(-)-Englerin-A Has Analgesic and Anti-Inflammatory Effects Independent of TRPC4 and 5

Abstract

Recently, we found that the deletion of TRPC5 leads to increased inflammation and pain-related behaviour in two animal models of arthritis. (-)-Englerin A (EA), an extract from the East African plant Phyllanthus engleri has been identified as a TRPC4/5 agonist. Here, we studied whether or not EA has any anti-inflammatory and analgesic properties via TRPC4/5 in the carrageenan model of inflammation. We found that EA treatment in CD1 mice inhibited thermal hyperalgesia and mechanical allodynia in a dose-dependent manner. Furthermore, EA significantly reduced the volume of carrageenan-induced paw oedema and the mass of the treated paws. Additionally, in dorsal root ganglion (DRG) neurons cultured from WT 129S1/SvIm mice, EA induced a dose-dependent cobalt uptake that was surprisingly preserved in cultured DRG neurons from 129S1/SvIm TRPC5 KO mice. Likewise, EA-induced anti-inflammatory and analgesic effects were preserved in the carrageenan model in animals lacking TRPC5 expression or in mice treated with TRPC4/5 antagonist ML204.This study demonstrates that while EA activates a sub-population of DRG neurons, it induces a novel TRPC4/5-independent analgesic and anti-inflammatory effect in vivo. Future studies are needed to elucidate the molecular and cellular mechanisms underlying EA’s anti-inflammatory and analgesic effects.

Biological Effects of Modifications of the Englerin A Glycolate

“…Englerin A, 1a , was discovered in extracts of the root and stem bark of the Tanzanian tree Phyllanthus engleri on the basis of its potent activity in the NCI 60 cell screen against most renal cancer cell lines and concomitant inactivity against most other cell types . Subsequent total syntheses of the molecule established its absolute configuration and have provided multiple synthetic pathways to the natural product. − Further work in several groups including our own has explored structure–activity relationships. − Plausible molecular mechanisms of action for englerin A in renal cancer cells have been proposed, including agonism of protein kinase C θ, as well as the ion channels transient receptor potential canonical (TRPC) 4 and 5. , While TRPC channels have been viewed as primarily gating the calcium ion, recent work has linked the cytotoxicity of englerins to entry of sodium ions in TRPC4 channels. , Other work has investigated englerin A activity in triple negative breast cancer cells, also implicating TRPC channels, while englerin A has also been found to be active in analgesic and anti-inflammatory models independent of TRPC 4 and 5 . Two recent reviews have summarized the progress. , …”

“…26,27 Other work has investigated englerin A activity in triple negative breast cancer cells, also implicating TRPC channels, 28 while englerin A has also been found to be active in analgesic and anti-inflammatory models independent of TRPC 4 and 5. 29 Two recent reviews have summarized the progress. 30,31 The most sensitive site for modification of englerin A is the glycolate ester C-9.…”