Eriodictyol: A flavonoid antagonist of the TRPV1 receptor with antioxidant activity

Rossato, Mateus; Trevisan, Gabriela; Walker, Cristiani Isabel Banderó; Klafke, Jonatas Zeni; Oliveira, Ana Paula de; Villarinho, Jardel Gomes; Zanon, Regina Basso; Royes, Luiz Fernando Freire; Athayde, Margareth Linde; Gomez, Marcus V.; Ferreira, Juliano

doi:10.1016/j.bcp.2010.11.004

Cited by 90 publications

(57 citation statements)

References 46 publications

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“…Thus, the highly potent and selective TRPM3 blockers described in this study may help disentangle the on-target and off-target effects that are related to the anti-inflammatory or antioxidant properties of flavanones. Within this context, a painalleviating effect of eriodictyol, another flavanone with antioxidant properties, has been described and attributed to TRPV1 inhibition (Rossato et al, 2011). As outlined earlier, we were unable to reproduce inhibition of TRPV1, but demonstrated that eriodictyol efficiently blocks TRPM3.…”

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confidence: 57%

Flavanones That Selectively Inhibit TRPM3 Attenuate Thermal Nociception In Vivo

et al. 2013

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Transient receptor potential melastatin 3 (TRPM3) is a calciumpermeable nonselective cation channel that is expressed in a subset of dorsal root (DRG) and trigeminal ganglia sensory neurons. TRPM3 can be activated by the neurosteroid pregnenolone sulfate (PregS) and heat. TRPM3 2/2 mice display an impaired sensation of noxious heat and thermal hyperalgesia. We have previously shown that TRPM3 is blocked by the citrus fruit flavanones hesperetin, naringenin, and eriodictyol as well as by ononetin, a deoxybenzoin from Ononis spinosa. To further improve the tolerability, potency, and selectivity of TRPM3 blockers, we conducted a hit optimization procedure by rescreening a focused library that was composed of chemically related compounds. Within newly identified TRPM3 blockers, isosakuranetin and liquiritigenin displayed favorable properties with respect to their inhibitory potency and a selective mode of action. Isosakuranetin, a flavanone whose glycoside is contained in blood oranges and grapefruits, displayed an IC 50 of 50 nM and is to our knowledge the most potent inhibitor of TRPM3 identified so far. Both compounds exhibited a marked specificity for TRPM3 compared with other sensory TRP channels, and blocked PregS-induced intracellular free Ca 21 concentration signals and ionic currents in freshly isolated DRG neurons. Furthermore, isosakuranetin and previously identified hesperetin significantly reduced the sensitivity of mice to noxious heat and PregS-induced chemical pain. Because the physiologic functions of TRPM3 channels are still poorly defined, the development and validation of potent and selective blockers is expected to contribute to clarifying the role of TRPM3 in vivo.

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confidence: 57%

Flavanones That Selectively Inhibit TRPM3 Attenuate Thermal Nociception In Vivo

et al. 2013

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“…The paw reaction test to a heat stimulus was performed as described previously (Hargreaves et al, 1988;Rossato et al, 2011). A radiant light beam from a 60-W light bulb was directed onto the right hind paw (99% of the total intensity was used).…”

Section: In Vivo Screening Of Trpv1 Antagonistsmentioning

confidence: 99%

“…The mechanical threshold was measured by using von Frey filaments in the up-anddown paradigm as described previously (Dixon, 1980;Rossato et al, 2011). First, mice were acclimated (1 h) in individual clear Plexiglas boxes (9 ϫ 7 ϫ 11 cm) on an elevated wire mesh platform to allow access to the plantar surface of the hind paws.…”

Section: In Vivo Screening Of Trpv1 Antagonistsmentioning

confidence: 99%

Identification of the Plant Steroid α-Spinasterol as a Novel Transient Receptor Potential Vanilloid 1 Antagonist with Antinociceptive Properties

