Hinshaw,et al.  Hydrogen peroxide as a potent bacteriostatic antibiotic: implications for host defense. , 1995, Free radical biology & medicine.

[35]  S. Holt,et al.  Implantation of Bacteroides gingivalis in nonhuman primates initiates progression of periodontitis. , 1988, Science.

[36]  N. Hamada,et al.  Porphyromonas gulae 41-kDa fimbriae induced osteoclast differentiation and cytokine production , 2014, The Journal of veterinary medical science.

[37]  S. Agarwal,et al.  Association of biomarkers of inflammation and oxidative stress with the risk of chronic kidney disease in Type 2 diabetes mellitus in North Indian population. , 2013, Journal of diabetes and its complications.

[38]  T. Maruyama,et al.  Vitamin C intake attenuates the degree of experimental atherosclerosis induced by periodontitis in the rat by decreasing oxidative stress. , 2009, Archives of oral biology.

[39]  Y. Murakami,et al.  Porphyromonas gingivalis fimbriae stimulate bone resorption in vitro , 1994, Infection and immunity.