Melatonin and Periodontitis-Related Systemic Diseases: Comparison
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Please note this is a comparison between Version 2 by Jessie Wu and Version 1 by Zhengguo Cao.

Periodontitis has become the main reason for tooth loss/edentulism in adults worldwide. It is also linked closely with other systemic diseases such as cardiovascular disease, Alzheimer’s disease, diabetes, and cancer, thus profoundly impairing people’s quality of life. As the most common chronic inflammatory disease of humans, periodontitis has brought about huge socioeconomic impacts and healthcare costs. Periodontitis as a highly prevalent chronic infection/inflammatory disease can eventually lead to tooth loss and masticatory dysfunction. It also has a negative impact on general health and largely impairs quality of life. The tissue destruction during periodontitis is mainly caused by the excessive immune–inflammatory response; hence, how to modulate the host’s reaction is of profound importance for effective periodontal treatment and tissue protection. Melatonin, as an endogenous hormone exhibiting multiple biological functions such as circadian rhythm regulation, antioxidant, and anti-inflammation, has been widely used in general healthcare. The application of melatonin as an adjunctive approach in the treatment of periodontitis and periodontitis-related systemic comorbidities is witnessed. 

  • periodontitis
  • melatonin
  • Systemic Diseases

1. Melatonin and Diabetes Mellitus

The relationship between diabetes mellitus and periodontitis has drawn people’s attention worldwide for many years. It has been long since diabetes was considered as a major risk factor of periodontitis [1]. Indeed, periodontitis has been regarded as the sixth complication of diabetes ever since the 1990s [2]. At the same time, periodontitis has a negative effect on glycemic control [3], and periodontitis patients have higher prevalence of type 2 diabetes [4]. Additionally, periodontal treatment contributes to better glycemic control within type 2 diabetes patients [5][6]. This bidirectional interrelationship between diabetes and periodontal diseases inspire us to treat them together with the cooperation of different departments.
Diabetes is characterized by high blood glucose levels and glucose intolerance, together with lipid and carbohydrate metabolic disorders [7]. These disturbances always cause inflammatory changes in the body, including enhanced RANKL/OPG ratio, increased proinflammatory mediator expression, and abundant ROS production [8]. Additionally, periodontitis-related tissue destruction is caused by too much ROS and an abnormal RANKL/OPG ratio. Herein, better control of diabetes could facilitate the treatment outcome of periodontitis. In vivo studies have proved that melatonin is able to decrease osteoclastic activity and reduce hyperglycemia-induced oxidative stress and alveolar bone loss in rats with diabetes and periodontitis [7][9]. Clinical trials have identified the moderating effects of melatonin on salivary RANKL/OPG ratio [10] as well as the reduction in salivary acid phosphatase, alkaline phosphatase, osteopontin, and osteocalcin concentration in patients with diabetes and periodontal disease [11]. Moreover, systemic administration or topical application of melatonin alleviates the inflammatory condition and improves periodontal status in diabetes patients with periodontitis [12][13][14]. Periodontal pocket depths were significantly reduced when combining melatonin with NSPT in periodontitis patients with diabetes [15].
Apart from the benefits to the local periodontal parameters, melatonin also favors the systemic conditions of diabetes patients with periodontitis. For instance, individuals with diabetes and periodontal disease may present high levels of serum C-reactive protein and IL-6, which could be decreased by local application of melatonin [16]. When combined with NSPT, melatonin leads to better glycemic control in periodontitis patients with type 2 diabetes [12][17]. In pinealectomyzed rats with periodontal disease, systemic administration of melatonin could prevent insulin resistance and increase plasma insulin levels [18]. Rats with apical periodontitis exhibit low insulin sensitivity and impaired insulin signaling, which could be rescued by melatonin [19].

2. Melatonin and Cardiovascular Diseases

The increased risk of periodontitis on cardiovascular diseases has been widely investigated. Periodontitis patients have a higher prevalence of cerebrovascular disease (CVD), and periodontal treatment produces a reduction in the incidence of CVD events [20][21]. It is postulated that the bacteremia caused by periodontitis results in bacterial invasion of endothelial cells, and this has been proved by the fact that specific oral bacterial species have been detected in cardiovascular specimens [22].
Only several studies explore how melatonin affects periodontitis-induced cardiovascular damage. For instance, melatonin combined with metronidazole reversed the superoxide radical production and proinflammatory cytokines elevated by P. gingivalis in human aortic endothelial cells. Thus, the combination of metronidazole and melatonin might be an alternative approach for atherosclerotic cardiovascular diseases [23]. Moreover, the expression levels of malondialdehyde (MDA), MMP-9, and cardiac Troponin-T (cTnT) in cardiac left ventricular tissue were upregulated in experimental periodontitis rats, and could be downregulated remarkably by melatonin [24]. Although no obvious antioxidant effects of melatonin were detected in this trial, another in vivo study demonstrated higher glutathione peroxidase level in periodontitis + melatonin group than periodontitis + saline solution group [25]. Thus, potential protective effects of melatonin on cardiovascular tissues might exist, but more investigations are required to support this conclusion.

