Troxerutin, hesperidin, escin, TTFCA, and diosmin are especially good for …

Enhancing Veins
and Brains

Protecting your veins, peripherally or centrally, is an
important way to preserve your health

By Will Block

Figure 1 Drawings of normal and abnormal artery-vein capillary interaction in the vein of Galen in the brain.
(click on thumbnail for full sized image)

T he great cerebral vein is one of the large blood vessels in the skull draining the cerebrum of the brain. Known as the “vein of Galen” (VG), it is named for its discoverer, the Greek physician Galen. Aside from VG aneurysmal malformations (see Fig. 1)—an aneurysm is a localized, blood-filled balloon-like bulge in the wall of a blood vessel—the most common form of symptomatic cerebrovascular malformation occurs in the newborn and infants, where VG’s are subject to blood clots. In adults, aneurysms may result in thrombosis of the great cerebral vein, a form of stroke due to a blood clot in the vein. Other types of stroke involving the veins of the brain include thrombosis of the cerebral veins and sinuses (CVST). Together, these affect just 3 to 8% of stroke patients, predominantly women.1 However, CVST is relatively uncommon and often misdiagnosed.

So why should we be concerned with the brain’s veins? Because it increasingly appears that many of the same nutrients that help protect veins throughout the body, also protect neural tissue in the brain, especially the type that plays a large role in the damage that defines Alzheimer’s disease. In this light, strengthening the brain’s venous system may help protect against memory loss, dementia, and Alzheimer’s disease.

Centella Asiatica—An Herb Offering Both Vein and Neural Tissue Protection

Consider the herb Gotu kola (Centella asiatica), widely used in the form of TTFCA (total triterpenic fraction of C. asiatica), a combination of three primary active ingredients of Centella: asiatic and madecassic acids and asia­ticoside in a specific ratio intended to optimize the value of each ingredient. These actives produce an extraordinarily wide range of preventive and therapeutic effects.

As far back as 2002 (see “Gotu Kola Combats Venous Hypertension” in the June, 2002 issue), we wrote about its benefits based on a notable collection of studies published in the journal Angiology (angiology is the study of blood vessels and lymph vessels) in a 2001 supplemental issue. Among the huge number of benefits found were: Centella rebuilds vein walls; Centella slows capillary leakage; Centella offers relief for patients with chronic venous insufficiency (CVI) including relief from edema, pain, restless limbs, etc.; Centella combats vasodilation; higher amounts of Centella yield better results; Centella produces improvement in all measures; and Centella makes arterial plaque more stable and thus less dangerous (see “Gotu Kola Can Help Prevent Heart Attack and Stroke” in the August, 2002 issue). Overall, seldom do research results point so clearly and unambiguously to the safety and efficacy of a nutritional supplement as in the case of Centella (as TTFCA).

Since then, there have been other studies. Most recently, in a systematic review, Centella was found to significantly improve microcirculatory parameters such as transcutaneous partial pressure of CO2 and O2, the rate of ankle swelling, and venoarteriolar response.2 While three of the eight studies did not provide quantitative data, these studies reported that patients treated with Centella showed significant improvement in CVI, a condition that affects the venous systems of the lower limbs causing leg heaviness, pain and edema.

And the net result of all of this is that CVI and varicose veins are far, far less of a problem. And, as if you haven’t been able to visualize this, reduced or negligible varicose veins can help to keep your legs beautiful (this is especially important if you are a female, but men can be vain too).

Centella for Improved Memory, Neuroprotection, and Alzheimer’s Disease

(click on thumbnail for full sized image)

It is interesting to note that asiatic acid, a triterpene of Centella (and one of the components of TTFCA), was patented as a treatment for dementia and an enhancer of cognition by the German pharmaceutical company Hoechst back in 2000.3

