The expression of the nitric oxide synthase enzyme in periodontal disease and orofacial pain: systematic review

Correspondence to: Gisele Maria Campos Fabri Faculdade de Odontologia da Universidade Federal de Juiz de Fora Rua José Lourenço Kelmer s/n- São Pedro 36036-900 Juiz de Fora, MG, Brasil. E-mail: gisele.fabri@ufjf.edu.br

Conflict of interests: none - Sponsoring sources: none.

AUTHORS’ CONTRIBUTIONS

Daniel Jackson Gonçalves Carvalho

Statistical Analysis, Funding Acquisition, Data Collection, Conceptualization, Resource Management, Project Management, Research, Methodology, Writing - Preparation of the original, Writing - Review and Editing, Software, Supervision, Validation,

Visualization Isis Pereira Cardoso

Data Collection, Conceptualization, Methodology, Writing - Preparation of the original, Supervision, Validation, Visualization

Iasminy Soares Oliveira

Data Collection, Conceptualization, Writing - Preparation of the original, Writing - Review and Editing, Supervision, Visualization

Maria das Graças Afonso Miranda Chaves

Research, Writing - Preparation of the original, Writing - Review and Editing, Supervision, Validation, Visualization

Gisele Maria Campos Fabri

Statistical Analysis, Funding Acquisition, Data Collection, Conceptualization, Resource Management, Project Management, Research, Methodology, Writing - Preparation of the original, Writing - Review and Editing, Software, Supervision, Validation, Visualization

Authors	Country	Study	Investigation	Sample	Results
Gullu et al.²³23 Güllu C, Ozmeric N, Tokman B, Elgun S, Balos K. Effectiveness of scaling and root planing versus modified Widman flap on nitric oxide synthase and arginase activity in patients with chronic periodontitis. J Periodont Res. 2005;40(2):168-75.	Turkey	Clinical and laboratory	Comparison of the expression of iNOS before and after the two therapeutic modalities (surgery x scraping) and evaluation of the arginase before and after the periodontal treatment.	Sites with clinical attachment loss ≥7mm from 13 patients (p < 0.05)	The patients with PD had a higher expression of iNOS and a lower concentration of arginase before treatment (p<0.05).
Batista et al.¹⁹19 Batista AC, Silva TA, Chun JH, Lara VS. Nitric oxide synthesis and severity of human periodontal disease. Oral Dis.2002;8(5):254-60.	Brazil	Laboratory	Quantification of iNOS positive.	19 cases of gingivitis 19 cases of periodontitis 13 healthy cases.	Increased iNOS labeling in patients with gingivitis and PD compared to control (p<0.05).
Shibata et al.²⁰20 Shibata K, Warbington ML, Gordon BJ, Kurihara H, Van Dyke TE. Nitric oxide synthase activity in neutrophils from patients with localized aggresive peridontitis. J Periodontol. 2001;72(8):1052-8.	England	Laboratory	Activity of NOS was rated by the radiolabeled L-arginine to L-citrulline conversion assay. Membrane associated-NOS (MA-NOS) and soluble NOS (S-NOS) were extracted from cells.	Neutrophils isolated from 10 patients with PD.	Greater number of NOS in periodontitis compared to inhibition of neutrophil chemotherapy (p<0.05).
Kendall et al.⁷7 Kendall HK, Haase HR, Li H, Xiao Y, Bartold PM. Nitric oxide synthase type-II is synthesized by human gingival tissue and cultured human gingival fibroblasts. J Periodont Res. 2000;(35):194-200.	Australia	Laboratory	The sharing of eNOS was analyzed in inflamed and non-inflamed samples of human gingiva using a monoclonal antibody against. eNOS	6 gingival samples from patients with PD and 3 samples from healthy controls.	Higher eNOS expression in inflamed compared to non-inflamed gingival tissue. Cells within the inflamed connective tissue expressed eNOS.
Lappin et al.²¹21 Lappin DF, Kjeldsen M, Sander L, Kinane DF. Inducible nitric oxide synthase expression in periodontitis. J Periodont Res. 2000;35(6):369-73.	Scotland	Clinical and laboratory	INOS expression in gums of patients with PD x control.	16 patients with PD and 5 control patients.	Increased iNOS expression in PD patients.

