Natural product; delta 5 desaturase

Sesamin pretreatment effectively reduced the excess nitric oxide production in rat primary microglia cells activated with lipopolysaccharide[1].

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Attenuation of NO production by Sesamin and sesamolin in LPS-stimulated microglia cells [1]
Microglia cells have been demonstrated to be the major source of inflammatory factors that mediated LPS-induced neurotoxicity in neuron-glia cultures. Therefore, rat primary microglia cells pretreated with Sesamin or sesamolin were subjected to LPS treatment, and the induced NO release was detected to evaluate whether sesamin and sesamolin could confer neuroprotective effects. The results show that excess generation of NO in the LPS-stimulated microglia cells was inhibited by pretreatment of sesamin or sesamolin in a dose-dependent manner (Fig. 1). For a significant attenuation of NO production in LPS-stimulated microglia cells, sesamolin seemed to be more potent than sesamin.

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Incubation with sesame oil increases the mycelial dihomo-gamma-linolenic acid content of an arachidonic acid-producing fungus, Mortierella alpina, but decreases its arachidonic acid content [Shimizu, S., K. Akimoto, H. Kawashima, Y. Shinmen and H. Yamada (1989) J. Am. Oil Chem. Soc. 66, 237-241]. The factor causing these effects was isolated and identified to be (+)-Sesamin. The results obtained in experiments with both a cell-free extract of the fungus and with rat liver microsomes demonstrated that (+)-Sesamin specifically inhibits delta 5 desaturase at low concentrations, but does not inhibit delta 6, delta 9 and delta 12 desaturases. Kinetic analysis showed that (+)-sesamin is a noncompetitive inhibitor (Ki for rat liver delta 5 desaturase, 155 microM). (+)-Sesamin, (+)-sesaminol and (+)-episesamin also inhibited only delta 5 desaturases of the fungus and liver. These results demonstrate that (+)-sesamin and related lignan compounds present in sesame seeds or its oil are specific inhibitors of delta 5 desaturase in polyunsaturated fatty acid biosynthesis in both microorganisms and animals [Lipids. 1991 Jul;26(7):512-6.].

Sesamin (op; 20 mg/kg/day) considerably lowers the infarct size by roughly 50% in male gerbils (60-85 g)[1]. The neuroprotective effect of Sesamin and sesamolin was also observed in vivo using gerbils subjected to a focal cerebral ischemia induced by occlusion of the right common carotid artery and the right middle cerebral artery. Repeated treatment of sesamin or a crude sesame oil extract containing both sesamin and sesamolin significantly reduced the infarct size, visualized via 2,3,5-triphenyltetrazolium chloride staining, by approximately 50% when compared with the control group. These results suggest that sesamin and sesamolin exert effective neuroprotection against cerbral ischemia.

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Neuroprotective effects of Sesamin and sesamolin on gerbils in cerebral ischemia The observation of the neuroprotective effect of Sesamin and sesamolin in the LPS-stimulated microglia cells provoked an inquiry if these sesame lignans could act as anti-ischemic agents in vivo. To examine this possibility, gerbils were repeatedly administered with sesamin or a crude sesame oil extract containing both sesamin and sesamolin prior to a focal cerebral ischemia. All the treated animals were found to have infarction in the cortex and caudate-putamen. Mean total infarct sizes, visualized by TTC staining (Fig. 2), in the three groups (control, purified sesamin, and crude sesame oil extract) were 91.9 mm3 (19.4 ± 2.0%), 46.5 mm3 (9.8 ± 3.1%), and 40.2 mm3 (8.5 ± 3.9%), respectively (Fig. 3). These results indicate that pretreatment with sesamin or the crude sesame oil extract for four days significantly reduced infarct sizes of gerbil brains in cerebral ischemia by 56% and 49%, respectively (p<0.05).