3. Melatonin and Kidney Disease

The association between kidney disease and periodontitis has been discussed for the past few years [26]. On one hand, the impaired immune system in patients with kidney disease leads to high risks of infectious diseases such as periodontitis. On the other hand, periodontal pathogens and their virulence factors such as LPS, fimbriae, and gingipains could transfer from periodontal lesions to the kidney by the bloodstream, and periodontitis-induced inflammatory cytokines cause kidney damage as well [27].
Very few studies investigate the role of melatonin in kidney damage within those periodontitis patients. It has been revealed that in LPS-induced periodontitis rats, the increased serum aspartate aminotransferase, alanine transaminase, and urea nitrogen levels could be ameliorated with melatonin treatment [28]. A recent study demonstrated that periodontitis enhanced the levels of proinflammatory cytokines (TNF-α and IL-1β), oxidative stress (MDA), and proteases (MMP-8, MMP-9, and cathepsin D) in rat kidneys, while melatonin suppressed them significantly. Nevertheless, melatonin failed to rescue the impaired renal function [29]. More investigations are needed to further explore the connection between periodontal treatment and kidney disease and how melatonin affects this process.

4. Melatonin and Obesity

It has been concluded that overweight or obese individuals have a higher risk of periodontitis. Bone marrow adiposity leads to decreased osteoblasts and increased osteoclastogenesis [30]. Excessive white adipose tissue results in enhanced ROS and inflammatory cytokines production, which in turn causes periodontal tissue damage [31]. Periodontitis patients with obese harbored higher levels of periodontopathogens such as A. actinomycetemcomitans, T. forsythia, and Fusobacterium nucleatum [32]. On the other hand, periodontitis could increase the risk of obesity as well [31]. Periodontitis-related insulin resistance results in hyperinsulinemia [33], which further promotes obesity [34]. Periodontitis-induced masticatory dysfunction forces patients to select a soft, high-fat/high-calorie diet, which facilitates fat accumulation [35].
Only two studies from the same group investigate the connections between melatonin and periodontitis associated with obesity. In rats with comorbidities of obesity and periodontitis, plasma melatonin levels were significantly lower with reference to controls and to those rats with only obese or periodontitis [36]. Notably, adjunctive melatonin therapy with periodontal treatment in these experimental rats remarkably prevented alveolar bone loss and exerted protective anti-inflammatory effects. These effects were much better than the adjunctive usage of chlorhexidine [37]. Although melatonin supplementation has been proved to reduce body weight and prevent obesity-related complications in obese patients or mice [38][39], there are still no reports on whether melatonin could facilitate body weight control in periodontitis patients associated with obesity. Additional investigations are required to verify the beneficial effects of melatonin on periodontitis-related obesity.

