Visnagin

Khellin and visnagin differentially modulate AHR signaling and downstream CYP1A activity in human liver cells.[Pubmed: 24069365]

PLoS One. 2013 Sep 19;8(9):e74917.

Khellin and Visnagin are two furanochromones that can be frequently found in ethnomedical formulations in Asia and the Middle East. Both compounds possess anti-inflammatory and analgesic properties, therefore modern medicine uses these compounds or structurally related derivatives for treatment of vitiligo, bronchial asthma and renal colics. Despite their frequent usage, the potential toxic properties of Visnagin and khellin are not well characterized up-to-now.
METHODS AND RESULTS:
The observed induction of several other members of the AHR gene battery, whose gene products are involved in regulation of cell growth, differentiation and migration, indicates that a further toxicological characterization of Visnagin and khelllin is urgently required in order to minimize potential drug-drug interactions and other toxic side-effects that may occur during therapeutic usage of these furanochromones.

Neuroprotective Effect of Visnagin on Kainic Acid-induced Neuronal Cell Death in the Mice Hippocampus.[Pubmed: 21165322 ]

Korean J Physiol Pharmacol. 2010 Oct;14(5):257-63.

Visnagin (4-methoxy-7-methyl-5H-furo[3,2-g][1]-benzopyran-5-one), which is an active principle extracted from the fruits of Ammi visnaga, has been used as a treatment for low blood-pressure and blocked blood vessel contraction by inhibition of calcium influx into blood cells. However, the neuroprotective effect of Visnagin was not clearly known until now.
METHODS AND RESULTS:
Thus, we investigated whether Visnagin has a neuroprotective effect against kainic acid (KA)-induced neuronal cell death. In the cresyl violet staining, pre-treatment or post-treatment Visnagin (100 mg/kg, p.o. or i.p.) showed a neuroprotective effect on KA (0.1 μg) toxicity. KA-induced gliosis and proinflammatory marker (IL-1β, TNF-α, IL-6, and COX-2) inductions were also suppressed by Visnagin administration.
CONCLUSIONS:
These results suggest that Visnagin has a neuroprotective effect in terms of suppressing KA-induced pathogenesis in the brain, and that these neuroprotective effects are associated with its anti-inflammatory effects.

Cardiovascular effects of visnagin on rats.[Pubmed: 10705731]

Planta Med. 2000 Feb;66(1):35-9.

The present article describes the effects of Visnagin on systolic blood pressure and heart rate in the anaesthetized rat.
METHODS AND RESULTS:
Intravenous administration of Visnagin (0.3-5 mg kg-1) produced dose-related decreases in blood pressure with no significative changes in heart rate. Under nitric oxide synthase inhibition (L-NAME, 50 mg kg-1) the hypotensive effects of Visnagin (5 mg kg-1) were not affected. Visnagin (5 x 10(-6) M-10(-4) M) produced a weak decrease in the rate and amplitude of spontaneous contractions in right atria. Visnagin also caused a weak decrease in peak contractile force and the df/dtmax with no significant changes in the time to peak tension or the time for total contraction in left atria driven at a basal rate of 1 Hz. Visnagin (10(-5) M, 5 x 10(-5) M and 10(-4) M) concentration-dependently decreased pressor response to KCl (IC50 = 5.1 +/- 2.5 x 10(-5) M) and noradrenaline (IC50 = 2.6 +/- 0.9 x 10(-5) M) in rat isolated mesenteric beds. Visnagin (3 x 10(-7) M-10(-4) M) induced a concentration-dependent relaxation of isolated mesenteric arteries contracted by noradrenaline (IC50 = 1.7 +/- 0.8 x 10(-5) M). The relaxant effects in the absence of functional endothelium were not significantly different (IC50 = 1.5 +/- 0.3 x 10(-5) M, P > 0.05) from those observed in segments with intact endothelium.
CONCLUSIONS:
In conclusion, the main mechanism responsible for the acute hypotensive effect of Visnagin is the vasorelaxant response induced by this drug in resistance arteries.

Effects of visnagin on cyclic nucleotide phosphodiesterases and their role in its inhibitory effects on vascular smooth muscle contraction.[Pubmed: 9888257]

Anti-inflammatory effect of visnagin in lipopolysaccharide-stimulated BV-2 microglial cells.[Pubmed: 21116788]

Arch Pharm Res. 2010 Nov;33(11):1843-50.

Visnagin, which is found in Ammi visnaga, has biological activity as a vasodilator and reduces blood pressure by inhibiting calcium influx into the cell.
METHODS AND RESULTS:
The present study demonstrates the anti-inflammatory effect of Visnagin on lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. When cells were treated with Visnagin prior to LPS stimulation, production of nitric oxide and expression of iNOS were attenuated in a dose-dependent manner. Visnagin also caused a significant decrease of mRNA expression and release of TNF-α, IL-1β and IFNγ. In addition, Visnagin reduced LPS-induced IL-6 and MCP-1 mRNA level. We further found that Visnagin dose-dependently inhibited LPS-induced AP-1 and NF-κB luciferase activities.
CONCLUSIONS:
Taken together, our results for the first time suggest that the anti-inflammatory effect of Visnagin might result from the inhibition of transcription factors, such as AP-1 and NF-κB.

