Abstract

The aim of this study was to evaluate the anti-inflammatory and anti-resorptive effect of atorvastatin (ATV) in an experimental alveolar bone loss (ABL) model. Wistar rats were subjected to ligature placement around the maxillary second molar for 11 days. The animals received 0.9% saline (2 mL/kg) or ATV (0.3, 3 or 27 mg/kg) daily by gavage. ABL was evaluated by resorption area and histopathological analysis. Serum bone-specific alkaline phosphatase (BALP) activity was also evaluated. Leukogram was performed at 0 h, 6th h, 2nd, 7th and 11th days. Kidney and liver conditions and the body mass variation were analyzed. ATV (3 and 27 mg/kg) inhibited ABL by 39% and 56%, respectively. Histopathological analysis showed that ATV 27 mg/kg prevented ABL and cemental resorption, and inflammatory cell infiltration induced by ligature. ATV (27 mg/kg) prevented serum BALP levels reduction. ATV (27 mg/kg) prevented leukocytosis and did not affect either kidney or liver function nor body mass weight. ATV showed a protecting effect in the ligature-induced periodontitis, without affecting system parameters, by inhibition of inflammatory process and by its anabolic activity on the alveolar bone.

Key Words:
alveolar bone loss; periodontitis; inflammation; atorvastatin.

Resumo

O objetivo do estudo foi avaliar o efeito anti-inflamatório e anti-reabsortivo da atorvastatina (ATV) no modelo de perda óssea alveolar experimental (POA). Para isto, ratos Wistar foram submetidos a inserção de ligadura ao redor do segundo molar maxilar durante 11 dias. Os animais receberam diariamente, por gavagem, soro fisiológico a 0,9% (2 mg/kg) ou ATV (0,3, 3 ou 27 mg/kg). A POA foi avaliada pela área de reabsorção e análise histológica. Dosagens séricas da atividade de fosfatase alcalina óssea foram avaliadas. Leucograma foi realizado a 0 h, na 6a h, 2^o, 7^o e 11^o dias. Foram analisadas condições de rim, fígado e variação de massa corpórea. As ATV (3 e 27 mg/kg) inibiram POA em 39% e 56%, respectivamente. A análise histopatológica mostrou que a ATV 27 mg/kg preveniu POA e reabsorção de cemento, e o infiltrado celular inflamatório induzido por ligadura. ATV (27 mg/kg) preveniu a redução dos níveis séricos de fosfatase alcalina óssea. ATV (27 mg/kg) preveniu leucocitose e não afetou função renal e hepática ou o peso corporal. ATV mostrou um efeito protetor na periodontite induzida por ligadura, sem afetar os parâmetros sistêmicos, através da inibição do processo inflamatório e pela atividade anabólica no osso alveolar.

Introduction

Periodontitis is an inflammation that extends deeply into the tissues causing loss of supporting connective tissue and alveolar bone. Periodontal disease (PD) is one of the two major dental problems, followed by caries, which affect human population at high prevalence rates ¹1. Petersen, PE; Ogawa, H. Strengthening the prevention of periodontal disease: The WHO Approach. J Periodontol 2005;76:2187-2193..

PD is currently understood as a result of a complex interplay between bacterial infection and host response, modified by behavioral factors. Periodontal inflammatory process initially has a protective role against bacterial invasion. However, it becomes destructive due to a prolonged over-expression of damaging mediators such as IL-1 and TNF, and expression of other mediators, such as prostaglandins, which lead to production of lytic enzymes and stimulate osteoclast recruitment ²2. Deo, V; Bhongade, ML. Pathogenesis of periodontitis: role of cytokines in host response. Dent Today 2010;29:60-62..

