dl-3-n-butylphthalide protects endothelial cells against oxidative/nitrosative stress, mitochondrial damage and subsequent cell death after oxygen glucose deprivation

[CausticSymmetry]

Brain Res. 2009 Jul 16.
dl-3-n-butylphthalide protects endothelial cells against oxidative/nitrosative stress, mitochondrial damage and subsequent cell death after oxygen glucose deprivation in vitro.
Li L, Zhang B, Tao Y, Wang Y, Wei H, Zhao J, Huang R, Pei Z.

Department of Neurology, First Affiliated Hospital, Sun Yat-Sen University, No. 58 Zhongshan Road 2, Guangzhou 510080, PR China.

dl-3-n-butylphthalide (NBP) has been used for stroke treatment in China for years. Recently, we found that NBP can reduce the incidence of stroke and have protective action on cerebral microvessels, suggesting a direct action of NBP on endothelial cells. However, it is difficult to evaluate the direct action of NBP on endothelial cells in vivo because of the interactions of endothelial cells with other types of neuronal cells. Therefore, we investigated whether NBP protects against oxygen glucose deprivation (OGD)-induced cell injury in an immortalized human umbilical vein endothelial cells (HUVEC) in vitro. Cells were exposed to OGD, leading to endothelial damage. Endothelial injury was assessed by measuring MTT and the changes in chromatin morphology. Mitochondrial superoxide, mitochondrial membrane potential and mitochondrial morphology were assessed using MitoSOX Red. Rhodamine 123 and MitoTracker, respectively. Nitrosative stress was assessed by measuring the production of peroxynitrite. The activity of superoxide dismutase (SOD) is evaluated using SOD assay kit-WST. The expression of hypoxia inducible factor-1 alpha (HIF-1alpha) was assessed at the protein level by immunofluorescence and Western blotting. NBP at doses between 0.01 and 100 mumol/L dose-dependently protected against OGD-induced cell death. In addition, NBP attenuated OGD-induced mitochondria superoxide, cellular formation of peroxynitrite, and decrease in SOD activity, mitochondria fragmentation and loss of mitochondrial membrane potential. In parallel, NBP enhanced OGD-induced HIF-1alpha expression. This study demonstrates that NBP can protect HUVEC against OGD-induced oxidative/nitrosative stress, mitochondrial damage and subsequent cell death. This protective effect is, at least in part, associated with its enhancement on OGD-induced HIF-1alpha expression.

This one below shows more protection against nitrosative & oxidative stress. Nutrosative stress involves inducible nitric oxide, the inflammatory kind, I think this would be very worth considering. It's already known as an effective anti-hypertensive and anti-gout medicine.

Yao Xue Xue Bao. 2008 Apr;43(4):366-70.
[Mechanism of action of butylphalide against the injury following oxygen glucose deprivation/reoxygenation in rat cortical neurons]

Wu LR, Luo Y.

First Affiliated Hospital, Chongqing Medical University, Key Lab of Neurology in Chongqing, Chongqing 400016, China.

To explore the mechanism of action of butylphalide (NBP) against the injury following oxygen glucose deprivation/reoxygenation (OGD/R) in rat cortical neurons, neurons of Wistar newborn rats were prepared by filtering through a mesh, centrifugation and trypsogen digestion. A simple, stable and reliable in vitro model of OGD/R of neurons was established. We studied the activation, the nuclear translocation of NF-kappaB p65 and the mRNA expression of iNOS affected by NBP in each group neuron by RT-PCR. NBP is proved to be able to add cellular vigor and decrease LDH release. The mRNA expression of iNOS in neurons after OGD 4 h/R 8 h decreased when treated with NBP. There is statistical difference between each concentration of NBP that it adds cellular vigor, decreases LDH release and expression of iNOS in neurons after OGD 4 h/R 8 h. There is also statistical difference between NBP (100 micromol x L(-1)) and PDTC (100 micromol x L(-1)). It is proved that NBP can protect neurons, block upregulation of iNOS mRNA, and restrain activation of NF-kappaB in neurons.

3-n-butylphthalide also possesses antiplatelet and antithrombotic activity and based on anecdotal results, it seems to lower blood sugar significantly.

[Amaranthaceae]

Good stuff .. my mother takes it, together with broccomax .. she seems pleased.

[kijumn]

cpio,

Is she taking Celery Seed Extract for dl-3-n-butylphthalide?

Or do you know a good source for dl-3-n-butylphthalide?

