The Promising Role of Antioxidant Phytochemicals in the Prevention and Treatment of Periodontal Disease via the Inhibition of Oxidative Stress Pathways: Updated Insights

Abstract

There is growing evidence on the involvement of oxidative stress, which is simply described as the imbalance between oxidants and antioxidants in favor of the former, in the development of periodontal disease that is the most common inflammatory disease in the oral cavity. Thus, the potential of antioxidant phytochemicals as adjunctively preventive and therapeutic agents against the initiation and progression of periodontal disease is a topic of great interest. The current review firstly aims to provide updated insights about the immuno-inflammatory pathway regulated by oxidative stress in periodontal pathology. Then, this work further presents the systemic knowledge of antioxidant phytochemicals, particularly the pharmacological activities, which can be utilized in the prevention and treatment of periodontal disease. Additionally, the challenges and future prospects regarding such a scope are figured out.

Keywords: antioxidant; inflammation; oral cavity; oxidants; oxidative stress; periodontal disease.

Figure 1

Schematic representation of the generation of major reactive species in periodontal tissues. In general, the main generator of ROS is the mitochondrial electron transport chain ETC, liberating superoxide, which further leads to the cascade of other ROS production. Besides, enzymatic reactions catalyzed by NADPH oxidase (NOX) or xanthine oxidase (XO) also significantly participate in ROS production. Upon the invasion of periodontal bacteria, ROS generation in periodontal tissues is enhanced via respiratory burst following the phagocytosis by immune cells, such as neutrophils. Of significance is the production of hypochlorous acid (HOCl) from hydrogen peroxide and chloride in a reaction catalyzed by myeloperoxidase (MPO) derived from neutrophils. On the other hand, nitric oxide (NO), which is product of the metabolism of L-arginine via the catalysis of nitric oxide synthase (NOS), is responsible for the production of another group of reactive species, namely reactive nitrogen species (RNS). Importantly, peroxynitrite (ONOO⁻), which is produced through the reaction between NO and superoxide, is not only a powerful RNS but also represents the merging of the ROS and NO pathways. In addition to internal sources, periodontal tissues are probably exposed to ROS from external stimuli as well.

Figure 2

Schematic representation of the double-edged effects of ROS in periodontal disease. At physiological levels, ROS may contribute to the killing of periodontal pathogens and function as the second messenger that mediates biological processes, providing cytoprotective effects. In contrast, excessive ROS can induce many adverse effects, generating a vicious circle among ROS and tissue breakdown via the immuno-inflammatory cascade.

Figure 3

Schematic representation of the functions of endogenous antioxidant defense systems. Endogenous antioxidants, which present in all body fluids and tissues, consist of enzymatic and non-enzymatic systems. They counteract ROS and maintain redox balance via three major modes of action. First, the preventive mode (prevention) functions as the quencher of singlet oxygen, suppressor of free radical (FR) production, and sequestrator of metal ions. Second, the detoxifying mode (detoxification) involves the scavenger of ROS or interruption of chain reactions. Third, the reparative mode (reparation) functions to remove or repair the biomolecules suffering from oxidative damage. In the oral cavity, saliva and gingival crevicular fluid represent important local reservoirs of endogenous antioxidants.

Figure 4

Schematic representation of the underlying pathways by which ROS-induced oxidative stress regulates inflammation, contributing to the progression of periodontal disease. First, oxidative stress may induce oxidation of vital biomolecules and activate matrix metalloproteinases MMPs, which are regulators of inflammation. Second, oxidative stress may enhance the production and expression of proinflammatory cytokines, chemokines, among others, through the activation of NF-κB-, JNK-, and NLRP3-dependent pathways. Moreover, the JNK route may induce apoptosis, whereas the NLRP3 route may cause pyroptosis. Besides, severe oxidative stress may also hinder the tolerant mechanism via suppression of the Nrf2 paradigm. Finally, oxidative stress may function as an inducer or inhibitor of autophagy activities.

Figure 5

Classification of antioxidant phytochemicals depending on their chemical structure and functional groups. There are two main categories, including carotenoids and phenolic compounds. Phenolic compounds can be further divided into subgroups, which are phenolic acids, flavonoids, and other phenolics. Phenolic acids consist of hydroxycinnamic acids and hydroxybenzoic acids, whereas flavonoids are composed of flavonols, flavones, isoflavones, flavanols, flavanones, and anthocyanins. Other phenolics are a heterogenous group in which anththraquinone, coumarins, curcumin, stilbenes, tannins, and xanthones are representatives. In addition, entities with different chemical structures belonging to alkaloids and organosulfur compounds are grouped together under one category. Every compound may have different mode of actions according to their specific structure but consistently exert remarkable antioxidative efficacy.

Figure 6

Schematic representation of the potential preventive and therapeutic role of antioxidant phytochemicals in the management of periodontal disease. Periodontal disease is initially caused upon the microbial challenge, then further progressed by the interplay among oxidative stress and immuno-inflammatory responses and tissue damage. Antioxidant phytochemicals seem to be capable of inhibiting oxidative stress pathways, both upstream and downstream, thereby controlling the progression of periodontal disease. There are four main pharmacological activities involved in such potency of these entities, including anti-microbial, anti-oxidative stress, immune regulatory and anti-inflammatory, and wound healing-promoting activities.