Statin or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor is a well-established pharmaceutical agent that effectively lowers serum cholesterol levels. Statins have been used for hypercholesterolemia treatment and atherosclerosis ³3. McLain, K; Edlund, BJ. Statin drugs: reducing cardiovascular risk in older adults. J Gerontol Nurs 2012;38:9-13.. Some studies have also suggested that statins may have other effects beyond lipid reducing function ⁴4. Maeda T; Matsunuma A; Kurahashi I; Yanagawa T; Yoshida H; Horiuchi, N. Induction of osteoblast differentiation indices by statins in MC3T3-E1 cells. J Cell Biochem 2004;92:458-471.. They are able to modulate inflammation by lowering cytokine concentrations and inhibiting recruitment, migration and cell adhesion to endothelium. Additionally, they have shown anabolic effect on bone tissue ⁵5. Horiuchi, N; Maeda, T. Statins and bone metabolism. Oral Disease 2006;1285-101..

Moreover, in the midst of various statins, atorvastatin (ATV) stands out not only due to its lipophilicity, which is closely linked to pleiotropic effects ⁴4. Maeda T; Matsunuma A; Kurahashi I; Yanagawa T; Yoshida H; Horiuchi, N. Induction of osteoblast differentiation indices by statins in MC3T3-E1 cells. J Cell Biochem 2004;92:458-471., but also due to few adverse effects and better cost-effectiveness relationship, compared with other statins, being therefore, widely used in clinical practice. Therefore, considering the pleiotropic effects of statins, this study was designed to evaluate the anti-resorptive effect of ATV over inflammatory response and bone loss in an experimental model of alveolar bone loss in rats.

Material and Methods

Animals

Thirty-six male Wistar rats (±200 g) (Rattus novergicus) were used in this study. Animals were kept in cages in temperature-controlled rooms, with free access to food and water during the whole experiment. Adequate measures were taken to minimize pain or discomfort to the animals. All procedures and animal treatment were conducted after approval by the institutional Ethics Committee (Protocol number 74/07).

Model of Ligature-Induced Alveolar Bone Loss

The model of ligature-induced alveolar bone loss (ABL) used in this study has previously been described ⁶6. Lima, V; Bezerra, MM; Alencar, VBM; Vidal, FD; Rocha, FA; Castro Brito, GA, et al.. Effects of chlorpromazine on alveolar bone loss in experimental periodontal disease in rats. Eur J Oral Sci 2000;108:123-129.. Rats were anesthetized with chloral hydrate (300 mg/kg, i.p.), and a nylon (00) thread ligature (Point Suture; Point Suture of Brazil, Fortaleza, CE, Brazil) was placed around the cervix of the maxillary left second molar. The ligature was then knotted on the buccal side of the tooth. The contralateral right side was used as the unligated control. Rats were euthanized on the 11^th day, time of peak of alveolar bone loss ⁶6. Lima, V; Bezerra, MM; Alencar, VBM; Vidal, FD; Rocha, FA; Castro Brito, GA, et al.. Effects of chlorpromazine on alveolar bone loss in experimental periodontal disease in rats. Eur J Oral Sci 2000;108:123-129.. The ligatures were blinded to the group.

Experimental Groups

Groups of 6 animals each received 0.9% saline solution (2 mL/kg), or 0.3, 3 and 27 mg/kg ATV (Lipitor(r); Pfizer; São Paulo, SP, Brazil), respectively, administrated by gavage 30 min before ligature and daily until the 11^th day.