Centella Supplemented Rats: Enhanced Learning Plus

Less than two years later, a study found memory benefits in rats at doses of 200 and 300 mg/kg of a Centella aqueous extract which showed a significant decrease in the brain levels of malondialdehyde along with simultaneous significant increase in levels of glutathione.4 There was also a significant increase in the levels of catalase (an important antioxidant produced within the body) at the 300 mg/kg. Altogether these results indicated that Centella has cognitive enhancing effect and that an antioxidant mechanism is involved. Another rat study found that Centella constituents showed a neuronal dendritic growth stimulating property indicating that the herb can be used for enhancing neuronal dendrites in stress and neurodegenerative and memory disorders.5 Yet another rat study showed improvement in spatial learning performance, and enhanced memory retention power demonstrating enhanced learning.6 In the International Journal of Alzheimer’s Disease, scientists found that when rats were chronically treated with Centella (at 150 and 300 mg/kg, orally) for a period of 25 days—beginning 4 days prior to colchicine (a medication used in gout treatment) administration—the rats experienced significantly lessened colchicine-induced memory impairment and oxidative damage.7 Besides, Centella significantly reversed colchicine’s expected increase in acetylcholinesterase (the brain enzyme that breaks down the memory molecule acetylcholine).

Ceramides have been found to contribute to the apoptotic processes of neuronal cells in neurodegenerative disorders including Alzheimer’s disease. A recent study investigated the potential neuroprotective effects of asiatic acid, a triterpenoid derived from Centella, against ceramide-induced cell death in rat cortical neuronal cells.8 Asiatic acid (0.01 to 1.0 μmol/l) reduced ceramide-induced cell death and mitochondria membrane potential loss in a concentration-dependent manner. As well, asiatic acid decreased cellular production of reactive oxygen species and partly counteracted the pro-apoptotic effects of the ceramide.

Centella Supplemented Mice: Anti-Alzheimer’s Benefits

Using a breed of mice that express the amyloid precursor protein (APP) and have the propensity to form spontaneous amyloid beta plaque, researchers showed that Centella alters the amyloid pathology at 2 months of age.9 This is prior to the onset of detectable amyloid deposition. Centella use was continued for either 2 months or 8 months. A significant decrease in amyloid beta 1–40 and 1–42 was detected following an 8-month treatment with 2.5 mg/kg of Centella. This confirms that Centella functions as an antioxidant in vitro, scavenging free radicals, reducing lipid peroxidation, and protecting against DNA damage. Furthermore, the study found that Centella could impede the amyloid cascade altering amyloid beta pathology and modulate the oxidative stress response that has been implicated in the neurodegenerative changes that occur with Alzheimer’s disease.

In a recent study—investigating the role of Centella for D-galactose-induced cognitive impairment, and oxidative and mitochondrial dysfunction—mice given D-galactose for a period of six weeks demonstrated significantly impaired cognitive task abilities and oxidative defense systems diminished their mitochondrial complex enzymes activities.10

When given Centella for six weeks (150 and 300 mg/kg, orally), treatment significantly improved behavioral alterations, oxidative control, and mitochondrial activities. Centella also reduced the activity of neurotransmitter-dismantling acetylcholinesterase enzyme levels in senescence mice given D-galactose. This highlights the protective effect of Centella against D-galactose induced behavioral, biochemical, and mitochondrial dysfunction in mice.

Centella Supplemented Humans: Anti-Alzheimer’s Benefits

Given that two of the currently licensed drugs for Alzheimer’s disease (AD) are based on natural products (galantamine and rivastigmine), it does not surprise us that many plants are now being investigated as a potential source of new therapies for AD. Among these is Centella.

Many of the same nutrients that help
protect veins throughout the body,
also protect neural tissue in the brain,
especially the type that plays a large
role in the damage that defines
Alzheimer’s disease.

While Centella has a reputation to restore declining cognitive function in traditional medicine and in animal models, to date there is little evidence regarding its efficacy in humans. However, there have been several randomized, placebo-controlled, double-blind studies in the past. In a 2008 study,11 28 healthy elderly participants received the plant extract at various doses ranging 250, 500 and 750 mg once daily for 2 months. Upon assessment, the results showed that the high dose of the plant extract enhanced working memory and increased self-rated mood following the Centella treatment. This suggested the potential of Centella to lessen the age-related decline in cognitive function and mood disorder in the healthy elderly.

