3. Drugs of Other Groups
3.1. Suppressive Cytokine Anti-Inflammatory Agents
In the late 1980s, a new class of anti-inflammatory drugs was developed, called cytokine suppressive anti-inflammatory drugs (CSAIDTM). The prototype of this class of compounds is SB203580, a drug with a new mechanism of action
[389][13]. These pyridine imidazole compounds have a potent inhibitory effect on the production of pro-inflammatory cytokines in vitro, and in vivo they can attenuate the inflammatory component of diseases in the absence of generalized immunosuppression. The molecular targets of CSAIDTM have been identified as a pair of closely related MAPK homologues, alternatively referred to as cytokine-suppressive binding protein (CSBP)
[390][14], p38
[391][15], or RK
[392][16]. p38 MAPK inhibitors have been shown to affect cytokine imbalance in a non-selective manner
[393][17], in contrast to ERK1/2 inhibitors that block TNF-α and IL-1β, but not IL-10
[394][18].
3.2. Renin Inhibitors
Aliskiren ((2S,4S,5S,7S)-5-amino-N-(2-carbamoyl-2-methylpropyl)-4-hydroxy-7-{[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl }-8-methyl-2-propan-2-ylnonanamide) is a renin inhibitor that reduces the level of angiotensin II with a subsequent decrease in the inflammatory response caused by the stimulation of the renin-angiotensin system
[395][19]. Its effectiveness has been proven previously in an experimental model of osteoarthritis due to its inhibitory effect on the renin-angiotensin system present in cartilage, with a subsequent reduction in erosion
[396][20]. Data have been accumulated on the local involvement of the renin-angiotensin system (RAS) in joint diseases
[397,398][21][22]. Aliskiren has been reported to facilitate bone cell turnover in experimental rats
[399][23]. In addition, the ability of aliskiren to reduce articular cartilage erosion was demonstrated in an experimental rat model of osteoarthritis
[396][20]. Additionally, aliskiren is involved in the regulation of cytokine balance. Thus, the reduction of pro-inflammatory cytokines (TNF-α and IL-6) and biomarkers of oxidative stress with aliskiren was confirmed in an experiment on an animal model
[400][24].
The relationship between the local renin-angiotensin system and the effect of RANKL on bone metabolism was revealed, which was confirmed, for example, by the study by Araújo et al.
[401][25]. Shuai et al.
[402][26] suggested that the local renin-angiotensin system in trabecular bone may contribute to corticoid-induced osteoporosis due to the enhanced effect of RANKL. The above effects of aliskiren may be related to the suppression of intracellular JAK-2/STAT-3 signaling, where an increase in prorenin and its receptor for STAT3 activation has been documented
[403][27]. In addition, various studies have shown that angiotensin II stimulates the JAK-2/STAT-3 pathway
[404][28]. Aliskiren has been shown to have a modulating effect on NOSs, including a decrease in iNOS expression and an increase in eNOS expression, which is consistent with the results of previous studies
[405][29]. The results of these studies provide further clarification of the therapeutic effects of aliskiren against collagen-induced arthritis
[316][30] and explain its potential role in slowing down the development of IDD. However, the efficacy and safety of using aliskiren to correct cytokine imbalance in patients with IDD needs to be clarified in the future.
3.3. Acetylcholinesterase Inhibitors
Physostigmine ((3aS-cis)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-ol methylcarbamate) is an inhibitor of acetylcholinesterase, an enzyme responsible for the breakdown of used acetylcholine. By influencing acetylcholine metabolism, physostigmine indirectly stimulates both nicotinic and muscarinic receptors due to a subsequent increase in available acetylcholine at synapses
[14][31]. Acetylcholine appears to play a role in inflammation control as it stimulates the vagus nerve, resulting in reduced cytokine synthesis through the activation of the α7 nicotinic acetylcholine receptors. Conversely, serum acetylcholinesterase activity can have detrimental effects on bone and cartilage erosion. Cholinesterase activity has been demonstrated to increase with age, contributing to the risk and severity of arthritis in the elderly
[406][32].
For example, the use of acetylcholinesterase inhibitors has shown a positive effect in the treatment of rheumatoid arthritis, which is associated with the control of the release of pro-inflammatory cytokines (e.g., TNF-α) and the mitigation of inflammation
[407][33]. Ahsan et al.
[408][34] showed that physostigmine significantly prevented the denaturation of albumin protein from hen egg and bovine serum sources in a dose-dependent manner and it also had a significant stabilizing effect on the erythrocyte membrane at higher concentrations, which may be due to the effect of removing free radicals or with the inhibition of the release of intracellular components and inflammatory mediators. In addition, physostigmine caused a significant decrease in serum levels of prostaglandin E2 and pro-inflammatory cytokine TNF-α.