Morphometric Analysis of Alveolar Bone

On the 11^th day, animals were sacrificed under anesthesia and had their maxillae removed and fixed in 10% neutral formalin for 24 h. Following, maxillae were split in half, dissected and stained with 1% methylene blue in order to differentiate bone from teeth ⁶6. Lima, V; Bezerra, MM; Alencar, VBM; Vidal, FD; Rocha, FA; Castro Brito, GA, et al.. Effects of chlorpromazine on alveolar bone loss in experimental periodontal disease in rats. Eur J Oral Sci 2000;108:123-129.. For the measurement of ABL, hemi-maxillae were placed in microscope slides and photographed with a digital camera (Nikon(r) D40, Melville, NY, USA). The acquired image was analyzed using the IMAGE J(r) software (ImageJ 1.32j; National Institute of Health, Bethesda, MD, USA) , according to the methodology described by Goes et al. ⁷7. Goes, P; Lima, AP; Melo, IM; Rêgo, ROCC; Lima, V. Effect of atorvastatin in radiographic density on alveolar bone loss in Wistar rats. Braz Dent J 2010;21193-198.^,88. Goes, P; Melo, IM; Dutra, CS; Lima, AP; Lima, V. Effect of alendronate on bone-specific alkaline phosphatase on periodontal bone loss in rats. Arch Oral Biol 2012;57:1537-1544.^,99. Goes, P; Melo, IM; Silva, LM; Benevides, NM; Alencar, NM; Ribeiro, RA, et al.. Low-dose combination of alendronate and atorvastatin reduces ligature-induced alveolar bone loss in rats. J Periodontal Res. 2014;49:45-54.

Histological Analysis of Alveolar Bone

Two additional groups of 6 animals submitted to ligature-induced ABL, which received saline or ATV (27 mg/kg), were sacrificed as described above and had their maxillae removed. The specimens were fixed in 10% neutral buffered formalin and demineralized in 10% nitric acid. Following this, the specimens were dehydrated, embedded in paraffin and sectioned along the molars in a mesiodistal plane for Mallory Trichrome staining ⁹9. Goes, P; Melo, IM; Silva, LM; Benevides, NM; Alencar, NM; Ribeiro, RA, et al.. Low-dose combination of alendronate and atorvastatin reduces ligature-induced alveolar bone loss in rats. J Periodontal Res. 2014;49:45-54. Four-micrometer-thick sections, corresponding to the area between the first and second molars were evaluated by light microscopy at 40× magnification. Parameters such as inflammatory cell infiltration, osteoclast number, and alveolar bone and cementum integrity, were determined using scores varying from 0 to 3 according to the intensity of findings, as follows: Score 0: absence or only discrete cellular infiltration, few osteoclasts, preserved alveolar process and cementum; Score 1: moderate cellular infiltration, presence of some osteoclasts, some but minor alveolar process resorption and intact cementum; Score 2: severe cellular infiltration, large number of osteoclasts, accentuated degradation of the alveolar process, and partial destruction of cementum; Score 3: severe cellular infiltrate, total destruction of alveolar process and cementum ⁶6. Lima, V; Bezerra, MM; Alencar, VBM; Vidal, FD; Rocha, FA; Castro Brito, GA, et al.. Effects of chlorpromazine on alveolar bone loss in experimental periodontal disease in rats. Eur J Oral Sci 2000;108:123-129..

Histomorphometric Analysis

The slides used for histological analysis were also used for the histometric study. The slide inclusion criteria were: presence of a bone crest and furcation roof in the same section. Images of these sections were captured at 40× magnification. After excluding the first and last sections, four equally distant sections of each tooth were selected for histometric analysis. An observer, blinded to the group to which the slide belonged to, used the IMAGEJ(r) software to obtain three area measurements between alveolar bone crest (ABC) and furcation roof (FR) of the maxillary second molar. This methodology was based on the study of Goes et al. ⁹9. Goes, P; Melo, IM; Silva, LM; Benevides, NM; Alencar, NM; Ribeiro, RA, et al.. Low-dose combination of alendronate and atorvastatin reduces ligature-induced alveolar bone loss in rats. J Periodontal Res. 2014;49:45-54, with some modifications, as the area between ABC-FR was determined by the mean of the 3 measurements.