Traditional Ayurveda medicine has used Centella since ancient times to improve cognitive functioning. A recent study investigated Centella’s ability to manage mild cognitive impairment (MCI) and other age-related problems in the elderly.12 MCI is a problem that may convert into Alzheimer’s disease in later stages. Several studies have shown that subjects with MCI can develop depression and disruptive behavior (e.g., agitation and aggression). There were sixty elderly subjects in the study, aged 65 and above. The principal diagnostic tool was the Mini Mental State Examination (MMSE). Also, parameters like Activities of Daily Living, Instrumental Activities of Daily living and Yesavage Geriatric Depression scale were also used to monitor the subjects.

Centella was prescribed in a dose of 500 mg twice a day (1000 mg daily) for 6 months. A favorable improvement in memory was observed in MCI along with other problems like hypertension, insomnia, loss of appetite, and constipation. The mean MMSE scoring showed significant improvement after administration of Centella for 6 months in elderly subjects with MCI. This finding indicates that Centella is useful clinically in the patients suffering from MCI.

Flavonoids—Herbs Offering Both Vein and Neuron Protection

Also of value for CVI and varicose veins, the naturally occurring flavonoids diosmin, hesperidin, and ­troxerutin have been shown to be effective and safe. Varicose veins and venous disease are thought to affect over a quarter of the adult population. Accordingly, the management of these conditions are a major cause of healthcare expense. As a class, flavonoids are plant pigments that give colors to flowers, fruits, and vegetables. Their colors attract pollinator animals, and in higher plants, flavonoids are involved in UV filtration and symbiotic nitrogen fixation. They may also act as cell cycle inhibitors, chemical messengers, and physiological regulators.

In combination, diosmin and hesperidin are used throughout much of the world as a treatment for CVI and related disorders. The standard formulation is called micronized purified flavonoid fraction (MPFF), a mixture of 90% diosmin and 10% hesperidin.

Diosmin for Reduced Hemorrhaging, Fatigue, Heaviness, and More

A recent Russian study enrolled 245 patients with varicose vein disease who underwent unilateral combined phlebectomy (a minimally-invasive surgical procedure that removes surface varicose veins).13 The main group (n=200) received micronized diosmin, 1000 mg/day) for 2 weeks before and 30 days after the procedure; the control group (n=45) did not receive diosmin in the pre- and postoperative period.

Pain severity and subjective feelings of limb heaviness and fatigability were evaluated at one week, two weeks, and 30 days after the procedure. Subjective symptoms and the area of subcutaneous hemorrhage were significantly lower in the test group, compared to controls. This trend was observed for limb heaviness and fatigability (characteristics of CVI). This group also reported exercise and improved orthostatic tolerance among patients in the early postoperative period. Micronized diosmin in the pre- and postoperative period after plebectomy helped to lessen pain, decrease postoperative hematomas, and accelerate their resorption, while increasing exercise tolerance in early postoperative period.

The study found that Centella could
impede the amyloid cascade altering
amyloid beta pathology and modulate
the oxidative stress response that
has been implicated in the
neurodegenerative changes that
occur with Alzheimer’s disease.

In another study, researchers evaluated the effects of a diosmin-hesperidin mixture in the standard ratio on circulatory tone of the venous system, and on the role of enlarged veins in the pathophysiology of pelvic congestion syndrome.14 Twenty women between the ages of 28–35 with chronic pelvic pain who had been diagnosed with the syndrome at laparoscopy participated.* They all had prominent broad ligaments and ovarian veins without other pathologies (such as endometriosis) to explain the cause of pelvic pain. Ten women were randomized in a fashion to receive 450 mg of diosmin and 50 mg of hesperidin twice/daily for six months (900 mg of diosmin and 100 mg of hesperidin per day), and ten women were used as controls.

* Laparoscopy is a common procedure to remove mild to moderate endometriosis, an outgrowth of the uterus.

After three months, the frequency and severity of pelvic symptoms started to decrease with the flavonoids, but not in the placebo arm. The deterioration was significantly less at the end of six months. The researchers concluded that the flavonoid formulation may restore pelvic circulation and relieve pelvic symptoms.