Detection of NO production [1]
NO production was assayed by measuring the level of nitrite, the stable NO metabolite, in the conditioned medium. Briefly, 100 L of culture supernatant was reacted with an equal volume of Griess reagent (1 part of 0.1% naphthylethylenediamine and 1 part of 1% sulfanilamide in 5% H3PO4) in 96-well tissue culture plates for 10 min at room temperature in the dark. The absorbance at 540 nm was recorded by a microplate reader.

LPS stimulation of microglia cells pretreated with Sesamin or sesamolin [1]
To evaluate if pretreatment of Sesamin and sesamolin possessed potential neuroprotective activity, a preliminary test was performed to detect their inhibitory capabilities on NO level of rat microglia cells stimulated by LPS. In this test, cells were incubated with Sesamin or sesamolin, dissolved in dimethyl sulfoxide (DMSO) with the final concentration of this solvent added to the cell cultures never exceeding 0.1%, for 1 h prior to the supplement of LPS.

Cerebral ischemia of gerbils [1]
Eighteen male gerbils (60-85 g) were randomly divided into three groups fed by regular meal supplemented (op., 20 mg/kg/day), respectively, with saline (control), purified Sesamin, and the crude sesame oil extract containing 90% Sesamin and 10% sesamolin. After feeding for 4 days, each gerbil was anesthetized with chlorohydrate (400 mg/kg) intraperitoneally and its body temperature was maintained at 37°C with a heating pad (CMA/150). A midline neck incision was made and the right carotid artery was exposed and separated from the vago-sympathetic trunk. The right carotid artery was loosely encircled with a 4-0 suture for later occlusion. The gerbil’s head was placed in a stereotaxic frame with the nose bar positioned 4.0 mm below the horizontal line. Following a midline incision, the skull was partially removed to expose the right middle cerebral artery. The middle cerebral artery was loosely encircled with an 8-0 suture for later occlusion. A focal cerebral ischemia was induced by occlusion of the right common carotid artery (CCA) and the right middle cerebral artery (MCA) for 60 min, followed by reperfusion for 3 h. MBF 3D, a laser probe (0.8 mm in diameter) of a Laser Doppler Blood Flow monitor was positioned onto the cortex with its tip close to the middle cerebral artery. Cerebral blood flow dropped to less than 5% of basal after the occlusion of the MCA. Cerebral blood flow reached its minimal level within 5 min after the start of the occlusion and was confirmed to remain at this level throughout the monitoring period to ensure the validity of the stroke model.

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LD50: Mice 3800mg/kg (i.g.); Rats 6150mg/kg (i.g.)

Mice and rats

[1]. Neuroprotective effects of sesamin and sesamolin on gerbil brain in cerebral ischemia. Int J Biomed Sci. 2006 Sep;2(3):284-8.

[2]. A new amide from Asarum forbesii Maxim. J Asian Nat Prod Res. 2005 Feb;7(1):1-5.

(-)-Sesamin has been reported in Antrodia cinnamomea, Eleutherococcus divaricatus, and other organisms with data available.

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(+)-sesamin is a lignan that consists of tetrahydro-1H,3H-furo[3,4-c]furan substituted by 1,3-benzodioxole groups at positions 1 and 4 (the 1S,3aR,4S,6aR stereoisomer). Isolated from Cinnamomum camphora, it exhibits cytotoxic activity. It has a role as an antineoplastic agent, a neuroprotective agent and a plant metabolite. It is a lignan, a member of benzodioxoles and a furofuran.
Sesamin has been reported in Otanthus maritimus, Apis, and other organisms with data available.
See also: Sesame Oil (part of).

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Sesamin and sesamolin, abundant lignans found in sesame oil, have been demonstrated to possess several bioactivities beneficial for human health. Excess generation of nitric oxide in lipopolysaccharide-stimulated rat primary microglia cells was significantly attenuated when they were pretreated with sesamin or sesamolin. The neuroprotective effect of sesamin and sesamolin was also observed in vivo using gerbils subjected to a focal cerebral ischemia induced by occlusion of the right common carotid artery and the right middle cerebral artery. Repeated treatment of sesamin or a crude sesame oil extract containing both sesamin and sesamolin significantly reduced the infarct size, visualized via 2,3,5-triphenyltetrazolium chloride staining, by approximately 50% when compared with the control group. These results suggest that sesamin and sesamolin exert effective neuroprotection against cerbral ischemia. [1]