Serum Dosage Variation of BALP Activity

Blood samples were collected from orbital plexus of anesthetized rats (saline and ATV 27 mg/kg) before the experiment and on the 11th day. BALP was evaluated by indirect method, after heating the sample to 56 °C for 10 min ⁸8. Goes, P; Melo, IM; Dutra, CS; Lima, AP; Lima, V. Effect of alendronate on bone-specific alkaline phosphatase on periodontal bone loss in rats. Arch Oral Biol 2012;57:1537-1544.. Since BALP is a thermosensible isoform of total alkaline phosphatase (TAP), its serum levels were calculated subtracting the values of heat alkaline phosphatase (HAP) from the ones of TAP. Methodology used followed the manufacturer's instructions (Labtest^{?#61614;?#63615;}; Lagoa Santa, MG, Brazil).

Hematologic Study

The method used for white blood cell count was as follows: 20 ?#61549;L of blood, taken from the rat's tail, was added to 380 ?#61549;L Turk solution. Total and differential white blood cell counts were performed using a Neubauer chamber and stained smears by Rapid Instant Prov Stain Set (Newprov Laboratory Products; São José dos Pinhais, PR, Brazil), respectively. Leukograms of the groups of rats (saline and ATV 27 mg/kg) were performed before alveolar bone loss induction, at 6th h and 2nd, 7th and 11 th day after the ligature.

Serum Biochemical Parameters of Kidney and Liver Function

At baseline and on the 11^th day, blood samples were collected from orbital plexus of anesthetized rats (saline and ATV 27 mg/kg). Serum levels of urea and creatinine were evaluated as renal function markers, while serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were used as liver function markers. Specific kits were used and methodology followed the manufacturer's instructions (Labtest^?#61614;?#63615;).

Body Mass Variation

Rats from groups SAL and ATV 27 mg/kg were weighted before ABL induction and then daily until the 11^th day.

Statistical Analysis

The data are presented as mean ± standard error of the mean (SEM) or median (minimum-maximum), where appropriate. Univariate analysis of variance (ANOVA), followed by Bonferroni test, were used to compare means, and Kruskal-Wallis and Mann Whitney tests were used to compare medians. A p value of <0.05 was considered as indicating significant differences. All measurements were made blind to the groups.

Results

Morphometric study demonstrated that ligature-induced ABL caused intense bone resorption (Table 1; Fig. 1B) compared to the normal hemi-maxillae (Table 1; Fig. 1A). Rats from SAL group presented intense alveolar resorption, root exposure and furcation lesion (Fig. 1B). Despite the lowest dose of ATV (0.3 mg/kg) not protecting alveolar bone, when compared to SAL (Table 1), the highest dose of ATV showed the greatest bone protection. The treatment with ATV (3 and 27 mg/kg) elicited significant dose-dependent alveolar bone protection by 39% and 56% (Table 1; Fig. 1C).

Histopathological analysis indicated intense alveolar bone and cementum resorption, associated to important infiltration of inflammatory cells (p<0.05) on SAL group (Table 1; Fig. 1E), compared with normal periodontium (Table 1; Fig. 1D). Rats treated with ATV (27 mg/kg) showed a significant inflammatory infiltrate attenuation and preservation of alveolar bone, periodontal ligament and cementum (Table 1; Fig. 1F), compared to SAL.

The histometric study corroborated the morphometric and histological findings. It was seen that 11 days of ligature-induced ABL caused intense bone resorption compared to normal periodontium (p<0.05). Treatment with ATV 27 mg/kg prevented ABL when compared to saline (p<0.05) (Table 1).

When BALP serum levels were evaluated, a significant decrease in SAL group was observed when compared to baseline. ATV prevented the reduction of BALP serum levels compared to SAL (Table 2).

