Parthenolide Relieves Pain and Promotes M2 Microglia/Macrophage Polarization in Rat Model of Neuropathy

Figure 6

The possible influence of PTL on microglial/macrophage cell polarization. The extent of neuroinflammation observed under neuropathic pain depends on the bidirectional interactions between neurons and immune cells. As was suggested by many authors microglia/macrophages are among the main effector cells of the inflammatory response that takes place on the spinal cord level after injury [9, 42]. Therefore, it seems that targeting microglial signaling might lead to more effective treatment of neuropathic pain. In vitro evidence indicates that M1 microglia/macrophages can directly induce neuronal death [95, 96]. The activation of spinal microglia and infiltration of peripheral macrophages in the spinal cord can result in the release of both algesic (IL-1β, IL-18, IL-6, and iNOS) and analgesic (IL-10 and TIMP1) mediators during neuropathic pain [42]. Polarization of microglia/macrophage can strongly influence nociceptive transmission in neurons [7, 97]. It is known that polarization of microglia/macrophage is divided into two phases: potentially neurotoxic M1, which is characterized by pronociceptive factors, for example, IL-1β, IL-18, IL-6, iNOS, and neuroprotective M2 state, which is associated with release of antinociceptive markers, such as IL-10 and TIMP1 [12–15]. The results of our studies suggest that by direct or indirect mechanisms parthenolide promotes the M2 polarization of microglia/macrophage. In the present study, we have shown for the first time that chronic PTL treatment prevented the upregulated protein levels of pronociceptive IL-1β, IL-18, iNOS, and also potentiated antinociceptive IL-10 and TIMP1 in CCI-exposed rats. Simultaneously, PTL affects directly and/or indirectly intracellular pathways, which play a key role in regulating the immune response: NF-κB, p38, ERK1/2, and STAT3. PTL induced reduction of NF-κB, p38, ERK1/2, and potentiated STAT3 activation. These molecular actions of PTL might be responsible for its analgesic effects during neuropathy and need future investigation. (PTL: parthenolide, IL: interleukin, iNOS: inducible nitric oxide synthase, TIMP: tissue inhibitor of metalloproteinases, NF-κB: nuclear factor-kappa B, ERK1/2: extracellular signal-regulated kinase 1/2, STAT: signal transducers and activators of transcription, GFRs: growth factor receptors, GPCRs: G protein–coupled receptors, TLRs: Toll-like receptors).