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.
Highlights
Transient Receptor Potential Canonical 5 (TRPC5) is a cation channel that responds to a variety of activators [1], the exact nature of which remains unclear
We looked at differences in nociceptive behaviour induced by carrageenan in2je.4ct.iEonAfIonldlouwceisnTgREPACp5rIentdreepaetnmdeenntt,CboebtawlteUenptWakTe,ainndCTuRltuPrCed5 DKOorsmalicReo.oAt sGoanbgseliraved above, eNeenuarnonins jection resulted in the progressive decrease of thermal thresholds (Figure 3D, sTuoppfulertmheenr tsaurpypToarbtloeuSr4)inanvdivmo eficnhdainnigcsa,l ntherxetswhoeldstsu(dFiiegdurtehe3Ee,ffseucpt polfeEmAenotnarTyRTPaCb5lemS5e)d, itahtaetdbreecsapmonesseisginnifpicraimntalryydsiefnfesroernytnfreoumronbsasinelcinueltuatre1. oNro2n-hserleescptievceticvaetliyo,nbicucthpaenankeelds saut c3haansdT4RPhC, i5nabreotahlsWo pTearnmdeaTbRlePCto5cKobOalmt iopnrse-[t1r3e]a.tmIt ewnatsrpedreuvcieodusbloythshtohwernmianl TanRdPCm5e-tcrhaannsifceacltehdypceerllaslginesciaulitnurceartrhaagteEeAnanco-iunljdecitneddupcaewths eincablocituhmWuTpatankde,TiRnPaCd5 oKseOdmeipceen. dent manner [8]
Englerin A (EA) has been shown to activate TRPC4 channels and we have found that dorsal root ganglion (DRG) neurons express TRPC4 channels [5]; we hypothesised that the TRPC4 channel could be responsible for mediating EA effects in the carrageenan model
Summary
Transient Receptor Potential Canonical 5 (TRPC5) is a cation channel that responds to a variety of activators [1], the exact nature of which remains unclear. TRPC5 expression is reduced in human synovial samples of osteoarthritis patients, compared to health post-mortem donor [4] Together, these results suggest that TRPC5 may by associated with an endogenous antiinflammatory/analgesic pathway in inflammatory joint conditions. Pre-treatment with 4 mg/kg EA significantly lowered the paw diameter at 2 and 4 h post-carrageenan injection, when compared to vehicle pre-treated mice. We found that the MPO levels detected in the paws of mice pre-treated with EA at 4 mg/kg were significantly reduced compared to vehicle-pre-treated carrageenan treated paws (Figure 1C) These results indicate that pre-treatment with EA reduced the magnitude of the oedema and inflammation induced by carrageenan. Pre-treatment with 4 mg/kg EA significantly lowered the paw diameter at 2 and 4 h post-carrageenan injec3toiof 1n2, when compared to vehicle pre-treated mice
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