Xanthine Derivative KMUP-1 Reduces Inflammation and Hyperalgesia in a Bilateral Chronic Constriction Injury Model by Suppressing MAPK and NFκB Activation

Abstract

Neuropathic pain is characterized by spontaneous pain, hyperalgesia, and allodynia. The aim of this study was to investigate whether KMUP-1 (7-[2-[4-(2-chlorobenzene)piperazinyl]ethyl]-1,3-dimethylxanthine) could improve pain hypersensitivity and reduce inflammatory mediators, and also explore possible mechanisms in the rat sciatic nerve using bilateral chronic constriction injury (CCI) to induce neuropathic pain. Sprague-Dawley rats were randomly divided into four groups: Sham, Sham+KMUP-1, CCI, and CCI+KMUP-1. KMUP-1 (5 mg/kg/day) was injected intraperitoneally starting at day 1 after surgery. Mechanical and thermal responses were assessed before surgery and at days 3, 7, and 14 after CCI. Sciatic nerves around the injury site were isolated for Western blots and enzyme-linked immunosorbent assay to analyze protein and cytokine levels. The results show that thermal hyperalgesia and mechanical allodynia were reduced in the KMUP-1 treated group as compared to that in the CCI group. Inflammatory proteins (COX2, iNOS, and nNOS) and proinflammatory cytokines (TNF-α and IL-1β) induced by CCI were decreased in the KMUP-1 treated group at day 7 after surgery. KMUP-1 also inhibited neuropathic pain-related mechanisms, including p38 and ERK activation, but not JNK. Furthermore, KMUP-1 blocked IκB phosphorylation (p-IκB) and phospho-nuclear factor κB (p-NF-κB) translocation to nuclei. Double immunofluorescent staining further demonstrated that p-IκB (an indicator of activated NFκB) and p-NFκB proteins were almost abolished by KMUP-1 in peripheral macrophages and spinal microglia cells at day 7 after surgery. On the basis of these findings, we concluded that KMUP-1 has antiinflammatory and antihyperalgesia properties in CCI-induced neuropathic pain via decreases in MAPKs and NF-κB activation.

Age‐dependent alterations to paraventricular nucleus insulin‐like growth factor 1 receptor as a possible link between sympathoexcitation and inflammation

“…In addition, previous studies have shown that an increase in MAPK/ErK is associated with up-regulated NADPH oxidase and oxidative stress (Morales et al 2014;Simões et al 2015). As a result, nNOS and other antioxidant (induced nitric oxide synthase and Cyclooxygenase) systems are depleted leading to an increase in inflammation through oxidative stress (Zhang et al 1998;DiCarlo et al 2002;Dai et al 2014).…”

Targeting the Microglial Signaling Pathways: New Insights in the Modulation of Neuropathic Pain

“…In our experiments, we have shown that the ERK1/2 phosphorylation is increased on day 7 after CCI [24,129], and this is correlated with enhanced glial cell activation [24]. These results suggest that ERK is essential for the intracellular signaling that leads to the production of various nociceptive factors, including cytokines such as TNFα and IL-1β and the enzymes COX-2, iNOS, and nNOS, that participate in the intensification of the neuropathic pain sensations [24,127, 129,156]. Previous studies have demonstrated that the administration of MEK-ERK pathway inhibitors such as PD198306 [157], U0126 [23,155], and PD98059 [123,127,129] reduce the nociceptive behavior in animal models of neuropathic pain, such as CCI, SNL and SCI.…”

Minocycline attenuates bone cancer pain in rats by inhibiting NF-κB in spinal astrocytes

“…When stimulated by appropriate signals, trimeric IKK is activated and phosphorylates IκB, which leads to its ubiquitination and degradation [51] . The liberated reactive NF-κB translocates to the nucleus and targets specific genes that are involved in chronic pain [10,14,52,53] . The algogenic effect of NF-κB has also been identified in BCP animals.…”

“…Moreover, nuclear factor kappa B (NF-κB), an important transcriptional factor mediating cytokine production [8,10,11] , is activated in spinal astrocytes during a chronic pain state [8,12] .…”