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Repeated pretreatment with Sesamin or the crude sesame oil extract containing both sesamin and sesamolin for four days significantly reduced infarct sizes by approximately 50% in the present study. Although the mechanism of neuroprotection is not understood, the combined results of in vitro and in vivo experiments suggest that a reduction of neuronal injury may be related to an inhibition of the induced NO release when the brain produces free radicals during cerebral ishemia at a rate sufficient to overcome endogenous antioxidant defenses. It has also been proposed that sesamin and sesamolin may act as free radical-scavengers and inhibitors of lipid peroxidation (8). The neuroprotective efficacy of sesamin and sesamolin may also reflect their ability to scavenge free radicals over-produced during cerebral ischmia.
In conclusion, oral administration of Sesamin or the crude sesame oil extract was neuroprotective in terms of reducing ischemic damage in experimental MCA+CCA occluded gerbils. The present results provide experimental data to sustain the potency of sesamin and sesamolin for neuroprotection against hypoxia or brain damage. Further investigation of optimal dosages of sesamin, sesamolin and the crude sesame oil extract are warranted in the future. Moreover, it is noteworthy that the crude sesame oil extract and the pure form of sesamin were equally effective in providing neuroprotection in this study. The pure form of sesamin requires many steps in its purification that leads to a relatively low recovery yield. Since the crude sesame oil extract demonstrates the same neuroprotective effect as the purified sesamin, this crude sesame oil extract seems to possess market potential as a supplement in health food products. [1]

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A highly unsaturated new amide, (2E,4Z,8Z,10Z)-N-isobutyl-2,4,8,10-dodecatetraenamide (1), was isolated in very small quantities from the whole plant of Asarum forbesii Maxim. together with four known compounds, (2E,4E,8Z,10E)-N-isobutyl-2,4,8,10-dodecatetraenamide (2), (-)-sesamin (3), (-)-asarinin (4) and (E)-asarone (5). The Z/E isomers, 1 and 2, were separated successfully by developed silver-ion medium-pressure liquid chromatography (SIMPLC). Compound 2 and the two diastereoisomers, 3 and 4, were isolated from this plant for the first time. The characterization of these compounds was achieved by various spectroscopic methods.[2]

C20H18O6

354.35

354.11

C, 67.79; H, 5.12; O, 27.09

13079-95-3

Sesamin;607-80-7

382073

White to off-white solid powder

1.4±0.1 g/cm3

504.4±50.0 °C at 760 mmHg

212.3±30.0 °C

0.0±1.2 mmHg at 25°C

1.623

3.32

0

6

2

26

482

4

C1[C@@H]2[C@@H](CO[C@H]2C3=CC4=C(C=C3)OCO4)[C@@H](O1)C5=CC6=C(C=C5)OCO6

PEYUIKBAABKQKQ-NSMLZSOPSA-N

InChI=1S/C20H18O6/c1-3-15-17(25-9-23-15)5-11(1)19-13-7-22-20(14(13)8-21-19)12-2-4-16-18(6-12)26-10-24-16/h1-6,13-14,19-20H,7-10H2/t13-,14-,19+,20+/m1/s1

5-[(3R,3aS,6R,6aS)-3-(1,3-benzodioxol-5-yl)-1,3,3a,4,6,6a-hexahydrofuro[3,4-c]furan-6-yl]-1,3-benzodioxole

(-)-sesamin; 13079-95-3; Sesamin, (-)-; AI3-21201; 9VCT11F572; SESAMIN, L-; 5-[(3R,3aS,6R,6aS)-3-(1,3-benzodioxol-5-yl)-1,3,3a,4,6,6a-hexahydrofuro[3,4-c]furan-6-yl]-1,3-benzodioxole; l-sesamin;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 100 mg/mL (282.21 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.06 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (7.06 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (7.06 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)