Thanks

[CausticSymmetry]

jdp710 - Here's one

http://www.iherb.com/Natural-Factors-Celery-Seed-Extract-60-Capsules/2710?at=0

I'm being really cheap and already ordered this one:

http://www.iherb.com/Nature-s-Herbs-Power-Herbs-Celery-Seed-Power-60-Capsules/4399?at=0

[kijumn]

Thanks CS. I just ordered the first link ... Natural Factors.

[Amaranthaceae]

NF is the more solid brand, good choice.

[kijumn]

Here's some interesting info

"The phthalides function by different mechanisms at a cellular level. They may induce beneficial enzymes, inhibit enzymes mediating inflammatory processes, or interact with ion channels or cell surface receptors.

Celery (Apium graveolens) has long been recommended in traditional Chinese medicine as a natural blood purifier and a cure for hypertension. In an animal model for human essential hypertension, 3-n-butylphthalide, one of the predominant phthalides in celery reduced the systolic blood pressure, which could be due to the relaxation of vascular smooth muscles. The studies suggest that butylphthalide blocked extracellular calcium influx into the smooth muscles, possibly by modulation of calcium channels, thereby causing a vasorelaxant effect. Besides 3-n-butylphthalide, butylidenephthalide, a closely related compound was also shown to have a hypotensive effect in animals. Phthalides are also reported to have diuretic effects.

In traditional Indian medicine, celery seed extract has been widely prescribed for gout and rheumatism. Clinical studies at three hospitals have shown that the phthalides from celery seed extract are very effective in reducing inflammation and pain associated with rheumatoid arthritis and gout. However, the mechanism of action has not been investigated in depth. It has been speculated that the improved blood circulation may remove the uric acid crystals from the joints, thereby reducing the discomfort and pain. The phthalides may inhibit the formation of inflammatory mediators. Further studies are necessary to determine the effects of phthalides on arachidonic acid metabolism.

The phthalides may also improve the blood circulation producing antiasthmatic effects. Donq quai (Angelica sinensis), a widely prescribed Chinese medicinal plant for asthma and poor blood circulation, has ligustilide and 3-n-butylphthalide as effective compounds. Studies have indicated that the phthalides relieve the asthma induced by histamine and acetylcholine in animals.

Chuan Xiong (Ligusticum wallichii), another well known Chinese medicinal plant has ligustilide, butylphthalide and sedanoic acid. In human studies, Chuan Xiong improved the microcirculation through inhibition of thrombus formation and decreasing platelet aggregation in ischemic patients. The effects were similar to or better than papaverine, dextran, and aspirin-persantin.

In animal experiments, 3-n-butylphthalide was effective in protecting the ischemic sites which lack blood supply due blood clots or other problems following cerebral ischemia. Butylphthalide administration inhibitied the increase in myeloperoxidase activity, infiltration of neutrophils into the ischemic site, inhibited nitric oxide synthase activity, as well as reduced the expression of intercellular adhesion molecule-1 (ICAM-1)and tumor necrosis factor-alpha (TNF-alpha), factors responsible for post-ischemic brain injury.

3-n-Butylphthalide has been shown to have anticonvulsant effects in experimental chronic epilepsy in rats. Its anticonvulsant effects were weaker than those of diazepam, but its ability in counteracting the learning and memory impairment was greater than that of diazepam, causing no damage to brain cells. Phthalides present in celery seed oil have also been reported to have sedative activities.

In animal studies, 3-n-Butylphthalide and sedanenolide were found to inhibit benzo[a]pyrene induced tumor formation in mice. The chemopreventive activity could be due to the induction of detoxifying enzymes in the target tissues. Both the compounds exhibited high activities with the ability to induce the detoxifying enzyme glutathione S-transferase in mouse liver and small intestinal mucosa."

http://www.phthalides.com/howwork.html

[Amaranthaceae]

Jdp, thanks for posting those details.

[kijumn]

IH & cpio,

I've been meaning to reply to this thread ...

I wanted to update that I don't believe small doses, 1 - 2 capsules of natural factors celery seed extract does much hair loss wise. Large doses of 4 capsules may have a benefit though.

So again, if you guys are still taking celery seed extract, it's the large doses that would have a benefit for hair loss but no clue how much of a benefit.

Here's another article

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Celery Extract
Celery is a member of the Umbelliferous family along with carrots, parsley, and fennel. The modern celery originated from wild celery native to the Mediterranean where its seeds were once highly valued as a medicine. Like many other folk medicines, modern research is upholding the medicinal value of this common plant. In particular, scientists are evaluating the most powerful of the healing factors of celery, a compound known as 3-nbutylphthalide or 3nB for short.

