Understanding Stroke

Table of Contents
Introduction
Natural Compounds Helpful in the Prevention and/of Recovery from Stroke
Blood Markers in Stroke
Biomarkers Elevated in Stroke
Natural Compounds that Target Biomarkers Involved in Stroke
Nutritional Support for Glutathione & Optimal Liver Detoxification
Botanical and Nutritional Strategies for Stroke Recovery

Introduction
Ischemic stroke is a major cause of adult death and disability, resulting in over 6 million deaths annually. The nerve cell death associated with cerebral ischemia is because of multiple factors resulting from the lack of oxygen, including the loss of ATP, excitotoxicity, oxidative stress, reduced neurotrophic support, and multiple other metabolic stresses. (Lapchak et al 2010)

Stroke generally refers to a local interruption of blood flow to the brain and is the leading cause of long-term disability, third leading cause of death in United States. Approximately 12% of strokes are hemorrhagic (rupture of a cerebral blood vessel), whereas the remaining 88% are ischemic and result from occlusion of a cerebral artery (either thrombolic or embolic). Hypertension is one of the significant risk factors for hemorrhagic stroke. Blockage of a cerebral artery results in interruption of the blood flow and supply of nutrients, glucose, and oxygen to the brain.  (Adibhatla & Hatcher 2008)

Certainly one of the challenges facing stroke treatment is that only a small percentage of patients can be transported to the hospital and begin treatment within the first 3 hours. The concept that ‘time is brain’ wins (the sooner the treatment, the better will be the recovery) since 2 million neurons die every minute after stroke. (Adibhatla & Hatcher 2008) 

Stroke initiates the immune response, activating inflammatory cells including microglia/macrophages and generating ROS. Several studies have provided evidence that ROS stimulate opening of L-type voltage-sensitive calcium channels (L-VSCC), leading to increased intracellular calcium. Disturbances in cellular calcium homeostasis are involved in the injury and death of neurons that occur as the result of both acute insults such as stroke and chronic neurodegenerative disorders including AD (Alzheimer’s disease). (Adibhatla & Hatcher 2008)

Although there are intracellular defenses against ROS (reactive oxygen species), increased production of ROS or loss of antioxidant defenses leads to progressive cell damage and decline in physiological function. Overproduction of these free radicals can damage all components of the cell, including proteins, carbohydrates, nucleic acids, and lipids, leading to progressive decline in physiological function and ultimately cell death. (Adibhatla & Hatcher 2008)

The brain is believed to be particularly vulnerable to oxidative stress as it accounts for only 2% of total body weight but consumes 20% of the body’s oxygen, contains high concentrations of PUFA (polyunsaturated fatty acids) that are susceptible to lipid peroxidation, is relatively high in redox transition metal ions, yet has relatively low antioxidant capacity compared to other organs. Of all the brain cells, neurons are particularly vulnerable to oxidative insults due to low levels of reduced glutathione. Oxidative stress is a component of many neurodegenerative disorders such as  PD (Parkinson’s disease), AD, MS, and amyotrophic lateral sclerosis (ALS). (Adibhatla & Hatcher 2008)

The energy needs of the brain are supplied by metabolism of glucose and oxygen for the phosphorylation of ADP to ATP. Phospholipid metabolism can consume up to 20% of net brain ATP. Most of the remaining ATP generated in the brain is utilized to maintain intracellular homeostasis and transmembrane ion gradients of sodium, potassium, and calcium. Energy failure results in collapse of ion gradients, and excessive release of neurotransmitters such as dopamine and glutamate, ultimately leading to neuronal death and development of infarction. (Adibhatla & Hatcher 2008)

Stroke is characterized by an ischemic core (infarct) surrounded by a “penumbra” (peri-infarct) region that has partial reduction in blood flow due to presence of collateral arteries. The ischemic core is generally considered unsalvageable, whereas the penumbra may be rescued by timely intervention and is a target for the development of therapeutic treatment. Local arterial blockage can be caused by either a thrombus (a clot that forms at the site of the arterial occlusion) or an embolus (a clot that forms peripherally, dislodges into the arterial circulation and is transported to the brain. Atherosclerosis, is the main risk factor for development of these embolisms. Inflammation poses as one of the high risk factors for stroke for its role in the initiation, progression and maturation of atherosclerosis. (Adibhatla & Hatcher 2008)

MMPs (matrix metalloproteinases) contribute to degradation of the fibrous cap surrounding the plaque, resulting in its rupture and formation of a blood clot. If the blood clot dislodges from the plaque, arterial blood flow can carry it to the brain, where it lodges in a cerebral artery (embolism) and causes an ischemic stroke. Excess free iron generates oxidative stress that hallmarks diseases of aging, including atherosclerosis. (Adibhatla & Hatcher 2008)

Atherosclerosis, a progressive disease of the arteries, is the most common cause of myocardial infarction, stroke, and cardiovascular disease . Atherosclerosis is believed to be predominantly an inflammatory condition produced as a response to injury. Atherosclerosis is defined by the accumulation in the arterial intima of mainly low-density lipoprotein (LDL)-derived lipids along with apolipoprotein B-100 (apoB100). (Adibhatla & Hatcher 2008)

It is now believed that a complex endothelial injury and dysfunction induced by a variety of factors such as homocysteine, toxins (smoking), mechanical forces (shear stress), infectious agents (Chlamydia pneumoniae), and oxidized LDL results in an inflammatory response that is instrumental in the formation and rupture of plaques, one of the greatest risk factors for ischemic stroke. (Adibhatla & Hatcher 2008)