In order to verify systemic repercussions after treatment with ATV, some parameters were evaluated. On leukogram, ligature-induced ABL caused leukocytosis at 6th h after ligature placement (19.5±0.9 leukocytes x 103/mm³⁾ (Fig. 2A), compared to the baseline (12.37±0.57 x 103/mm³⁾. The leukocytosis observed at 6th h was marked by neutrophilia (6.8±0.9 x 103/mm³⁾ (Fig. 2b). Following, a new leukocytosis was observed at the 11th day (18.2±1.2 leukocytes x 103/mm³⁾ with prevalence of mononuclear cells (15.8±0.6 x 103/mm³⁾ (Fig. 2c). ATV (27 mg/kg) significantly reduced leukocytosis (13.9±1.2 leukocytes x 103/mm³⁾ (Fig. 2A) and neutrophil count at the 6th h (4.4±0.4 x 103/mm³⁾ (Fig. 2b). At the 11th day, ATV also significantly lowered mononuclear cell count (12.1±1.3 x 103/mm³⁾ (Fig. 2A).

Kidney (urea and creatinine) and liver (AST and ALT) enzymes were analyzed (Table 2). In the saline group an increase on creatinine serum levels was observed (p<0.05)compared to baseline. ATV (27 mg/kg) prevented this increase. No change was seen in urea serum levels after ATV treatment. For liver transaminases, a significant increase was seen in ALT serum levels in the SAL group compared to baseline. ALT levels were increased (p<0.05) in ATV group compared to saline or baseline. No modification was observed in AST serum levels after ATV treatment.

Considering body mass variation, ligature-induced ABL caused significant loss in body mass after ligature placement from 2nd until the 6th day, compared to normal animals. Animals treated with ATV did not show additional loss of body weight when compared to SAL (Fig. 3).

Discussion

This study demonstrated that ligature-induced ABL caused significant bone resorption, periodontal inflammation and decrease on BALP serum levels as demonstrated previously ⁸8. Goes, P; Melo, IM; Dutra, CS; Lima, AP; Lima, V. Effect of alendronate on bone-specific alkaline phosphatase on periodontal bone loss in rats. Arch Oral Biol 2012;57:1537-1544.. The treatment with ATV significantly prevented ABL alveolar bone loss, which is in accordance with other authors ⁷7. Goes, P; Lima, AP; Melo, IM; Rêgo, ROCC; Lima, V. Effect of atorvastatin in radiographic density on alveolar bone loss in Wistar rats. Braz Dent J 2010;21193-198.. ATV also prevented inflammation as well as reduction of BALP serum levels.

As a hypolipemiant drug, ATV is also known to have pleiotropic effects. Beyond lipid lowering action, it has been reported that ATV is able to inhibit important inflammatory mediators such as interleukins (IL) -6 and -1 and tumor necrosis factor (TNF) ¹⁰10. Zhang, YY; Fan, YC; Wang, M; Wang, D; Li, XH. Atorvastatin attenuates the production of IL-1β, IL-6, and TNF-α in the hippocampus of an amyloid β1-42-induced rat model of Alzheimer's disease. Clin Interv Aging 2013;8:103-110. Since these cytokines are also involved in alveolar bone resorption ¹¹11. Fentoğlu, O; Kirzioğlu, FY; Ozdem, M; Koçak, H; Sütçü, R; Sert, T. Proinflammatory cytokine levels in hyperlipidemic patients with periodontitis after periodontal treatment. Oral Dis 2012;18:299-306., the anti-inflammatory effect of ATV contributes to bone protection, as seen in this study.

In vitro studies have shown that ATV has anabolic bone properties. Statins may increase up to 50% new bone formation and promote osteoblastic differentiation and mineralization ¹²12. Mundy, G; Garret,t R; Harris, S; Chan, J; Chen, D; Rossini, G, et al.. Stimulation of bone formation in vitro and in rodents by statins. Science 1999;286:1946-1949.. Regarding the alveolar bone, a clinical trial suggested that ATV might have beneficial effects on bone alveolar loss and tooth mobility in subjects with periodontal disease ¹³13. Fajardo, ME; Rocha, ML; Sánchez-Marin, FJ; Espinosa-Chávez, EJ. Effect of atorvastatin on chronic periodontitis: a randomized pilot study. J Clin Periodontol 2010;371016-1022.. Such bone anabolic property seems be related to the drug lipophilicity and this ATV chemical characteristic may elicit greater mineralization process ⁴4. Maeda T; Matsunuma A; Kurahashi I; Yanagawa T; Yoshida H; Horiuchi, N. Induction of osteoblast differentiation indices by statins in MC3T3-E1 cells. J Cell Biochem 2004;92:458-471..