What is 3nB?
3nB is a compound that is unique to celery and is responsible for the characteristic flavor and odor of celery. 3nb was discovered as the active component of celery in response to investigations by researchers seeking to explain some of the medicinal effects of celery including the lowering of blood pressure and the relief of arthritis. 3nB first drew significant scientific attention when researchers at the University of Chicago Medical Center identified it as the factor in celery responsible for the blood pressure lowering effect of celery.1 The research was prompted by one of the researcher's father, who after eating a quarter-pound of celery every day for one week observed his blood pressure dropped from 158 over 96 to a normal reading of 118 over 82. Subsequent animal studies found that a very small amount of 3nB lowered blood pressure by 12 to 14% and also lowered cholesterol by about 7%.

How does 3nB lower blood pressure?
The blood pressure lowering effect of 3nB appears to be a result of several effects. First of all, let me explain exactly what blood pressure refers to. It refers to the force with which your blood flows through the vessels. High blood pressure is usually the result of too much fluid there is in your blood and how flexible or resistant your blood vessels are. Retention of sodium (salt) leads to increase fluid volume in the blood while hardening of the arteries and the hormones released during stress lead to loss of flexibility or constriction of blood flow. If you put your thumb over a garden hose, the pressure against your thumb and the resultant pressure of the flow of water out of the hose can be reduced by either turning down the faucet (reducing the fluid volume) or by letting more water flow out the end of the hose (dilating the vessel). In treating high blood pressure, doctors usually prescribed diuretics (water pills) to reduce the fluid volume and vasodilators to relax the arteries to reduce the resistance of blood flow or beta-blockers to turn down the pumping action of the heart. 3nB appears to help lower blood pressure by both acting as a diuretic and vasodilator through impacting the production of prostaglandins (discussed below) as well as acting in a similar manner to drugs known as calciumchannel blockers.2 3nB has also been shown to lower blood cholesterol levels and reduce the formation of arterial plaque in experimental studies (animal and test tube studies).3,4 This effect may increase the elasticity of the blood vessels and also lead to lower blood pressure readings. 3nB also appears to promote some effects on areas and systems of the brain that control vascular resistance.

The benefit of celery extract in high blood pressure is its apparent safety and the fact that it has a very unusual mechanism of action as a diuretic. Most diuretics change the ratio of sodium to potassium in the blood and as a result dangerous side effects can occur as a result of either too much potassium or sodium. In contrast, celery extract acts as a diuretic but does not alter the ratio of sodium to potassium in the blood. The research on the blood pressure lowering effect of celery and celery extracts is quite preliminary, but I think it is certainly worth the effort to give it a try as some people have noted significant reductions. What research will probably show is that some people with high blood pressure will respond to celery extract while others will not. This occurrence is not unusual as physicians treating high blood pressure will tell you that there is a similar phenomena with conventional drugs used in high blood pressure.

Another real advantage of celery extract over conventional drugs used in high blood pressure is that the drugs lower blood flow to the brain. While this effect is helpful in reducing the likelihood of stroke, it often leaves people taking these drugs feeling tired, depressed, dizzy, and forgetful. Celery extract on the other hand has actually been shown to not only help prevent stroke in animal studies, but also improve blood flow as well and act to protect the brain and enhance energy production with the brain in a similar manner to Ginkgo biloba extract.5-8 It has produced dramatic recovery in neurological and brain function in animals in studies that simulate a stroke.6-10 It has also been shown to significantly increase lifespan in animal studies.11

What other effects have been noted with 3nB?
3nB has shown tremendous promise as an anticancer phytonutrient and detoxification aid in an experimental animal model,12 but it is its use as a pain reliever in arthritis, fibromyalgia, and gout that is getting most of the attention.

A celery extract standardized to contain 85% 3nB and other celery phthalides has been evaluated in the treatment of "rheumatism" – the general term used for arthritic and muscular aches and pain.13,14 In these studies efficacy was evaluated by well-established clinical protocols used to measure the effectiveness of conventional drugs used in arthritis and muscular pain. This protocol allows objective measures of clinical pain that can be assessed statistically and for individual comparisons. Due to the chronic, fluctuating nature of rheumatism, the design of the study was a longitudinal study. This sort of study compares the results achieved when using the active substance to a time when it is not used.