Trevisan

Rossato

Walker

et al. 2012

J Pharmacol Exp Ther

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The transient receptor potential vanilloid 1 (TRPV1) receptor is relevant to the perception of noxious information and has been studied as a therapeutic target for the development of new analgesics. The goal of this study was to perform in vivo and in vitro screens to identify novel, efficacious, and safe TRPV1 antagonists isolated from leaves of the medicinal plant Vernonia tweedieana Baker. All of the fractions and the hydroalcoholic extract produced antinociception in mice during the capsaicin test, but the dichloromethane fraction also had antioedematogenic effect. Among the compounds isolated from the dichloromethane fraction, only ␣-spinasterol reduced the nociception and edema induced by capsaicin injection. Moreover, ␣-spinasterol demonstrated good oral absorption and high penetration into the brain and spinal cord of mice. ␣-Spinasterol was able to displace [ 3 H]resiniferatoxin binding and diminish calcium influx mediated by capsaicin. Oral administration of the dichloromethane fraction and ␣-spinasterol also produced antinociceptive effect in the noxious heat-induced nociception test; however, they did not change the mechanical threshold of naive mice. The treatment with ␣-spinasterol did not produce antinociceptive effect in mice systemically pretreated with resiniferatoxin. In addition, ␣-spinasterol and the dichloromethane fraction reduced the edema, mechanical, and heat hyperalgesia elicited by complete Freund's adjuvant paw injection. The dichloromethane fraction and ␣-spinasterol did not affect body temperature or locomotor activity. In conclusion, ␣-spinasterol is a novel efficacious and safe antagonist of the TRPV1 receptor with antinociceptive effect.

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“…The effects of flavonoids on humans can be attributed to antioxidant, antioncogenic, anti-inflammatory, antimicrobial, anticancer, and cardiovascular actions (1,7). For example, eriodictyol plays critical roles in the pathogenesis of diabetes mellitus, can inhibit immunoglobulin E (IgE)/antigen (Ag)-induced type I hypersensitivity, and has antinociceptive and hyperthermic effects (8)(9)(10).…”

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confidence: 99%

Efficient Synthesis of Eriodictyol from l -Tyrosine in Escherichia coli

Zhu

et al. 2014

Appl Environ Microbiol

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The health benefits of flavonoids for humans are increasingly attracting attention. Because the extraction of high-purity flavonoids from plants presents a major obstacle, interest has emerged in biosynthesizing them using microbial hosts. Eriodictyol is a flavonoid with anti-inflammatory and antioxidant activities. Its efficient synthesis has been hampered by two factors: the poor expression of cytochrome P450 and the low intracellular malonyl coenzyme A (malonyl-CoA) concentration in Escherichia coli. To address these issues, a truncated plant P450 flavonoid, flavonoid 3=-hydroxylase (tF3=H), was functionally expressed as a fusion protein with a truncated P450 reductase (tCPR) in E. coli. This allowed the engineered E. coli to produce eriodictyol from L-tyrosine by simultaneously coexpressing the fusion protein with tyrosine ammonia lyase (TAL), 4-coumarate-CoA ligase (4CL), chalcone synthase (CHS), and chalcone isomerase (CHI). In addition, metabolic engineering was employed to enhance the availability of malonyl-CoA so as to achieve a new metabolic balance and rebalance the relative expression of genes to enhance eriodictyol accumulation. This approach made the production of eriodictyol 203% higher than that in the control strain. By using these strategies, the production of eriodictyol from L-tyrosine reached 107 mg/liter. The present work offers an approach to the efficient synthesis of other hydroxylated flavonoids from L-tyrosine or even glucose in E. coli.

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Eriodictyol: A flavonoid antagonist of the TRPV1 receptor with antioxidant activity

Cited by 90 publications

References 46 publications

Flavanones That Selectively Inhibit TRPM3 Attenuate Thermal Nociception In Vivo

Flavanones That Selectively Inhibit TRPM3 Attenuate Thermal Nociception In Vivo

Identification of the Plant Steroid α-Spinasterol as a Novel Transient Receptor Potential Vanilloid 1 Antagonist with Antinociceptive Properties

Efficient Synthesis of Eriodictyol from l -Tyrosine in Escherichia coli

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