br Cytokines as targets for the development of drugs
Cytokines as targets for the development of drugs Since the first scientific evidence describing the large number of cytokines and their functional roles and involvement in molecular mechanism of various diseases or disorders researchers have targeted cytokines. (Isaacs and Lindenmann, 1957), Despite this, there is still a lack of drugs that are selective in relation to specific cytokines. This paradoxical hiatus has encouraged clinical researchers to seek solid evidence of the cytokine/disease relationship (Hur et al., 2012). Moreover, T helper Th1 and Th2 cytokines have been shown to playan important role in the mechanism of inflammation, pain, allergic and infectious processes and transplantation rejection (Gandhi et al., 2018). Several studies and patent applications have shown a trend in the search for new drugs that act on specific cytokines that participate in crucial stages in certain diseases or clinical conditions (Jin and Dong, 2013; Oliveira et al., 2017; Bevivino and Monteleone, 2018). Cytokine therapy emerged from the need to enhance immunity for tumors using the lymphocyte activator and proliferative factor, interleukin-2 (IL-2) (Rider et al., 2016). Based on its therapeutic effectiveness in pre-clinical studies, cancer patients with renal cell carcinoma (RCC) and melanoma were treated with high doses of IL-2, but the results were double-edged due to its high toxicity, despite showing good antitumor properties (Atkins et al., 1999). Another example is the TNF-α inhibitor etanercept (Enbrel®) which was the first biopharmaceutical on the market approved by U.S. F.D.A to treats chronic autoimmune and inflammatory diseases such as rheumatoid arthritis, juvenile rheumatoid arthritis and psoriatic arthritis (Rider et al., 2016). A further example is, Adalimumab (Humira®), a fully human monoclonal antibody against TNF-α, that can relieve symptoms of autoimmune diseases, reduce pkm2 and inhibit chronic pain (Aitken et al., 2018). The TNF-α inhibitors, certolizumab and golimumab, were also approved for the treatment of rheumatoid arthritis, psoriatic arthritis, and Crohn's disease unresponsive to regular medications (Rider et al., 2016). Numerous studies have shown that IL-1 and TNF-α, prototypic pro-inflammatory cytokines, play a pivotal role in the mechanisms involved in inflammatory disorders and chronic diseases, such as rheumatoid arthritis, neuropathic pain (NP), sepsis and septic shock (Zanotti et al., 2002; Gabay, 2002). These reviews, which demonstrated the results of clinical trials with TNF-α inhibitors and a specific IL-1 inhibitor (IL-1 receptor antagonist [IL-1Ra]), are potentially highly significant in relation to the treatment of NP, sepsis and in septic shock management. Anakinra (Kinere®), a recombinant non-glycosylated form of IL-1Ra, which can be administered at home by subcutaneous injection, is clinically indicated for the treatment of rheumatoid arthritis, but has side-effects that include headaches, and it has been shown to increase levels of cholesterol in patient blood (Rider et al., 2016). Although some drugs already available in the pharmaceutical market which act by modulating cytokines, new drugs are urgently needed for the management of intractable inflammatory diseases or to help improve the recovery of patients with greater effectiveness and safety. Natural products, such as flavonoids and terpenes, that act as anti-inflammatory agents, painkillers, anti-allergic substances, along with other pharmacological activities are often cytokine modulators, and can, therefore, be interesting substances for the control of clinical conditions that depend on the management of strategic cytokines (Hur et al., 2012; Gandhi et al., 2018). The pro-inflammatory cytokines TNF-α, IL-1β and IL-6, and a range of others, have been shown to be important cytokines modulated by natural products. (Paul et al., 2006). Recently, our group demonstrated the effect of terpenes on inflammatory response based on the modulation of two main cytokines: TNF-α and IL-1β (Souza et al., 2014). These cytokines were the main ones described in this review (see Table 1).