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Effect of Aminoguanidine in Ligature-induced Periodontitis in Rats
R. Di Paola1,
S. Marzocco2,
E. Mazzon3,
F. Dattola1,
F. Rotondo1,
D. Britti4,
M. De Majo5,
T. Genovese1 and
S. Cuzzocrea1,*
1 Institute of Pharmacology, School of Medicine, University of Messina, Torre Biologica, Policlinico Universitario, Via C. Valeria, Gazzi, 98100 Messina, Italy;
2 Department of Pharmaceutical Sciences, University of Salerno, Fisciano-Salerno, Italy;
3 Department of Biomorphology, School of Medicine, University of Messina, Italy;
4 Department of Veterinary and Agricultural Science, University of Teramo, Italy; and
5 Department of Veterinary Medicine and Pharmacology University of Messina, Italy;
Correspondence: * corresponding author, salvator{at}unime.it
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ABSTRACT
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The role of nitric oxide and reactive oxygen species is well-demonstrated in inflammation. In this study, we evaluated the effect of aminoguanidine, a nitric oxide synthase inhibitor, in a rat model of periodontitis. We induced periodontitis in rats by placing a piece of 2/0 braided silk around the lower left 1st molar. At day 8, the gingivomucosal tissue encircling the mandibular 1st molar was removed for biochemical and histological analysis. Ligation significantly increased inducible nitric oxide synthase activity and expression, and damaged tissue revealed increased neutrophil infiltration, lipid peroxidation, and positive staining for nitrotyrosine formation and poly (ADP-ribose) polymerase activation. Ligation significantly increased Evans blue extravasation in gingivomucosal tissue and alveolar bone destruction. Aminoguanidine (100 mg/kg i.p., daily for 8 days) treatment significantly reduced all these inflammatory parameters, indicating that it protects against the tissue damage associated with periodontitis by reducing nitric oxide production and oxidative stress.
Key Words: aminoguanidine • periodontitis • inducible nitric oxide synthase • poly (ADP-ribose) polymerase • alveolar bone loss
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INTRODUCTION
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During inflammation and shock, pro-inflammatory cytokines and bacterial wall components stimulate the production of nitric oxide by inducible nitric oxide (Moncada et al., 1991; Nathan, 1992). Analysis of recent data suggests that some of the cytotoxic effects of nitric oxide may be related to the production of peroxynitrite, a reactive oxidant formed by the rapid reaction of nitric oxide and superoxide (Beckman et al., 1990; Pryor and Squadrito, 1995). Enhanced formation of nitric oxide following the induction of inducible nitric oxide synthase and/or peroxynitrite formation has been implicated in the pathophysiology of various inflammatory conditions, including gastrointestinal diseases (Miller et al., 1995). The gastrointestinal epithelium represents an important surface for absorption and defense against ingested pathogens. In the oral cavity, continuously replaced bacteria may obtain firm anchorage on the non-shedding tooth surface, thereby remaining in the soft tissues surrounding the tooth long enough to evoke inflammation. The chronic inflammatory disease of the periodontal tissues is periodontitis, one of the most frequent human diseases. The inflammatory reaction associated with periodontitis may damage the surrounding cells and connective tissue structures, including alveolar bone, causing tooth loss (Lindhe and Nyman, 1987). It has been recently demonstrated that the most frequent cause of periodontitis is bacteria. The toxins, enzymes, and metabolites of the bacteria present in the dental plaque play a key role in the initiation of the inflammatory process (Listgarten, 1987). Recently, increased inducible nitric oxide synthase activity and immunoreactivity have been reported in a rat experimental model of periodontitis (Lohinai et al., 1998), suggesting that the gingivomucosal immune and epithelial cells are able to induce inducible nitric oxide synthase, similar to the responses of other parts of the gastrointestinal tract in response to nitric oxide synthase stimulation or bacteria (Tepperman et al., 1994). Thus, the cytotoxic potential of nitric oxide and peroxynitrite made it important to seek pharmacological approaches to neutralize nitric oxide and peroxynitrite-induced damage. Among inducible nitric oxide synthase inhibitors, investigators have developed some compounds characterized by the same guanidine group of the aminoacid L-arginine, such as guanidine, aminoguanidine, and mercaptoethylguanidine (MacAllister et al., 1994; Southan and Szabò, 1996; Zhang et al., 2001).