Troxetrutin for Varicose Veins and Ulcers

In a recent meta-analysis conducted by the Imperial College in London, troxerutin and MPFF were found, separately, to demonstrate clinical benefits in patients with venous disease, including varicose veins and varicose ulcers.15

An interesting study compared the affects of a diosmin/hesperidin formulation and a troxerutin complex in subjects who had CVI.16 The measure of success was venous-related quality of life (Ve-QOL). Using a questionnaire, the researchers found that there was a significant decrease (46.8%) in Ve-QOL score; that is, improvement was observed in the troxerutin group and far less so in the diosmin/hesperidin treatment (15.5%). CVI, venous microangiopathy, and edema were significantly improved by the treatment with troxerutin; the improvement in Ve-QOL was significantly greater in the troxerutin group.

Flavonoids for Improved Memory, Neuroprotection, and Alzheimer’s Disease

In a study investigating the mechanism underlying the neuroprotective effect of troxerutin, it was shown that troxerutin improved behavioral performance in D-gal-treated mice by elevating Cu, Zn-superoxide dismutases (Cu, Zn-SOD) activity, and decreasing reactive oxygen species levels.17 D-galactose- causes cognitive impairment in mice.

Troxerutin significantly promoted nerve growth factor mRNA expression, and enhanced neuronal survival; it also improved cognitive performance. However, the neuroprotective effect of troxerutin was blocked by treatment with K252a, an antagonist for TrkA. In conclusion, administration of troxerutin to D-gal-injected mice reduced cognitive impairment and brain oxidative stress through the activation of NGF/TrkA signaling pathway.

CVI, venous microangiopathy, and
edema were significantly improved by
the treatment with troxerutin.

In a study designed to explore the mechanism of hesperidin action via the nitric oxide pathway for protecting against ischemic reperfusion cerebral injury-induced memory dysfunction, male Wistar rats were subjected to bilateral carotid artery occlusion for 30 min followed by 24 hours of reperfusion.18 Hesperidin (50 and 100 mg/kg, orally) pretreated the rats for 7 days before animals were subjected to cerebral injury. Various behavioral tests, biochemical parameters, mitochondrial complex enzyme dysfunctions, and histopathological alterations were subsequently assessed in hippocampus.

Seven days of hesperidin (50 and 100 mg/kg) treatment significantly improved neurobehavioral alterations (delayed fall off time and increased memory retention), oxidative defense, and mitochondrial complex enzyme activities in hippocampus compared to control animals. Hesperidin treatment significantly attenuated histopathological alterations compared to controls. Interestingly, L-arginine (100 mg/kg) pretreatment reduced the protective effect of the lower dose of hesperidin. Nonetheless, L-NAME (a nonselective nitric oxide synthase inhibitor) pretreatment significantly potentiated the protective effect of hesperidin. This study suggests that the L-arginine-NO signaling pathway is involved in the protective effect of hesperidin against cerebral I/R-induced memory dysfunction and biochemical alterations in rats.

In a new study,19 researchers evaluated the effect of troxerutin on cognitive impairment induced by brain insulin resistance in mice fed a high-cholesterol diet, and explored its potential mechanism. Results showed that oral administration of troxerutin to these mice significantly improved behavioral performance in a step-through passive avoidance task and a Morris water maze task, partly by decreasing the levels of reactive oxygen species, protein carbonyl and advanced glycation end products, and blocking endoplasmic reticulum stress via reduced phosphorylation of the pancreatic endoplasmic reticulum-resident kinase and eukaryotic translation initiation factor 2α.

Furthermore, troxerutin significantly inhibited the activation of kinases induced by endoplasmic reticulum stress and enhanced insulin signaling pathway, preventing obesity, restoring normal levels of blood glucose, fatty acids and cholesterol. Furthermore, troxerutin significantly inhibited endoplasmic reticulum stress-induced apoptosis and decreased the activation of caspase-12 and caspase-3 (inflammatory enzymes). These results suggest that troxerutin might help prevent cognitive deficits in type 2 diabetes mellitus and Alzheimer’s disease.

Another recent study investigated whether flavonoids, such as hesperetin and hesperidin, inhibited amyloid β (Aβ)-impaired glucose utilization through regulating cellular autophagy in insulin-stimulated neuronal cells.20

Troxerutin might help prevent
cognitive deficits in type 2 diabetes
mellitus and Alzheimer’s disease.

