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(-)-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.

SUBMITTER: de Sousa Valente J

PROVIDER: S-EPMC8232259 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Inflammatory pain is caused by peripheral tissue injury and inflammation. Inflammation leads to peripheral sensitization, which may further cause central sensitization, resulting in chronic pain and progressive functional disability. Neuroimmune crosstalk plays an essential role in the development and maintenance of inflammatory pain. Studies in recent years have shown that acupuncture can exert anti-inflammatory and analgesic effects by regulating peripheral (i.e., involving local acupoints and inflamed regions) and central neuroimmune interactions. At the local acupoints, acupuncture can activate the TRPV1 and TRPV2 channels of mast cells, thereby promoting degranulation and the release of histamine, adenosine, and other immune mediators, which interact with receptors on nerve endings and initiate neuroimmune regulation. At sites of inflammation, acupuncture enables the recruitment of immune cells, causing the release of opioid peptides, while also exerting direct analgesic effects via nerve endings. Furthermore, acupuncture promotes the balance of immune cells and regulates the release of inflammatory factors, thereby reducing the stimulation of nociceptive receptors in peripheral organs. Acupuncture also alleviates peripheral neurogenic inflammation by inhibiting the release of substance P (SP) and calcitonin gene-related peptide from the dorsal root ganglia. At the central nervous system level, acupuncture inhibits the crosstalk between glial cells and neurons by inhibiting the p38 MAPK, ERK, and JNK signaling pathways and regulating the release of inflammatory mediators. It also reduces the excitability of the pain pathway by reducing the release of excitatory neurotransmitters and promoting the release of inhibitory neurotransmitters from neurons and glial cells. In conclusion, the regulation of neuroimmune crosstalk at the peripheral and central levels mediates the anti-inflammatory and analgesic effects of acupuncture on inflammatory pain in an integrated manner. These findings provide novel insights enabling the clinical application of acupuncture in the treatment of inflammatory diseases.

Project description:BackgroundThe medicinal plant Siegesbeckia orientalis L. has been commonly used for the treatment of acute arthritis, rheumatism, and gout in Vietnam. However, pharmacological research of this plant associated with gout has not been reported. Anti-hyperuricemic and anti-inflammatory effects were evaluated and observed for the crude ethanol extract (CEE) of S. orientalis. Retention of these biological properties was found in a n-butanol-soluble fraction (BuOH fr.) of the extract, and therefore further biological and chemical investigations were undertaken on the BuOH fr. to support the medical relevance of this plant.MethodsThe aerial part of S. orientalis was obtained in the mountainous region of Vietnam. The crude ethanol extract (CEE) and its BuOH fr. were prepared from the plant materials. Anti-hyperuricemic activities of the CEE and BuOH fr. were tested in vivo using the model oxonate-induced hyperuricemia rats through determination of serum uric acid levels and inhibitory effects on xanthine oxidase (XO) in the rat liver. Anti-inflammatory activities of the BuOH fr. were also evaluated in vivo using carrageenan-induced paw edema and urate-induced synovitis in rats. Active components of the BuOH fr. were characterized by comparison of HPLC retention time (t R) and spectroscopic data (UV, 1H-NMR) with those of reference compounds.ResultsThe CEE of S. orientalis displayed anti-hyperuricemic activity, and the BuOH fr. was found to be the most active portion of the extract. Further in vivo studies on this fraction showed 31.4% decrease of serum uric acid levels, 32.7% inhibition of xanthine oxidase (XO), 30.4% reduction of paw edema volume, symptomatic relief in urate-induced synovitis and significant analgesic effect at the dose of 120 mg/kg, as compared to the corresponding values of the control groups. Chemical analysis of the BuOH fr. revealed high phenolic content, identified as caffeic acid analogues and flavonones.ConclusionsThis study suggested that anti-hyperuricemic and anti-inflammatory mechanism of S. orientalis is related to XO inhibitory effect of the phenolic components. Our findings support the use of this plant as the treatment of gout and other inflammatory diseases.

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

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