Considering the effect of ATV on osteoblastic differentiation and mineralization, it was decided to evaluate BALP serum level, an isoenzyme of total alkaline phosphatase (TAP) considered a bone formation marker, due to its linkage with osteoblastic differentiation and mineralization of newly formed bone ¹⁴14. Couttenye, MM; D´Haese, PC; Van, Hoof VO; Lemoniatou, E; Goodman, W; Verpooten, GA et al.. Low serum levels of alkaline phosphatase of bone origin: a good marker of adynamic bone disease in haemodialysis patients. Nephrol Dial Transplant 1996;111065-1072.. Thus, BALP plays an important role in the regulation of bone formation and turnover rate. The results showed that ATV treatment prevented BALP reduction. Several studies have examined the relationship between statin use and biochemical markers of bone turnover. Clinical trials have supported this finding, reporting that ATV treatment does not modify or promote small variations on BALP serum levels in hypercholesterolemic patients ¹⁵15. Majima, T; Komats, Y; Fukao, A; Ninomiya, K; Matsumura, T; Nakao, K. Short-term effects of atorvastatin on bone turnover in male patients with hypercholesterolemia. Endocrine J 2007;54:145-151., actually contributing to bone homeostasis.

Regarding systemic parameters, this study revealed that ATV prevented neutrophilia and lymphomonocytosis. Considering the markers of kidney and liver function, ATV prevented creatinine raise, as seen in SAL group, but did not prevent ALT increase. However, no changes on AST serum levels were observed after therapy with ATV. ATVdid not alter body mass compared to SAL.

Considering the leukocyte counts, ATV prevented peripheral neutrophilia and lymphomonocytosis, as seen in saline group on 6th and 11th days, respectively. In agreement with the present data, studies have shown that ATV treatment caused significant reduction in peripheral leukocyte ¹⁶16. Medeiros, CA; Leitão, RF; Macedo, RN; Barboza, DR; Gomes, AS; Nogueira, NA et al.. Effect of atorvastatin on 5-fluorouracil-induced experimental oral mucositis. Cancer Chemother Pharmacol 2011;67:1085-1100., preventing neutrophilia. Additionally, ATV has been described to reduce circulating classical monocytes in humans after heart transplantation ¹⁷17. Fildes, JE; Shaw, SM; Mitsidou, A; Rogacev, K; Leonard, CT; Williams, SG et al.. HMG-CoA reductase inhibitors deplete circulating classical and non-classical monocytes following human heart transplantation. Transpl Immunol 2008;19:152-157..

As the ATV treatment significantly decreased creatinine serum levels, it could be assumed that this drug does not produce renal disturbances. In fact, several studies have reported that statin therapy does not induce tubular dysfunction ¹⁸18. Paulsen, L; Holm, C; Bech, JN; Starklint, J; Pedersen, EB. Effects of statins on renal sodium and water handling. Nephrol Dial Transplant 2007;0:1-6. or alter glomerular filtration, even in higher doses ¹⁹19. Paulsen, L; Matthesen, SK; Bech, JN; Starklint, J; Pedersen, EB. Acute effects of atorvastatin on glomerular filtration rate, tubular function, blood pressure, and vasoactive hormones in patients with type 2 diabetes. J Clin Pharmacol 2010;50:816-822. and that may afford protection of renal function in acute unilateral ureteral obstruction ²⁰20. Kamdar, C; Chou, SY; Mooppan, UM; Kim, H; Gulmi, FA. Atorvastatin protects renal function in the rat with acute unilateral ureteral obstruction. Urology 2010;75853-857..