In the present study, we investigated the effect of aminoguanidine in a rat experimental model of periodontitis.
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MATERIALS & METHODS
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Surgical Procedure
Male Sprague-Dawley rats (each weighing from 280 to 400 g) were lightly anesthetized with surgical doses of sodium pentobarbitone (35 mg/kg). Sterile 2-0 black braided silk thread was placed around the cervix of the lower left first molar and knotted mesially (Györfi et al., 1994). After the rats had recovered from the anesthetic, they were allowed to eat commercial laboratory food and drink tap water ad libitum. Animal care and protocol were in compliance with Italian regulations (D.M. 116192), EEC regulations (O.J. of E.C. L 358/1 12/18/1986), with the guidelines of the institutional Animal Care and Use Committee of both St. Louis University Medical School and the National Institutes of Health.
Experimental Groups
Rats were randomly allocated into the following groups: (i) Ligature + vehicle group—rats (n = 10) were subjected to ligature-induced periodontitis and received vehicle intraperitoneally (i.p.) daily for 8 days; (ii) Aminoguanidine group—same as the Ligature + vehicle group (n = 10), except that the rats were treated with aminoguanidine (100 mg/kg i.p.) daily for 8 days; (iii) Sham + saline group—rats (n = 10) were subjected to surgical procedures identical to those experienced by the above groups, except that the ligature was not placed around the cervix of the lower left first molar, and the rats were maintained under anesthesia for the duration of the experiment; (iv) Sham + aminoguanidine group (n = 10)—identical to the Sham + saline group, except for the administration of aminoguanidine (100 mg/kg i.p.) daily for 8 days).
Measurement of Arterial Blood Pressure Indirectly in Conscious Rats
Mean arterial blood pressure in conscious rats was measured by a Blood Pressure Recorder (UGO BASILE, Biological Research Apparatus, 21025 Comerio, Italy) as previously described (Gerold et al., 1966).
Nitric Oxide Synthase Assay
Calcium-independent conversion of L-arginine to L-citrulline in homogenates of gingivomucosal tissues served as an indicator of tissue-inducible nitric oxide synthase activity. Gingivomucosal tissues’ iNOS activity was assessed as previously described (Cuzzocrea et al., 1998).
Measurement of Vascular Permeability by Evans Blue Extravasation
To assess vascular permeability, we administered Evans blue (2.5% dissolved in physiological saline, at a dose of 50 mg/kg) via a femoral venous catheter in each animal. Five min later, a cannula was introduced into the abdominal aorta. Ten min later, the right atria were cut, and the dye remaining in the gingivomucosal capillaries was removed by retrograde intra-aortic injection of 40 mL of isotonic saline solution. Extravasated Evans blue in the excised gingivomucosal tissue samples was extracted with 1 mL of formamide for 48 hrs at room temperature for spectrophotometric determination at 620 nm and expressed as mg/g gingivomucosal tissue (Györfi et al., 1994).
Measurement of Alveolar Bone Loss
In the same set of experiments used for the plasma extravasation measurements, the distance from the cemento-enamel junction of first lower molars to the alveolar crest was measured with a modification of the method of Crawford et al.(1978). The measurements were performed by an independent investigator who was unaware of the treatment regimens. The alveolar bone loss induced by the ligature was expressed as a difference between the left and the right sides.
Histological Examination
For histopathological examination, gingivomucosal tissue was taken 8 days after the ligature induction of periodontitis. The tissue slices were fixed in 10% neutral-buffered formaldehyde for 5 days, embedded in paraffin, and sectioned. The sections were stained with hematoxylin and eosin.
Radiography
Mandibles were placed on a radiographic box 90 cm from the x-ray source. Radiographic analysis of normal and ligated mandibles was performed by means of an x-ray machine (Philips X12, Munich, Germany) with a 40-kW exposure for 0.01 sec.
A radiographic examination 8 days after ligature placement revealed bone matrix resorption in the lower first left molar.
Myeloperoxidase Activity
Myeloperoxidase activity, an index of polymorphonuclear leukocyte accumulation, was determined in the gingivomucosal tissue collected at the specified time as previously described (Cuzzocrea et al., 1998).
Malondialdehyde Levels
Malondialdehyde levels in the gingivomucosal tissue were determined as an indicator of lipid peroxidation as previously described (Cuzzocrea et al., 1998).
Immunohistochemical Localization of Nitrotyrosine and Poly (ADP-ribose) Polymerase
Nitrotyrosine formation and poly (ADP-ribose) polymerase formation were detected by immunohistochemistry in the gingivomucosal tissue sections as previously described (Cuzzocrea et al., 2002). Immunocytochemistry photographs (n = 5 photos from each sample collected from all rats in each experimental group) were assessed by densitometry by means of a Macintosh personal computer equipped with Optilab Graftek software (Milano, Italy).
Data Analysis
All values in the Figs. and text are expressed as mean ± standard error of the mean of n observations, where n represents the number of animals studied. Datasets were examined by one- and two-way analyses of variance, and individual group means were then compared with Bonferroni’s or Student’s unpaired t test. A P-value less than 0.05 was considered significant. In the experiments involving histology or immunohistochemistry, the Figs. shown are representative of at least 3 experiments performed on different experimental days.
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RESULTS
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Effects of Aminoguanidine in Nitric Oxide Production in Periodontitis
There were significant amounts of constitutive nitric oxide synthase activity in the gingivomucosal tissues of control (sham-ligated) rats (data not shown), and there was also a small amount of inducible nitric oxide synthase activity detectable in the gingivomucosal tissues of these animals (Fig. 1A ). Ligation caused a significant, more than three-fold, increase in inducible nitric oxide synthase activity, whereas it did not significantly affect inducible nitric oxide synthase activity on the contralateral side (Fig. 1A). Ligation on the ipsilateral, but not the contralateral, side also tended to cause a decrease in constitutive nitric oxide synthase activity (data not shown). Aminoguanidine treatment was able to attenuate inducible nitric oxide synthase activity significantly (Fig. 1A). Eight days following ligation, there was a marked increase in positive staining for inducible nitric oxide synthase in the gingivomucosal tissues. Aminoguanidine treatment was unable to reduce the positive staining for inducible nitric oxide synthase in the gingivomucosal tissues treated with aminoguanidine (data not shown). There was no staining for inducible nitric oxide synthase in gingivomucosal tissues obtained from the sham group of rats (data not shown).
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Figure 1. Inducible nitric oxide synthase (A) and myeloperoxidase activity (B), malondialdehyde levels (C), and Evans blue content (D) in gingivomucosal tissue was significantly increased by ligature compared with the contralateral side. Aminoguanidine (100 mg/kg i.p., daily for 8 days) significantly reduced inducible nitric oxide synthase and myeloperoxidase activity, malondialdehyde levels, and Evans blue content. Data are means ± SEM of n = 10 rats for each group. * P < 0.01 vs. non-ligated. P < 0.01 vs. ligated.
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Effects of Aminoguanidine on Neutrophil Infiltration and Lipid Peroxidation in Periodontitis
Myeloperoxidase activity, an index of neutrophil infiltration, was significantly elevated at 8 days after ligature (Fig. 1B ), and aminoguanidine treatment significantly reduced these levels. Malondialdehyde levels, indicative of lipid peroxidation, were significantly increased in the gingivomucosal tissues of ligature-operated rats (Fig. 1C). The degree of gingivomucosal tissues’ malondialdehyde levels was significantly reduced in rats treated with aminoguanidine (Fig. 1C). No significant changes in either myeloperoxidase activity or malondialdehyde levels were observed in the gingivomucosal tissues from the contralateral side.
Effects of Aminoguanidine on Nitrotyrosine and Poly (ADP-ribose) Polymerase
Eight days following ligation, we took gingivomucosal tissue sections to determine the immunohistological staining for nitrotyrosine or anti-poly (ADP-ribose) polymerase. Sections of gingivomucosal tissues from the contralateral side did not reveal any immunoreactivity for nitrotyrosine (Figs. 2A, 4D) or for anti-poly (ADP-ribose) polymerase (Figs. 2D, 4D) within the normal architecture. A positive staining for nitrotyrosine (Figs. 2B, 4D) and for anti-poly (ADP-ribose) polymerase (Figs.e 2E, 4D) was found in the gingivomucosal tissues from ligature-operated rats. Aminoguanidine (100 mg/kg, i.p.) reduced the staining for both nitrotyrosine and anti-poly (ADP-ribose) polymerase (Figs. 2C, 2F, 4D).
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Figure 2. Immunohistochemical localization of nitrotyrosine and poly (ADP-ribose) polymerase formation. No staining for nitrotyrosine (A) and poly (ADP-ribose) polymerase (D) was observed in sham gingivomucosal tissue, while positive staining was observed after ligature (B,E). In gingivomucosal tissue of aminoguanidine-treated rats (100 mg/kg i.p., daily for 8 days), no positive staining was observed both for nitrotyrosine (C) and poly (ADP-ribose) polymerase (F). Original magnification: x125. Fig. is representative of at least 3 experiments performed on different experimental days.
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Figure 4. The alveolar bone from rats ligated for 8 days demonstrated alveolar bone resorption (A). Aminoguanidine treatment suppressed alveolar pathology in the rat alveolar bone (B). A significant increase in the distance between the cemento-enamel junction and the alveolar crest at the mediolingual root of the first molar was observed in ligature-treated rats. (C) Aminoguanidine treatment significantly reduced the increase in the distance between the cemento-enamel junction and the alveolar crest. Densitometry analysis of immunocytochemistry photographs (D; n = 5 photos from each sample collected from all rats in each experimental group) for PAR and nitrotyrosine from gingivomucosal tissue was conducted. The assay was carried out by means of a Macintosh personal computer (CPU G3-266) equipped with Optilab Graftek software. The radiographic Fig. is representative of at least 3 experiments performed on different experimental days. Densitometry data are expressed as % of total tissue area. * P < 0.01 vs. non-ligated. P < 0.01 vs. ligated.
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Effects of Aminoguanidine on Ligature-induced Periodontitis
When compared with gingivomucosal tissue sections taken from the contralateral side (Fig. 3A), histological examination of gingivomucosal tissue sections of ligature-operated rats showed edema and tissue injury, as well as infiltration of the tissue with inflammatory cells (Fig. 3B). Aminoguanidine treatment reduced the degree of gingivomucosal tissue injury (Fig 3C).
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Figure 3. Gingivomucosal section from non-ligature-treated rats (A) demonstrating no tissue damage. Inflammatory cell infiltration and edema were observed in gingivomucosal sections from ligature-treated rats (B). Significantly less edema and inflammatory cell infiltration were observed in gingivomucosal sections from ligature-treated rats which had been treated with aminoguanidine (100 mg/kg i.p., daily for 8 days) (C). Original magnification, x125. Fig. is representative of at least 3 experiments performed on different experimental days.
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Effect of Aminoguanidine on Plasma Extravasation and Bone Destruction
Before the measurement of Evans blue extravasation, mean arterial pressure of vehicle-treated and aminoguanidine-treated animals was recorded. In agreement with previous studies (Mattson et al., 1998), aminoguanidine treatment did not affect mean arterial blood pressure, indicative of a lack of effect on constitutive, endothelial nitric oxide production (vehicle-treated, 110+4 mm Hg, n = 10; aminoguanidine-treated, 108+6 mm Hg, n = 10). After Evans blue injection, in contrast to the contralateral side, a definite blue belt could be observed in the gingiva around the neck of the tooth, even in non-ligated control animals (not shown). Ligation significantly increased Evans blue extravasation in gingivomucosal tissue compared with tissue on the contralateral side (Fig. 1D). Aminoguanidine treatment prevented this increase in Evans blue extravasation, but did not change the Evans blue content of the contralateral side (Fig. 1D).
A significant alveolar bone loss between the lower first left and the right first molars induced by the left-side ligature was observed in vehicle-treated rats (Fig. 3); aminoguanidine treatment resulted in a significant inhibition of alveolar bone loss after ligation (Fig. 3). Therefore, a radiographic examination of the mandibles 8 days after ligature placement revealed bone matrix resorption in the lower first left molar after ligation (Fig. 4A). There was no evidence of pathology in the right first molar (data not shown). Aminoguanidine markedly reduced the degree of bone resorption in the lower first left molar after ligation (Fig. 4).