During the active phase of the 12-week study, the 15 subjects suffering from either osteoarthritis, osteoporosis or gout received 34 mg of a proprietary celery extract standardized to contain 85% phthalides twice daily. The pain had been present for approximately 10 years in a remittent or continual form and it led to a lack of joint mobility and pain that prevented the carrying out of household duties, hobbies and activities involved in employment of these subjects. The results of the study were extremely positive and quite statistically significant. The chance that such a positive effect in reducing pain in these subjects was a placebo effect was less than 1 in 1000. Subjects experienced significant pain relief after 3 weeks of use with the average reduction in pain scores of 68% and some subjects experiencing complete 100% relief from pain. Most subjects achieved maximum benefit after six weeks of use although some did notice improvements the longer the extract was used. Detailed blood chemistry as well as clinical evaluation in these test subjects did not turn up any side effects. Many subjects noticed a diuretic effect, but no changes were noted in the sodium and potassium balance (the significance of this effect was discussed above).

Based on the positive results in this small pilot study, a larger 70 patient study was conducted. Test subjects received 75 mg of the celery extract twice daily for three weeks. At this higher dosage, subjects reported even better results than in the pilot study. Statistically and clinically significant reductions were noted in pain scores, mobility, and quality of life. Again no side effects were noted other than the diuretic effect with no changes in the sodium and potassium balance. It appears to be particularly helpful for sufferers of gout as 3nB appears to lower the production of uric acid by inhibiting the enzyme xanthine oxidase.15

What is the proper dosage and are their any side effects?
Over 100,000 people in Australia have now used this proprietary celery seed extract standardized at 85% phthalides without any reports of side effects. The current recommendations for joint and muscle complaints based on the information now available from trials as well as clinical experience are the following (based upon using a celery seed extract standardized to contain 85% 3nB and other phthalides):

For the relief of join and muscle pain (include ing pain due to osteoarthritis, rheumatoid arthritis, and fibromyalgia): one tablet two to three times daily.
For gout: two tablets twice daily. NOTE: The initial blood uric acid measurements may increase in people with gout as uric acid crystals begin to dissolve.
Do you have to take the celery extract continuously to maintain benefits in relieving joint and muscle pain?
Yes. Results from the studies conducted to date indicate that as long as the celery extract is used it keeps pain at bay. But, if it is stopped the pain tends to recur.

How much celery or celery extract should I take for high blood pressure?
My recommendation is to either consume 8 ribs of celery per day or take a celery extract standardized to contain 85% 3nB and other celery phthalides at a dosage of 75 to 150 mg twice daily.

Can I take celery extract with conventional anti-inflammatory drugs?
Yes. There does not seem to be any adverse interactions with conventional drugs.

Are there any contraindications?
Since the effects of celery extract have not been evaluated for safety in pregnancy, it is generally recommended that it not be used during pregnancy or lactation. No other contraindications are presently known. I would advise individuals taking the drug Coumadin (warfarin) to be closely monitored by their physician when starting to use celery extract. It is just a precautionary recommendation.

How does 3nB work to produce all of these benefits?
Based upon al of the existing research it is clear that 3nB exerts a profound effect on many of the body’s control systems. Chief among them the prostaglandin system. Prostaglandins are chemicals that mediate or control many important body processes including regulating inflammation, pain, and swelling; blood pressure; and heart, digestive, and kidney function as well. Some of the effects noted for 3nB on the prostaglandin system are quite unique and novel. Rather than simply inhibiting the production of prostaglandins by blocking enzymes that produce them like aspirin or even the more expensive and selective Cox-2 inhibitors, 3nB appears to help restore balance in the prostaglandin system.16 Exactly how it accomplishes this effect is still a mystery. Drug companies are researching the unique effects of 3nB in order to develop drugs that can be patented and sold for a huge profit. It does not look like that line of research is necessary, however.

[Amaranthaceae]

Jdp, I think that is correct it does not directly benefit hair .. It is still great for many many reasons, and indirectly it may help. I take it everyday. I think it helps the body get rid of waste-acids, and detoxify some organs and is anti-septic in the intestines. On top of that anti-inflammatory and circulation benefits.

[CausticSymmetry]

I second cpio on that. I really dig this stuff. I've been using the cheap stuff from Nature's Herb's.

[Amaranthaceae]

I also use the cheap stuff from Nature's herbs. The good stuff from NF I give to my mother since I'm a good boy, LOL

I second cpio on that. I really dig this stuff. I've been using the cheap stuff from Nature's Herb's.

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