About liver biomarkers, it was seen that ATV did not alter AST serum levels, but promoted increase on ALT compared to baseline and saline group. It has been reported that all statins can induce asymptomatic mild elevation of serum transaminases with a quoted incidence between 1% and 1.5%, but this rarely requires withdrawal of the drug ²¹21. Bolego, C; Baetta, R; Bellosta, S; Corsini, A; Paoletti, R. Safety considerations for statins. Curr Opin Lipidol 2002;13637-644.. The elevation of serum transaminases is often self-limiting and thought to be related to alteration of the hepatocyte cellular membrane with enzyme leakage, rather than to direct liver injury ²²22. Calderon, RM; Cubeddu, LX; Goldberg, RB; Schiff, ER. Statins in the treatment of dyslipidemia in the presence of elevated liver aminotransferase levels: a therapeutic dilemma. Mayo Clin Proc 2010;85:349-356.. The risk of a significant increase in serum transaminases while using statins, especially ATV, is considered to be dose-dependent ²²22. Calderon, RM; Cubeddu, LX; Goldberg, RB; Schiff, ER. Statins in the treatment of dyslipidemia in the presence of elevated liver aminotransferase levels: a therapeutic dilemma. Mayo Clin Proc 2010;85:349-356.. In comparison to other statins, ATV is a significantly longer acting drug. It has been hypothesized that the longer exposure to ATV could explain an increased risk of hepatic toxicity compared to other statins ²²22. Calderon, RM; Cubeddu, LX; Goldberg, RB; Schiff, ER. Statins in the treatment of dyslipidemia in the presence of elevated liver aminotransferase levels: a therapeutic dilemma. Mayo Clin Proc 2010;85:349-356.. However, as ATV has a more pronounced activity in lowering serum low-density lipoprotein, this in turn could influence the structure of cellular membranes, leading to greater leakage of cellular enzymes and increased incidence of 'transaminitis' without direct hepatic toxicity ²³23. Dujovne, CA. Side effects of statins: hepatitis versus "transaminitis"-myositis versus "CPKitis". Am J Cardiol 2002;891411-1413..

About body mass variation, it was observed that the ligature-induced important weight loss in the first 2 days of experiment, due to the trauma during ligature placement, as seen in previous reports ⁶6. Lima, V; Bezerra, MM; Alencar, VBM; Vidal, FD; Rocha, FA; Castro Brito, GA, et al.. Effects of chlorpromazine on alveolar bone loss in experimental periodontal disease in rats. Eur J Oral Sci 2000;108:123-129.^,88. Goes, P; Melo, IM; Dutra, CS; Lima, AP; Lima, V. Effect of alendronate on bone-specific alkaline phosphatase on periodontal bone loss in rats. Arch Oral Biol 2012;57:1537-1544.. The treatment with ATV did not prevent the initial loss of weight presented similar body mass variation compared to saline, confirming that statin therapy does not interfere on body mass index ²⁴24. Georgescu, EF; Georgescu, M. Therapeutic options in non-alcoholic steatohepatitis (NASH). Are all agents alike? Results of a preliminary study. J Gastrointestin Liver Dis 2007;1639-64., probably due to ATV being devoid of analgesic action ²⁵25. Jaiswal, SR; Sontakke, SD. Experimental evaluation of analgesic and anti-inflammatory activity of simvastatin and atorvastatin. Indian J Pharmacol 2012;44:475-479..

In summary, this study showed an important protecting effect of ATV in ligature-induced periodontitis, without affecting systemic parameters. It can be suggested that in addition to its anti-inflammatory effect, ATV (27 mg/kg) protectively acted by its anabolic activity on the alveolar bone. Accordingly, the possibility of considering the ATV therapy as adjuvant treatment in human periodontitis deserves further investigation.

Acknowledgements

This work was supported by Ceará State Foundation for Technological and Scientific Development (FUNCAP) and National Counsel for Technological and Scientific Development (CNPq), Brazil.

References

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