In this study, researchers used a toxic Aβ1-42 peptide to impair insulin-stimulated glucose utilization. This study also hypothesized that Aβ-induced autophagy might be emerging as a key process regulating neuronal glucose uptake. As well, hesperetin and hesperidin were also used to test the neuroprotective effect against Aβ-induced impairment of glucose utilization.

The data showed that Aβ-stimulated autophagy activation impaired neuronal energy metabolism, including glucose uptake, glucose transporters, and insulin signaling cascades. They also confirmed that the downregulation of Aβ-stimulated autophagy could increase insulin-stimulated neuronal glucose uptake. However, treatment with hesperetin and hesperidin improved Aβ-impaired glucose utilization by inhibiting Aβ-induced autophagy in neuronal cells.

Thus the downregulation of autophagy may be one of the approaches to control the impairment of energy metabolism leading to neuronal injury in the early development of Alzheimer’s disease, and hesperetin or hesperidin may be potential agents in preventing the progression of Alzheimer’s disease.

Alzheimer’s disease (AD) is a neurodegenerative disorder with a progressive cognitive decline and memory loss. The factors of decline include aggregated β-amyloid (Aβ), neuro­fibrillary tangles (NFTs), cholinergic dysfunction and oxidative stress. Aβ, a major constituent of the senile plaques, is a potent neurotoxic peptide and has a pivotal role in cognitive deficit and reduced synaptic plasticity in AD.

In a new study21 researchers examined the protective effect of troxerutin on Aβ (1–42)-induced impairment in hippocampal neurons in male Wistar rats. The rodents were divided into four groups including Aβ (42–1), Aβ (1–42), Aβ (1–42) plus troxerutin and Aβ (42–1) plus troxerutin groups.

The downregulation of autophagy by
hesperidin may help control the
impairment of energy metabolism
leading to neuronal injury in the early
development of Alzheimer’s disease,
thus preventing Alzheimer’s
disease progression.

Aβ was injected intracerebrally into right lateral ventricle and after two weeks the evoked field potential was used to assess paired pulse paradigm and long term potentiation (LTP). Administration of Aβ (1–42) drastically lessened the LTP of dentate gyrus neurons, while there was no significant difference in evoked field potentials between Aβ (1–42) plus troxerutin group with respect to Aβ (42–1) group. However, troxerutin improved the synaptic failure induced by Aβ peptide and can be introduced as a promising multi-potent pharmacological agent in prevention or treatment of AD.

Escin—An Herb Offering Both Vein and Neuron Protection

A meta-analysis examined the existing research on the safety and efficacy of horse chestnut seed extract (HCSE) for CVI. The goal was to integrate the results of many individual, carefully selected clinical trials into one unified study—a meta-analysis. Since such a study is by nature far more comprehensive and substantial than any individual trial, a high degree of credibility typically attaches to the results. The results in this case suggest that HCSE should be widely used for CVI.

Photograph © Andrew Dunn
The authors identified 28 randomized, controlled trials, and of these, 16 (published between 1976 and 2002) met certain standards of scientific validity that were adopted as inclusion criteria for the meta-analysis. Of the 16 trials, ten were placebo-controlled, five were controlled by comparison with other medications, and one was controlled by comparison with compression stockings and placebo. Thirteen of the trials used an amount of HCSE that was standardized to deliver 100 mg/day of escin (the chemical component of HCSE that is thought to be most active in combating CVI); 2 used 150 mg/day; and 1 used 50 mg/day.

Horse Chestnut Is Effective (and Safe) Against CVI

The principal conclusion reached in the meta-analysis was that HCSE is a safe and effective treatment for a wide variety of CVI-related symptoms, including:

  • Leg pain – Of seven placebo-controlled trials (PCTs) that assessed leg pain, six showed statistically significant reductions with HCSE.

  • Edema – Of six PCTs that assessed edema, four showed statistically significant reductions with HCSE.

  • Pruritus (itching) –This may not sound like much of a complication, but intense itching, or pruritus, can actually be quite painful and lead to skin abrasions that can then progress to infections. Of eight PCTs that assessed pruritus, four showed statistically significant reductions with HCSE.

  • Leg volume – Of six PCTs that assessed leg volume (a measure of excess fluid accumulation), five provided adequate data for analysis, and they showed statistically significant reductions with HCSE.