Authors	Country	Study	Investigation	Total of sample	Results
Aguilar et al.²⁵25 Aguilar FME, Casas BA, Rus A, Haro RMTP, Martos JMM, Molina F et al. Among nitric oxide and enkephalinases with fibromyalgia symptoms. Nurs Res. 2020;70(2):11-20.	Spain	Clinical and laboratorial	The relationships between serum NO levels (chemiluminescence-based assay), oxytocinase activity and enkephalin-degrading aminopeptidase (EDA) activity (fluorometrically determined) and pain-related clinical manifestations in women with fibromyalgia were evaluated.	Fifty-eight women diagnosed with fibromyalgia.	Significant relations were observed between levels of NO and dominant occiput pressure pain thresholds, non-dominant occiput pressure pain thresholds, and fibromyalgia effects.
Van der Schueren et al.²²22 Van der Schueren BJ, Verbrugge FH, Verbesselt R, Van Hecken U, Depré M, de Hoon JN. No arguments for increased endothelial nitric oxide synthase activity in migraine based on peripheral biomarkers. Cephalalgia. 2010;30(11):1354-65.	Belgium	Clinical and laboratorial	Each individual received L-arginine infusion or placebo and the nasal and exhaled NO and NO metabolites were evaluated.	20 patients with migraine and 20 healthy subjects.	Increased nasal and exhaled NO of patients with migraine in the initial evaluation compared to controls and lower production of metabolites after l-arginine infusion in patients with migraine, indicating eNOS dysfunction (p = 0.81).
Gruber et al.¹⁷17 Gruber HJ, Bernecker C, Lechner A, Weiss S, Wallner BA, Meinitzer A, et al. Increased nitric oxide stress is associated with migraine. Cephalalgia. 2010;30(4):486-92.	Austria	Clinical and laboratorial	Several parameters of the NO pathway, such as nitrate, nitrite, arginine, citrulline, nitrosylated proteins, asymmetric dimethylarginine, symmetrical dimethylarginine, expression of eNOS and iNOS and two eNOS polymorphisms were investigated.	130 patients with migraine and 76 control subjects.	Migraine patients suffer under sustained increased nitrosative stress in the headache-free period, which is associated with a 3.6-fold higher risk for migraine.
Toriello et al.¹⁸18 Toriello M, Oterino A, Pascual J, Castillo J, Colás R, Alonso-Arranz A, et al. Lack of Association of endothelial nitric oxide synthase polymorphisms and migraine. Headache. 2008;48(7):1115-9.	Spain	Laboratorial	Genetic study of eNOS alleles.	337 patients with migraine and 341 controls.	The distribution of the alleles was not different between the groups (p <0.01).
Takahashi et al.²⁴24 Takahashi T, Homma H, Nagai H, Seki H, Kondoh T, Yamazaki Y, et al. Specific expression of inducible nitric oxide synthase in the synovium of the diseased temporomandibular joint. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2003;95(2):174-81.	Japan	Clinical and laboratorial	Analysis of iNOS expression in synovial biopsies of patients with TMD.	15 patients with symptomatic internal derangement (ID) or osteoarthritis (OA) and 8 control patients (3 with habitual luxation of the mandible, one with ID with clicking, and 4 with mandibular condyle fractures).	Intense iNOS immunoreactivity in both synovial lining cells and TMJ endothelial cells with internal derangement and osteoarthritis and correlation of iNOS with synovitis and not with cartilage degeneration.
Sjöstrand et al.¹⁴14 Sjöstrand C, Modin H, Masterman T, Ekbom K, Waldenlind E, Hillert J. Analysis of nitric oxide synthase genes in cluster headache. Cephalalgia. 2002;22(9):758-64.	Sweden	Laboratorial	Study of genetic variation of NOS genes in patients with migraine headache.	91 patients with migraine headache and 111 control subjects.	The phenotype and allele frequencies were similarly distributed in patients with migraine and controls, except for the iNOS allele that was significantly more common in controls. It’s unlikely that variation in NOS genetics is associated with susceptibility to headache in salvage (p<0.05).

Authors	Country	Type of study	Investigation	Total of sample Results of NOS in PD
Fabri et al¹⁶16 Fabri GMC, Sannomiya P, Prado CM, Leick-Maldonado EA, De Siqueira SRDT, Tibério IFC, et al. The expression of nitric oxide in the gingival tissue in subjects with periodontitis and chronic pain. Int J Odontostomat. 2014;8(2):279-87.	Brazil	Clinical and laboratory	Evaluation of iNOS and eNOS expression in the gingiva samples of patients with OP and PD compared to patients with PD without chronic pain	38 (20 patients with High expression of iNOS and eNOS PD and OP and 18 pa- in patients with PD and OP compatients with PD) red to patients with PD without OP (p <0.001)

[1] Correspondence to: Gisele Maria Campos Fabri Faculdade de Odontologia da Universidade Federal de Juiz de Fora Rua José Lourenço Kelmer s/n- São Pedro 36036-900 Juiz de Fora, MG, Brasil. E-mail: gisele.fabri@ufjf.edu.br

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The expression of the nitric oxide synthase enzyme in periodontal disease and orofacial pain: systematic review

ABSTRACT

BACKGROUND AND OBJECTIVES

CONTENTS

CONCLUSION: