Resveratrol Treatment and Periodontal Disease: Comparison
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Resveratrol is an anti-inflammatory compound found in several foods. Periodontal disease (PD) is associated to other systemic diseases, and inflammation may be responsible for the association. 

  • Periodontitis
  • Oral Health
  • Mouth Diseases
  • Functional Food

1. Introduction

Resveratrol (3,5,4′-trihydroxystilbene) is a polyphenol stilbene found in red wine [1], peanuts [2], apples, several vegetables and berries, and others [3]. This compound has gained attention due to the “French Paradox” that indicates a low incidence of cardiovascular diseases and even consuming a high saturated fat diet [4]. The explanation for this paradox is associated with the consumption of red wine in France that naturally contains “therapeutic doses” of resveratrol [5]. Recently, resveratrol was also linked to several other health benefits such as cardioprotective effects, antitumor activity, and a life span increase [6][7]. Consequently, resveratrol has been investigated for the prophylaxis and therapeutic treatment of periodontal disease (PD) based on its anti-inflammatory and antioxidant properties [3][8].
PD embraces a group of inflammatory conditions affecting teeth supporting tissues [9]. It may be limited to the gums (gingivitis) or may affect the alveolar bone and periodontal ligament (periodontitis), causing apical epithelial migration and alveolar bone resorption [9]. This inflammation frequently involves a host response against biofilm accumulation and is mostly clinically asymptomatic in its early stages [10]. The direct consequences of PD involve gingival bleeding, tooth mobility, and even tooth loss, leading to aesthetic impairment and a poor quality of life [10]. In addition, PD is also associated with other systemic diseases such as cardiac, renal, and respiratory dysfunction; rheumatoid arthritis; metabolic syndrome; and even cancer [11].
It is estimated that the prevalence of PD in the world population exceeds 50% of adults older than 30 year. Approximately 10% of these individuals present the more severe forms [12][13]. Population growth and aging have been contributing to an increase of severe periodontitis cases [13][14], generating a universal public health issue [13][15]. Risk factors for the development and progression of PD involve mainly genetic polymorphisms, stress, obesity and diabetes, smoking, and alcoholism [16]. Proper oral hygiene and regular dental care (including scaling and root planning) are conventional therapies employed in dental practice [17]. Alternatively, maintaining an ideal weight and consuming a high-quality diet can also help to improve periodontal health [18], besides avoiding smoking and excessive alcohol drinking.