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DISCUSSION
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In periodontitis, inducible nitric oxide synthase expression may have beneficial as well as detrimental roles. Beneficial effects may include antimicrobial activity, immune modulation, and inhibition of microvascular thrombosis, as well as increased tissue perfusion. On the other hand, detrimental effects may include a cytotoxic action toward the host tissues, including alveolar bone resorption due to the stimulating effect of nitric oxide on the activity of the osteoclasts (Hukkanen et al., 1995). To investigate the potential role of inducible nitric oxide synthase in the pathophysiology of periodontitis, we evaluated, in a well-established rat periodontal model, the effect of aminoguanidine, an inhibitor of inducible nitric oxide synthase, with selectivity toward the inducible isoform and with an additional, anti-oxidant, activity (Schroeder and Lindhe, 1975; Làszlò et al., 1995; Southan and Szabò, 1996). Our results demonstrated that aminoguanidine exerted a significant inhibitory effect on plasma extravasation and reduced the degree of bone resorption during periodontitis. Our study also confirmed earlier findings that one of the characteristic signs of inflammation, Evans blue extravasation, was higher on the ligated side than on the opposite side at the 8th day (Györfi et al., 1994), and that various nitric oxide synthase inhibitors reduced the endotoxin-induced vascular leakage (Làszlò et al., 1995). Our experiment confirmed that ligature induces significant alveolar bone resorption (Zappa et al., 1991), as measured at 8 days, an effect which was blocked by aminoguanidine treatment. In a rat experimental arthritis model, a nitric oxide synthase inhibitor also suppressed pathological changes (Cuzzocrea et al., 2002). The exact mechanism by which aminoguanidine inhibits alveolar bone resorption remains to be established in further studies. Aminoguanidine does not inhibit the catalytic activity of endothelial constitutive nitric oxide synthase in therapeutically relevant doses, and does not raise blood pressure in anesthetized rats in the doses used (Làszlò et al., 1995), as confirmed in the present study. We also report here that ligature-induced periodontitis in the rat results in a significant infiltration of inflammatory cells in the gingivomucosal tissues, and we also demonstrated that treatment with aminoguanidine reduces inflammatory cell infiltration and moderates tissue damage, as evaluated by histological examination. Neutrophils can contribute to tissue destruction by the production of reactive oxygen metabolites, granule enzymes, and cytokines that further amplify the inflammatory response (Salvemini et al., 2001). Furthermore, we found that the tissue damage induced by ligature in vehicle-treated rats was associated with high levels of lipid peroxidation. An intense positive staining of nitrotyrosine formation also suggested that a structural alteration of gingivomucosal tissues had occurred, most probably due to the formation of highly reactive nitrogen derivatives.
Therefore, in this study, we clearly demonstrate that aminoguanidine treatment prevents the induction of inducible nitric oxide synthase and the formation of peroxynitrite. Reactive oxygen species producing DNA damage activates the ’poly (ADP-ribose) polymerase suicide hypothesis’ (Szabò et al., 1997), which also plays an important role in inflammation (Szabò et al., 1997), and we demonstrate here that aminoguanidine treatment reduced the activation of poly (ADP-ribose) polymerase during ligature-induced periodontitis. In conclusion, this study provides the first evidence that aminoguanidine causes a substantial reduction in ligature-induced periodontitis in the rat. Finally, our findings suggest that interventions, which may reduce the generation or the effects of inducible nitric oxide synthase, may be useful in conditions associated with local or systemic inflammation.
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ACKNOWLEDGMENTS
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This study was supported by a grant from a University Minister (PRIN 2003). The authors thank Giovanni Pergolizzi and Carmelo La Spada for their excellent technical assistance during this study, Mrs. Caterina Cutrona for secretarial assistance, and Miss Valentina Malvagni for editorial assistance with the manuscript.
Received for publication July 14, 2003.
Revision received January 22, 2004.
Accepted for publication January 22, 2004.
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Journal of Dental Research, Vol. 83, No. 4,
343-348 (2004)
DOI: 10.1177/154405910408300414
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ABSTRACT
INTRODUCTION