Isotalatizidine, a C19-diterpenoid alkaloid, attenuates chronic neuropathic pain through stimulating ERK/CREB signaling pathway-mediated microglial dynorphin A expression

Abstract

Background: Isotalatizidine is a representative C 19-diterpenoid alkaloid extracted from the lateral roots of Aconitum carmichaelii, which has been widely used to treat various diseases on account of its analgesic, anti-inflammatory, anti-rheumatic, and immunosuppressive properties. The aim of this study was to evaluate the analgesic effect of isotalatizidine and its underlying mechanisms against neuropathic pain. Methods: A chronic constrictive injury (CCI)-induced model of neuropathic pain was established in mice, and the limb withdrawal was evaluated by the Von Frey filament test following isotalatizidine or placebo administration. The signaling pathways in primary or immortalized microglia cells treated with isotalatizidine were analyzed by Western blotting and immunofluorescence. Results: Intrathecal injection of isotalatizidine attenuated the CCI-induced mechanical allodynia in a dosedependent manner. At the molecular level, isotalatizidine selectively increased the phosphorylation of p38 and ERK1/2, in addition to activating the transcription factor CREB and increasing dynorphin A production in cultured primary microglia. However, the downstream effects of isotalatizidine were abrogated by the selective ERK1/2 inhibitor U0126-EtOH or CREB inhibitor of KG-501, but not by the p38 inhibitor SB203580. The results also were confirmed in in vivo experiments. Conclusion: Taken together, isotalatizidine specifically activates the ERK1/2 pathway and subsequently CREB, which triggers dynorphin A release in the microglia, eventually leading to its anti-nociceptive action.

Effects of alkaloids on peripheral neuropathic pain: a review

“…Being consistent with this, MAPKs and microglial inhibitors remarkably attenuated neuropathic pain [134]. Shao et al [25] found that isotalatizidine stimulated p38 and ERK1/2 in a cultured BV-2 cell line or primary microglia, which was completely inhibited by the respective inhibitors. Moreover, isotalatizidine induced phosphorylation of CREB is specifically mediated by the ERK1/2 pathway but not the p38 pathway.…”

“…The results support that the antinociceptive effects of lappaconitine are entirely blocked by intrathecal injection of the specific dynorphin A antibody and κ-opioid receptor antagonist [29]. Interestingly, it seems that the alkaloids bioactive components from the medicinal plants of Ranunculus can induce the production of dynorphin A in the spinal cord [25,135,139]. Huang et al explored the analgesic mechanism of BA by studying the release of inflammatory factors and microglia dynorphin A.…”

“…Alkaloids matrine [95] reduced among mechanical allodynia, cold allodynia, and thermal hyperalgesia, whereas guanfu base A [96] reduced mechanical and thermal hyperalgesia. Sinomenine [97], levo-tetrahydropalmatine [98], berberine [99], brucine [100], dehydrocrenatidine [101], koumine [102] and isotalatizidine [25] reduced mechanical allodynia. Besides, brucine, koumine, gelsenicine [26], and isorhynchophylline [103] inhibited CCI-induced thermal hyperalgesia.…”

“…The alkaloids derived from Chinese herbal medicines, as valuable sources of pharmaceutical products and leading compounds, have been of great significance in the research and development of antineuropathic pain drugs. More and more studies have demonstrated that low-dose alkaloids possess potential analgesic effects in various neuropathic pains models [24][25][26][27][28][29][30]. The present review focuses on the alkaloids, mainly quinolizidine alkaloids, isoquinoline alkaloids, indole alkaloids, diterpenoid alkaloids, and their analgesic effects on peripheral neuropathic pain.…”

Radiation-induced abscopal reproductive effect is driven by TNF-α/p38 MAPK/Rac1 axis in Sertoli cells

“…p38 MAPK, Rho GTPase and Rap1 were obtained. To demonstrate whether p38 MAPK activation played central roles in RIARE, SB202190 32 and SB203580 33 , two highly specific inhibitors of p38 MAPK were administrated to male mice (12 mice per group) before HF-IR, respectively. The administration of either SB202190 or SB203580 to irradiated male mice both notably ameliorated the conception rate of mated virgin female mice from approximately 50% to nearly 80% (Figure 1 E).…”