5. Melatonin and Coronavirus Disease 2019 (COVID-19)

COVID-19 has spread globally and brought about huge disasters for almost the past three years. Many components of the established cytokine storm during COVID-19 are similar to the cytokine expression profile of periodontitis [40]. Thus, the possible influence of periodontitis on COVID-19 has been broadly discussed. It has been demonstrated that periodontitis patients had a higher risk of acquiring severe COVID-19 complications, death, ICU admissions, or assisted ventilation [41][42]. The underlying mechanisms have been identified as well [43]. For instance, angiotensin-converting enzyme 2 (ACE2), one of the key receptors for the invasion of SARS-CoV-2, is highly expressed on the epithelial cells of oral mucosa [44], and could be upregulated in patients with periodontal disease and diabetes [45]. Moreover, periodontopathogens aspirated into the lungs could facilitate more SARS-CoV-2 invasion and replication [46]. Therefore, better management of periodontitis may help to reduce infection and transmission of SARS-CoV-2.
Increasing evidence has proved that melatonin as an adjunctive agent exhibited beneficial effects for COVID-19 prevention and treatment [47][48], although there is still no direct evidence supporting the possible role of melatonin in COVID-19 outcomes with periodontitis patients. It is hypothesized that melatonin may prevent the activation of NLRP3 inflammasome, thus protect tissue damage from COVID-19 and periodontitis [49]. Thus, more investigation from both laboratory work and clinical tests are still required to support the hypothesis.
Above all, periodontitis is closely related with multiple systemic diseases and disorders, and melatonin exhibits beneficial effects not only on periodontal health but also on general conditions (Table 1). Nevertheless, the current investigations are far from enough, more research is required to explore how melatonin facilitates the treatment of other periodontitis-related comorbidities such as Alzheimer’s disease, adverse pregnancy outcomes, and rheumatoid arthritis. Overall, based on the present evidence, the application of melatonin should be promising and harbors a bright future.
Table 1.
Melatonin and periodontitis-related systemic diseases.
Periodontitis-Related Systemic Diseases Function Mechanisms of Melatonin Application Methods of Melatonin Reference
Diabetes mellitus
  • Decreasing osteoclastic activity; reducing hyperglycemia-induced oxidative stress and alveolar bone loss
  • Male Wistar rats, intraperitoneal injection of 10 mg/kg/day for 4 weeks
 [7]
  • Male Sprague Dawley rats, 10 mg/body weight intraperitoneal dose of melatonin once a day for 14 days
 [9]
  • Moderating salivary RANKL/OPG ratio
  • Diabetic patients, topical application of melatonin (1% orabase cream formula) once daily for 20 days
 [10]
  • Reduction in salivary acid phosphatase, alkaline phosphatase, osteopontin, and osteocalcin concentration
  • Diabetic patients, topical application of melatonin (1% orabase cream formula) once daily for 20 days
 [11]
  • Ameliorating inflammation; improving periodontal status
  • Diabetic patients, tablets containing 6 mg of melatonin, once a day for 8 weeks, 1 h before bedtime
 [12]
  • ● Diabetic patients, tablets containing 6 mg of melatonin, once a day for 8 weeks, 1 h before bedtime
 [13]
  • Diabetic patients, topical application of melatonin (1% orabase cream formula) once daily for 20 days
 [14]
  • Reducing periodontal pocket depths
  • Systematic review and meta-analysis
 [15]
  • Reducing serum C-reactive protein and IL-6
  • Diabetic patients, topical application of melatonin (1% orabase cream formula) once daily for 20 days
 [16]
  • Leading to better glycemic control combined with NSPT
  • ● Diabetic patients, tablets containing 6 mg of melatonin, once a day for 8 weeks, 1 h before bedtime
 [17]
  • Preventing insulin resistance; increasing plasma insulin levels
  • Male Wistar albino rats, 5 mg/kg body weight in drinking water for 28 days
 [18]
  • Improving insulin sensitivity; rescuing impaired insulin signaling
  • Male Wistar rats, 5 mg kg−1 melatonin (diluted in drinking water) for 60 days
 [19]
Cardiovascular diseases
  • Reversing the superoxide radical production and proinflammatory cytokines when combined with metronidazole
  • C57BL/6J mouse, 5 mg/kg intraperitoneal dose of melatonin once a day for 16 weeks
 [23]
  • Downregulating MDA, MMP-9, and cTnT expression levels
  • Male Sprague-Dawley rats, 10 mg/body weight intraperitoneal dose of melatonin once a day for 14 days
 [24]
  • Improving glutathione peroxidase level
  • ● Wistar Albino male rats, intraperitoneal injection of 10 mg/kg/day for 2 weeks
 [25]
Kidney diseases
  • Downregulating serum aspartate aminotransferase, alanine transaminase, and urea nitrogen levels
  • Female Wistar albino rats, intraperitoneal injection 50 mg/kg of melatonin, daily for 10 d
 [28]
  • Suppressing expression levels of proinflammatory cytokines (TNF-α and IL-1β), oxidative stress (MDA and OSI), and proteases (MMP-8, MMP-9, and CtD)
  • Male Sprague Dawley rats, daily intraperitoneal dose of 10 mg/kg of melatonin
 [29]
Obesity
  • ● Preventing alveolar bone loss and exerting protective anti-inflammatory effects
  • Wistar rats, 25 μg/mL of melatonin dissolved in the drinking water for 4 weeks
 [37]
COVID-19
  • Preventing the activation of NLRP3 inflammasome
  • ● Hypothesis
 [49]
Abbreviation: RANKL, receptor activator of nuclear factor kappa-Β ligand; OPG, osteoprotegerin; IL, interleukin; NSPT, nonsurgical periodontal therapy; MDA, malondialdehyde; MMP-9, matrix metalloproteinase-9; cTnT, cardiac Troponin-T; TNF, tumor necrosis factor-alpha; OSI, oxidative stress index; CtD, cathepsin D; NLRP3, NOD-like receptor thermal protein domain associated protein 3.

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