3.4. Xanthines
Theophylline (1,3-dimethylxanthine) is a smooth muscle relaxant, cardiac and central nervous system stimulant. Theophylline acts as a phosphodiesterase inhibitor, adenosine receptor blocker, and histone deacetylase activator
[14][31].
Theophylline may be a promising agent for the treatment of immunological inflammatory conditions, including the correction of cytokine imbalance in IDD. Liang et al.
[409][35] reported an immunomodulatory effect of theophylline in an animal model. Theophylline modulates cytokine status and NO synthesis
[410][36]. Ghasemi-Pirbaluti et al.
[411][37] demonstrated that this drug can modulate myeloperoxidase and the production of pro-inflammatory cytokines. It has been demonstrated that theophylline has a good anti-inflammatory effect due to the activation of histone deacetylases, as well as the modulation of MMPs and other inflammatory mediators
[412][38]. Additionally, it can modulate JAK/STAT/RANKL cytokine signaling in animals treated with complete Freund’s adjuvant, growth hormone, or a combination of the two. Thus, physostigmine plays an important role in the activation and differentiation of osteoclasts
[413][39].
3.11.5. Nitrates
3.5. Nitrates
Nicorandil (2-(pyridine-3-carbonylamino)ethyl nitrate) is an effective oral vasodilator and antianginal agent that causes the vasodilation of arterioles and large coronary arteries by activating potassium channels
[14][31].
It has been reported that nicorandil promotes the opening of potassium channels and has anti-inflammatory and immunomodulatory potential against inflammation in the experiment
[414][40]. Nicorandil was found to prevent ulcerogen-induced TNF-α production
[415][41]. The results of Gaafar et al.
[413][39] demonstrated that this drug significantly inhibited JAK/STAT/RANKL/cytokine pathway signaling. It has immunomodulatory and anti-inflammatory effects mediated by the modulation of this signaling pathway
[416][42]. According to Zhao et al.
[417][43], substances that open potassium channels can protect in vitro against neuroinflammation caused by oxygen/glucose deficiency by inhibiting the activation of pro-inflammatory cytokines and the signal transduction of the Toll-like receptor 4.
3.11.6. Direct Oral Anticoagulants
3.6. Direct Oral Anticoagulants
Apixaban (1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)phenyl]-4,5-dihydropyrazolo[5,4-c]pyridine-3-carboxamide) is a potent, selective, reversible direct inhibitor of Hageman factor (FXa); it is used to prevent venous thromboembolism
[418][44]. In addition, apixaban has powerful anti-inflammatory and remodeling effects on many diseases. These effects can be explained by the inhibition of the poly-ADP ribose polymerase (PARP) enzyme on extravascular cells
[419][45].
Previously, a significant correlation has been established between the activation of blood coagulation factors and the stimulation of various inflammatory pathways
[420][46]. Anticoagulant therapy not only affects the coagulation cascade but can also inhibit inflammatory mediators (including pro-inflammatory cytokines), indicating a wide interaction between these processes
[421][47]. It has been shown that FXa is an effective inducer of kinase phosphorylation, which is associated with a significant increase in the level of P-JAK2, P-STAT3, and P-MAPK in synovial tissue. Additionally, an increase in P-JAK2, P-STAT3, and P-MAPK levels was observed when Freud’s complete adjuvant group of experimental animals were stimulated with FXa. Apixaban significantly interfered with the expression of P-JAK2, P-STAT3, and P-MAPK in the synovium. The inhibition of FXa by apix-aban promoted the potent inhibition of JAK2/STAT3 and MAPK-activated pathways. It has been shown that the activation of FXa coagulation induces mRNA expression of the PAR-2 gene
[422][48]. Bae et al.
[423][49] reported that FXa exerts its action through the PAR-2 receptor. Consistent with the findings of Hollborn et al.
[424][50] and Senden et al.
[425][51], the results of El-Ghafar et al.
[422][48] showed a significant increase in the levels of platelet growth factor and the pro-inflammatory cytokine IL-6 after FXa activation. Tissue PAR-2 levels, serum levels of platelet growth factor, and IL-6 levels were significantly reduced in all apixaban-treated rats compared to normal controls. Apixaban had a lower inhibitory effect on IL-6 compared to the other parameters listed above. This can be explained by its main action as a selective inhibitor of FXa, which subsequently leads to a significant inhibition of FXa-activated parameters such as PAR-2, platelet growth factor, and (to a lesser extent) IL-6, since the increase in the level of IL-6 expression is dependent on various signals and does not depend solely on FXa activation
[426][52]. However, FXa-induced JAK2/STAT3 and MAPK phosphorylation may be directly related to platelet growth factor and IL-6 activation
[427][53]. This effect may be indirectly related to PAR-2 activation, which mediates kinase and tyrosine phosphorylation, including the JAK, STAT, and MAPK pathways
[428,429][54][55].