Gen Pharmacol. 1999 Jan;32(1):71-4.

METHODS AND RESULTS:
1. Visnagin relaxed aortae previously contracted by noradrenaline. This effect was unalterated by endothelium removal and potentiated, at high concentrations, by the previous incubation with sodium nitroprusside. 2. Visnagin weakly inhibited the hydrolytic activity of the cyclic nucleotide phosphodiesterase (PDE) isozymes (PDE5, PDE4, PDE3, cyclic GMP activated PDE2 and PDE1).
CONCLUSIONS:
3. The present results indicate an involvement of PDE inhibition in the relaxant effect of Visnagin at high concentration (>5x10(-5) M).

An aqueous extract of Ammi visnaga fruits and its constituents khellin and visnagin prevent cell damage caused by oxalate in renal epithelial cells。[Reference: WebLink]

Phytomedicine. 2010 Jul; 17(0): 653–658.

Teas prepared from the fruits of Ammi visnaga L. (syn. “Khella”) have been traditionally used in Egypt as a remedy to treat kidney stones. It was the aim of our study to evaluate the effect of a Khella extract (KE) as well as the two major constituents khellin and Visnagin on renal epithelial injury using LLC-PK1 and Madin-Darby-canine kidney (MDCK) cells.
METHODS AND RESULTS:
Both cell lines provide suitable model systems to study cellular processes that are possibly involved in the development of a renal stone. LLC-PK1 and MDCK cell lines were exposed to 300 μM oxalate (Ox) or 133 μg/cm2 calcium oxalate monohydrate (COM) in presence or absence of 10, 50, 100 or 200 μg/mL KE. To evaluate cell damage, cell viability was assessed by determining the release of lactate dehydrogenase (LDH). KE (e.g. 100 μg/ml) significantly decreased LDH release from LLC-PK1 (Ox: 8.46± 0.76%; Ox + 100 μg/ml KE: 5.41± 0.94%, p<0.001) as well as MDCK cells (Ox: 30.9± 6.58%; Ox + 100 μg/ml KE: 17.5± 2.50%, p<0.001), which indicated a prevention of cell damage. Similar effects for KE were observed in both cell lines when COM crystals were added. In LLC-PK1 cells khellin and Visnagin both decreased the % LDH release significantly in cells that were pretreated with Ox or COM crystals. However, khellin and Visnagin exhibited different responses in MDCK cells. Whereas khellin slightly reduced the % LDH release after exposure of the cells to Ox and COM crystals, Visnagin significantly decreased % LDH release only after COM crystal exposure. Overall both compounds were more active in LLC-PK1 than in MDCK cells.
CONCLUSIONS:
In summary, exposure of renal epithelial cells to Ox or COM crystals was associated with a significant release of LDH indicating cell injury. Our data demonstrate that KE as well as khellin and Visnagin could prevent renal epithelial cell damage caused by Ox and COM and could therefore play a potential role in the prevention of stone formation associated with hyperoxaluria.

Visnagin protects against doxorubicin-induced cardiomyopathy through modulation of mitochondrial malate dehydrogenase.[Pubmed: 25504881]

Sci Transl Med. 2014 Dec 10;6(266):266ra170.

Doxorubicin is a highly effective anticancer chemotherapy agent, but its use is limited by its cardiotoxicity.
METHODS AND RESULTS:
To develop a drug that prevents this toxicity, we established a doxorubicin-induced cardiomyopathy model in zebrafish that recapitulates the cardiomyocyte apoptosis and contractility decline observed in patients. Using this model, we screened 3000 compounds and found that Visnagin (VIS) and diphenylurea (DPU) rescue the cardiac performance and circulatory defects caused by doxorubicin in zebrafish. VIS and DPU reduced doxorubicin-induced apoptosis in cultured cardiomyocytes and in vivo in zebrafish and mouse hearts. VIS treatment improved cardiac contractility in doxorubicin-treated mice. Further, VIS and DPU did not reduce the chemotherapeutic efficacy of doxorubicin in several cultured tumor lines or in zebrafish and mouse xenograft models. Using affinity chromatography, we found that VIS binds to mitochondrial malate dehydrogenase (MDH2), a key enzyme in the tricarboxylic acid cycle. As with VIS, treatment with the MDH2 inhibitors mebendazole, thyroxine, and iodine prevented doxorubicin cardiotoxicity, as did treatment with malate itself, suggesting that modulation of MDH2 activity is responsible for VIS' cardioprotective effects.
CONCLUSIONS:
Thus, VIS and DPU are potent cardioprotective compounds, and MDH2 is a previously undescribed, druggable target for doxorubicin-induced cardiomyopathy.