2. Current Insights on Resveratrol Treatment and Periodontal Disease

In this work, we investigated the effects of resveratrol administration on PD progression in preclinical studies. Out of the eleven selected studies, ten evaluated ABL and nine observed improvement of this parameter after resveratrol administration [19][20][21][22][23][24][25][26][27]. Such results may be related to an improvement of oxidative stress and anti-inflammatory properties [3][8].
Resveratrol increases the activity of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD), which are key components against reactive oxygen species (ROS) [28]. Moreover, the host response to periodontal pathogens promotes local and systemic elevations of proinflammatory cytokines that alter the expression of the receptor activator of nuclear factor-kappa B ligand (RANKL) on the osteoblast surface [29]. RANKL is responsible for activating osteoclasts through its interaction with the receptor activator of nuclear factor-kappa B (RANK), initiating bone resorption [29]. High levels of ROS acting as intracellular signal transducers result in autophagy, which plays a dual role in periodontitis by promoting cell death or blocking apoptosis in infected cells [30]. In addition, ROS may influence the activation of signaling nuclear factor-κB (NF-κB), resulting in an increase of proinflammatory cytokines and, consequently, stimulating the differentiation of osteoclasts [30]. Considering that PD can be worsened due to the increase of pro-inflammatory cytokines and ROS, resveratrol acts on both fronts attenuating the progression of this disease [8].
One of the retrieved studies, Chin et al. [31] found no significant improvement in ABL in animals treated with resveratrol (even with the largest dose of 25 mg/kg/day). However, the treatment period was maintained for only seven days. [31]. It is possible that there is some mechanism related to the time of action or even to the administration period of this (prior to or following induction of PD). More studies should be conducted to determine the effective optimal dose and duration needed to attenuate ABL. Regarding toxicity, no side effects were reported for resveratrol consumption in any of the selected studies.
Regarding administration route, only two studies evaluated the injectable administration of resveratrol [21][27]. Even a single 0.001% (w/w) dose delivered one day prior to PD induction promoted ABL reduction, inflammatory profile, and oxidative stress improvements in C57BL/6J wild-type mice [27]. The highest percentages of ABL reduction were observed in studies where resveratrol was injected [21][27]. This fact may be related to the reduction of resveratrol bioavailability after gastrointestinal absorption [32].
The mechanisms involved in resveratrol regulation in periodontal inflammation have not yet been fully elucidated [21]. It is known that resveratrol can decrease the expression of toll-like receptor type 4 (TRL4) which is activated by lipopolysaccharides (LPS) [21]. An activation of TLR4 observed in chronic periodontitis increases the production of proinflammatory cytokines [33]. Another possible mechanism is by increasing anti-inflammatory mediators such as IL-4 [26], as well as a suppression of both matrix metalloproteinase (MMP-2 and MMP-9) and cyclooxygenase-2 (COX-2) [21]. IL-4 suppress the production of IL-17 and IL-1β [26], which play an important role in the periodontitis pathogenesis and inhibit both Th1 pro-inflammatory response and bone resorption [34].
All analyzed studies used rat or mice. Rodent periodontium has a good similarity with humans [35]. The induction of periodontitis involved the ligature in all experiments. This model has several advantages such as low cost and the possibility of investigation in a wide genetic variety of rodents, besides allowing the exploration of the interaction between the oral microorganisms and host response during the development of periodontitis [7]. Even though rats are not natural hosts for some bacteria found in human oral cavity, both A. actinomycetemcomitans and P. gingivalis have been reported in rodents’ microbiota after ligature [36][37][38].
Regarding the quality assessment of studies, most of the categories were classified as excellent or average. A previous systematic review [39] using the ARRIVE guidelines reported that most animal studies lack a clear indication of the reasons for choosing a particular animal model, contributing to a lower score for this item. This item also received the lowest score. This aspect is considered an important criterion for preclinical animal trials [39]. Thus, even if it is already well-known that some results of studies in rodents can be extrapolated to humans, it is important to highlight the relevance of the model used.
Another ARRIVE item that scored as low in several studies was the “interpretation/scientific implications” since only a few articles commented about the limitations and bias as well as mentioned the 3Rs (replacement, refinement, and reduction) principles adopted in experiments with animal studies. Similar results were also reported by Dereka et al. [40], in which only 10% of the studies attended this question.
Among the risk of bias assessed, the domains “allocation concealment”, “random housing”, “blinding of participants and personnel”, “random outcome assessment”, and “blinding of outcome assessment domains” presented a high risk of bias or were not clearly described. These same domains were classified as unclear or with a high risk of bias according to the Syrcle tool in previous study [41]. In a systematic review of animal studies [39], 40% and 60% of studies presented a high risk of bias and an unclear risk in the “allocation concealment” domain, respectively. Randomized housing during the experiment reduces the bias risk once these conditions (such as lighting, humidity, temperature, etc.) are known to influence study outcomes [42]. An implementation of a blind evaluation in animal studies is also crucial, especially for subjective measurements [43].
This systematic review was conducted according to the PRISMA criteria [44] and the protocol for the preparation, registration, and publication of systematic reviews of animal intervention studies [45]. In order to minimize bias, each step of searching or ranking was performed by two independent researchers. Additionally, to prevent the exclusion of any article, a careful search was conducted. It is important to emphasize that, in the searches performed, we have not found previous systematic review or meta-analysis studies involving the main question addressed in this study.
The results of meta-analysis demonstrated that, in rats, bone loss was significantly lower due to resveratrol administration. However, only a few studies were eligible for the meta-analysis (seven), and it was not possible to assess the publication bias. Considering the potential benefits of resveratrol on periodontal health, further studies should be conducted investigating the effects of this compound in PD models. In addition, future studies should focus on reducing the risk of bias, especially in the areas related to “allocation concealment” and "blinding of participants and personnel" which contributed to the greatest risk of bias.

3. Conclusions

We concluded from preclinical studies that resveratrol can improve periodontal disease probably due to the modulation of both oxidative stress and inflammatory profile. The results obtained through ARRIVE showed a good quality of the studies overall. However, the analysis by the Syrcle tool demonstrated that some aspects related to randomization and blinding should be considered to reduce the risk of bias.
The findings of this systematic review and meta-analysis demonstrated promising effects of resveratrol on periodontal disease, which may stimulate future studies in humans. Because of species-specific variables such as oral microbiota, dose-response effect, and the route of administration, the results in humans may vary from those observed in animals. Clinical studies are essential to confirm the results observed in animal studies.

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