Isosakuranetin

Phytochemistry, 1997, 46(2):245-8.

The effect of isosakuranetin (5,7-dihydroxy 4′-methoxy flavanone) on potassium uptake in wheat root segments.[Reference: WebLink]

Isosakuranetin (ISK; 5,7-dihydroxy 4′-methoxy flavanone) is a plant exudate with known cytotoxic and fungicide properties.
METHODS AND RESULTS:
When tested on wheat root segments at a concentration of 70μM it inhibited K+ dependent H+ extrusion and net uptake of K+, while leaving the membrane potential (PD) unaltered. Fusicoccin (FC) + ISK treatment resulted in a slight membrane depolarization, while ISK alone did not alter O2 consumption or alternative oxidase activity. ISK did not increase the pyruvate content in incubated root tissues or inhibit Fe2+ uptake. The observed drop in K+ net uptake depended on a decrease in K+ influx into the cell, leading to the suggestion that ISK may act on wheat root segments as an inhibitor of K+ permeation.
CONCLUSIONS:
The lack of proton leakage and membrane disruption by ISK made this compound a weak candidate as a phytoalexin, and suggesting a major role as an allelopathic molecule.

Mol Pharmacol. 2013 Nov;84(5):736-50.

Flavanones that selectively inhibit TRPM3 attenuate thermal nociception in vivo.[Pubmed: 24006495]

Transient receptor potential melastatin 3 (TRPM3) is a calcium-permeable 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⁻/⁻ 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.
METHODS AND RESULTS:
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 IC₅₀ 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 Ca2⁺ 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.
CONCLUSIONS:
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.

Pharmacology . 2017;100(3-4):201-207.

Antinociceptive Effects of Isosakuranetin in a Rat Model of Peripheral Neuropathy[Pubmed: 28715803]

Abstract Chronic pain remains a challenging clinical reality, yet currently available analgesics are insufficient to meet clinical needs. Increasing attention has been paid to bioactive compounds from natural plants, which may be efficacious against pain. This study examined the antinociceptive effects of Isosakuranetin, a plant-derived transient receptor potential melastatin 3 blocker, in a rat model of peripheral neuropathy. Adult male Sprague-Dawley rats were first allowed to go through the chronic constriction injury surgery to develop neuropathic pain. They were then treated with Isosakuranetin (1.5, 3, or 6 mg/kg) intraperitoneally and the effects on mechanical, thermal, and cold hyperalgesia were assessed using the von Frey filament test, Hargreaves' plantar test, and cold plate test, respectively. Isosakuranetin dose-dependently alleviated mechanical, thermal, and cold hyperalgesia and the antinociceptive potency was similar across the assays. In the rotarod test, Isosakuranetin did not significantly affect motor performance within the doses tested, confirming the antinociceptive specificity. In summary, these findings suggest that Isosakuranetin may be useful in treating neuropathic pain and deserves further investigation. Keywords: Chronic constriction injury; Hyperalgesia; Isosakuranetin; Neuropathic pain; Rats; Rotarod test.

Life Sci. 2015 Dec 15;143:43-9.

Isosakuranetin, a 4'-O-methylated flavonoid, stimulates melanogenesis in B16BL6 murine melanoma cells.[Pubmed: 26524968 ]

The beneficial effects of 4'-O-methylated flavonoids on induction of melanogenesis are well established. Here, we report the effect of Isosakuranetin (Iso) on melanogenesis in B16BL6 melanoma cells and an analysis of the signaling pathways involved in this activity.
METHODS AND RESULTS:
B16BL6 melanoma cells were treated with several concentrations of Iso and melanin content was measured. Activation and expression of factors involved in melanogenesis were assessed via western blotting. Iso (15 and 30μmol/L) strongly stimulated melanogenesis in a dose-dependent manner. Iso increased tyrosinase activity and up-regulated tyrosinase (Tyr), tyrosinase related protein 1 (TRP1), and tyrosinase related protein 2 (TRP2) in a time-dependent manner. Iso decreased B16 cell proliferation at a concentration above 45μmol/L, and had no effect on cell viability as revealed by MTT and trypan blue assays. Iso up-regulated expression of microphthalmia transcription factor (MITF), with a maximum effect after 12h. H89, a specific inhibitor of PKA, showed that MITF up-regulation is mediated through PKA/CREB activation. Furthermore, Iso decreased phosphorylation of MITF at Ser73 after 24h and 48h of exposure, activating MITF and leading to up-regulation of Tyr, TRP1, and TRP2. Iso inhibited phosphorylation and activation of ERK1/2 after 12h, while no significant effects on p38 and JNK phosphorylation were observed. Iso inhibited AKT phosphorylation and led to activation of GSK3β.
CONCLUSIONS:
Iso stimulates melanogenesis in B16 melanoma cells via up-regulation of MITF. Furthermore, Iso-induced inhibition of ERK1/2 and PI3K/AKT signaling pathways activate MITF and subsequent expression of Tyr, TRP1, and TRP2.