  • Calf and ankle circumference – Of seven PCTs that assessed calf and ankle circumference (which likewise indicate fluid accumulation), five showed statistically significant reductions at the ankle, and three at the calf, with HCSE.

This solid scientific evidence for the efficacy of HCSE in alleviating the symptoms of CVI is gratifying, of course, but it would be worthless unless there were also evidence of HCSE’s safety—and there is. Of the 13 PCTs that reported on side effects associated with the use of HCSE, four reported no side effects, four reported good tolerability, and five reported only minor side effects, such as stomach upset and headache.

Troxerutin can be introduced as
a promising multi-potent
pharmacological agent in prevention
or treatment of AD.

Evidence has accumulated indicating an important role for inflammation in ischemic brain injury and its contribution to greater cerebral damage after ischemia. This supports the idea that blocking the inflammatory reaction can promote neuroprotection and shows therapeutic potential for clinical treatment of ischemic brain injury.

In a recent study, escin, a natural mixture of triterpenoid saponin found in the seed of the horse chestnut, demonstrates antiedematous and anti-inflammatory effects.22 The researchers assessed neuroprotective effects of escin after inducing transient global cerebral ischemia by occluding both common carotid arteries. Treatment with escin was initiated ½ hour after ischemia induction and given once a day for three consecutive days was followed by assessment using the Morris water-maze test and step-down passive avoidance test.

Strengthening the brain’s venous
system—while doing so for the rest of
the body—may also help protect
against memory loss, dementia, and
Alzheimer’s disease.

Acetylcholinesterase activity, histological pathology, and expression of inflammatory genes in the hippocampus were determined, showing that escin significantly improved learning and memory recovery and reduced hippocampal damage in the cerebral ischemic mice. Furthermore, the researchers found that escin significantly downregulated certain inflammatory gene expression and upregulated expression of granulocyte-macrophage colony-stimulating factor, which was recently reported as a neuroprotective protein in the brain.

What’s more, there is a patent (Composition containing horse chestnut extract for anti-angiogenic and matrix metalloproteinase inhibitory activity, WO 2003035092 A1) indicating that escin inhibits matrix metalloproteinase (MMP) activity. MMP is a pro-inflammatory factor that is thought to involved in the development of Alzheimer’s disease.23

Against Memory Loss, Dementia, and Alzheimer’s Disease

While the mechanisms suggested in this article typically involve the antiinflammation and antioxidative properties of the nutrients discussed, it appears to become clearer that strengthening the brain’s venous system—while doing so for the rest of the body—may help protect against memory loss, dementia, and Alzheimer’s disease. Given the evidence presented, you might want to treat both your brain and your veins at the same time by supplementing with troxerutin, hesperidin, escin, TTFCA, and diosmin.


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  12. Tiwari S, Singha S, Patwardhan K, Gehlot S, Gambhira IS. Effect of Centella asiatica on mild cognitive impairment (MCI) and other common age-related clinical problems. Dig J Nanomater Bios. 2008;3:215-20.
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  18. Gaur V, Kumar A. Hesperidin pre-treatment attenuates NO-mediated cerebral ischemic reperfusion injury and memory dysfunction. Pharmacol Rep. 2010 Jul-Aug;62(4):635-48.
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  20. Huang SM, Tsai SY, Lin JA, Wu CH, Yen GC. Cytoprotective effects of hesperetin and hesperidin against amyloid β-induced impairment of glucose transport through downregulation of neuronal autophagy. Mol Nutr Food Res. 2012 Apr;56(4):601-9. doi: 10.1002/mnfr.201100682. Epub 2012 Mar 1.
  21. Babri S, Mohaddes G, Feizi I, Mohammadnia A, Niapour A, Alihemmati A, Amani M. Effect of troxerutin on synaptic plasticity of hippocampal dentate gyrus neurons in a b-amyloid model of Alzheimer’s disease: An electrophysiological study. Eur J Pharmacol. 2014 Mar 25;732C:19-25. doi: 10.1016/j.ejphar.2014.03.018. [Epub ahead of print]
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Will Block is the publisher and editorial director of Life Enhancement magazine.

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