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    • Analgesia is an important ancillary property

    2018-10-29

    Analgesia is an important ancillary property of all anti-inflammatory agents. Most of the anti-inflammatory drugs increased pain threshold in various animal models [44]. This is natural because many endogenous chemical mediators of inflammation play a part in generating pain impulses (for example, histamine, serotonin and prostaglandins) and some other mediators such as bradykinin and cytokines, are involved in prolongation of the sensation of the pain [45]. RA is an inflammatory condition of the joint that is associated with hyperalgesia and functional impairment [46]. Joint inflammation induced by AIA is associated with hyperalgesia and slight compression of the joint which caused leg withdrawal and squeaking. The hyperalgesia associated with arthritis has been reported to involve prostaglandin synthesis [47]. Increased levels of substance P, ap-1 gene-related peptide and up-regulation of neurokinin-1 receptor in the dorsal horn of the rat spinal cord have been reported to play an important role in modulating both inflammation and hyperalgesia in the FCA model [48]. However, in the present study, TAPP did not prevent reduction pain latency in Randall–Selitto assay. Therefore, nociception-related mediators (substance-P, calcitonin gene-related peptide and neurokinin-1) are not involved in mechanism of action of TAPP. This also pointed toward the possibility of disease modification as possible mechanism of action of TAPP against RA. AIA has been generally believed to be the result of a delayed-type hypersensitivity (DTH) response to a disseminated antigen probably derived from the injected bacterial cell wall [49]. AIA in rats is a useful model of inflammatory cachexia that mimics the human pathophysiology in many important ways [50]. AIA induces inflammation as primary lesion which reached to peak after 3–5d with secondary lesions occur after a delay of about 11–12d. Secondary reactions in AIA are characterized by immune responses, inflammation and decrease of weight (cachexia). In our study, the test compound, TAPP significantly protected rats from cachexia because of arthritis induction. In the past, many plant-derived procyanidines reported to have cytokine inhibitory effect in vitro[51,52]. Similar effects were also attributed to Cinnamon bark extract and polyphenols [16,53]. In vitro pre-challenge with cinnamon extract is reported to suppress lipopolysaccharide (LPS)-induced cytokines expression [54]. Recently, immune regulatory action of TAPP in mouse 3T3-L1 adipocytes is attributed to TTP (tristetraprolin) [55]. Besides, TAPP is capable of affecting immune responses by regulating anti-inflammatory mediators as well as the TTP gene expression in macrophages [16]. Taken together, cytokine inhibition emerges as a probable mechanism of TAPP responsible for cachexia reducing effects in AIA-induced established polyarthritis in rats. This probability is also supported by our result that TAPP reduces serum C-reactive protein (CRP) levels of rats on day-21 compared to day-12 levels (Table 2) whereas AIA control rats showed sustained increase in CRP till day-21 (Table 2). CRP is an acute-phase protein and has been identified as an important biomarker for various inflammatory, degenerative, and neoplastic diseases [56,57]. Elevated levels of CRP have been found in the blood during almost all diseases associated with active inflammation or tissue destruction, particularly in RA patients [57,58]. Sustained increase in serum CRP levels suggests a lasting production and stimulation of acute-phase proteins during disease progression. In our study, serum turbidity (showed by absorbance of serum samples) of AIA control rats was found to be significantly reduced compared with normal rats (Fig. 1). Treatment from day-12 to day-21 with TAPP but not diclofenac sodium (an NSAID) prevented AIA-induced fall in turbidity (Fig. 1). The decrease in serum turbidity in AIA control rats, is known to be caused by denatured products and was shown to be correlated with severity [59] and immune response seen in AIA [60]. Further, increased levels of serum lysozyme levels were reported to be strongly correlated with decreases in serum turbidity in AIA [59]. Therapeutically useful anti-inflammatory drugs were shown to reverse this decrease in serum turbidity [32]. Taken together, our results strongly pointed to disease-modifying properties of TAPP and its potential to slow down the RA progression.