Two critical events involved in atherogenesis involve accumulation and oxidation of LDL in the arterial intima and recruitment of monocytes to the developing lesion. Evidence indicates that LDL uptake and retention are increased at plaque sites, which may involve degradation or binding to cellular and matrix components. A second critical event in atherosclerosis is an inflammatory response that triggers expression of adhesion molecules (selectins and integrins) in the arterial endothelium, stimulating adhesion of monocytes to the endothelium. Monocytes penetrate into the arterial intima, differentiate into macrophages and eventually become foam cells. Macrophages accumulate massive amounts of lipoprotein-derived lipids. The macrophage foam cells generate ROS, produce tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1), and matrix metalloproteinase 9 (MMP-9) that promote atherosclerosis, degrade the fibrous cap, and eventually lead to plaque rupture. (Adibhatla & Hatcher 2008)

Macrophage MMP-9 degrades extracellular matrix components, including the fibrous cap of atheromatous plaques. Rupture of the fibrous cap exposes the blood to the inner components of the plaque, particularly tissue factor released from apoptotic macrophages. Tissue factor binds to activated coagulation factor VII and triggers the coagulation cascade, resulting in formation of a blood clot. Destabilization of this clot results in release of an embolus into the blood stream, which can be transported to the brain, where it can lodge in a cerebral artery and induce an ischemic stroke. (Adibhatla & Hatcher 2008)

Stroke initiates the immune response, activating inflammatory cells including microglia/macrophages and generating ROS. ROS can further stimulate release of cytokines that cause upregulation of adhesion molecules, mobilization and activation of leukocytes, platelets, and endothelium. These activated inflammatory cells also release cytokines, MMPs, nitric oxide, and additional ROS in a feedback fashion. Inflammatory response after stroke suggests that cytokines (TNF-α, IL-1α/β, and IL-6) affect the phospholipid metabolism and subsequent production of eicosanoids, ceramide, and ROS that may potentiate stroke injury. (Adibhatla & Hatcher 2008)

A systemic inflammatory response involving upregulation of TNF-α and IL-1 is believed to be instrumental in the formation and destabilization of plaques, one of the risk factors for ischemic stroke. There is considerable clinical data indicating that this systemic inflammation is associated with unfavorable outcome in stroke patients. However, this inter-relationship of systemic inflammation with stroke pathology has not been well studied. (Adibhatla & Hatcher 2008)

Inflammation is obvious within several hours during ischemia/reperfusion injury; it contributes to secondary damage caused by the microglial activation and resident perivascular and parenchymal macrophages, as well as infiltration of peripheral inflammatory cells. (Wu et al 2010)

Stroke is the third most common cause of death worldwide. Recent findings showed that the severity of cerebrovascular diseases including ischemic stroke correlates with inflammation mediated responses in the neural cells. During ischemia, inflammatory mediators including tumor necrosis factor-alpha (TNF-α) and nitric oxide are produced by microglia, which play a central role in the pathogenesis of the disease. (Or et al 2011)

A less well-studied factor that can contribute to acute brain injury is the accumulation of free heme as a consequence of hemorrhage and hemolysis, which also exerts cytotoxic effects on neurons through oxidative mechanisms. Since under pathological conditions, oxidative stress can be mediated by different free radical species generated through multiple pathways, effective neuroprotective therapies may need to be broad-based.

Free heme released from extravasated red blood cell hemoglobin is known to be a potent inducer of neuronal and astrocyte cell death following injury to the brains of both mature and immature animals. Heme toxicity results from its catalysis of oxidative alterations to proteins, membrane lipids, and DNA. Oxidative damage to these molecules is also promoted by heme catabolites (Fe, biliverdin, CO). (Soane et al 2010)

Oxidative stress refers to the imbalance between the production and removal of reactive oxygen species (ROS). Due to the reaction between ROS and macromolecules, generation of ROS can lead to damage or death of cells in various tissues. Brain tissue is most vulnerable to oxidative stress due to its high glucose metabolism rate and low antioxidant defense enzyme level. Natural antioxidants are promising candidates of chemopreventive agents for treating neurodegenerative diseases such as Alzheimer’s disease (AD), cerebral ischemia and Parkinson’s disease (PD). (Jeong et al 2011)

Sufficient evidence has indicated that neutrophils play a key role in the development of ischemic brain damage, and the depletion of circulating neutrophils or inhibition of neutrophil infiltration is demonstrated to ameliorate ischemic cerebral injury. (Wu et al 2010)

ROS bursts and excitatory amino acid toxicity caused by ischemic reperfusion will lead to intracellular Ca²⁺overload. Ca²⁺ overload in neurons is an essential signal of catastrophic events leading to irreversible neuronal injury. The main pathways of Ca²⁺ overload after cerebral ischemia and reperfusion are as follows: 1) the depletion of ATP leads to inactivation of Na⁺,K⁺-ATPase, an enzyme regulating ionic concentration gradients for the generation of action potentials in neurons, with resultant depolarization of cell membrane potential and further opening of Ca²⁺-permeable cation channels such as voltage-gated calcium channels (VGCCs). (Wu et al 2010)

ASICs (acid-sensing ion channels), especially ASIC1, which has been reported to be activated by extracellular acidosis, play a key role in ischemic cerebral injury. In recent studies, puerarin, extract from Radix puerariae, has been reported to inhibit ASICs current in both natural cells and transfected cells. (Wu et al 2010)

It is believed that VEGF is beneficial for the recovery of neurological function after cerebral ischemia, at least partly because newly formed neuroblasts migrate into the damaged striatum and survive for several months after stroke. Cornel iridoid glycoside has been reported to provide a better microenvironment for angiogenesis and cell proliferation by increasing VEGF levels. (Wu et al 2010)

Recent studies have demonstrated that some of these compounds, such as paeoniflorin, emodin-8-O-β-D-glucoside, baicalin, and curcuma oil, have the ability to penetrate the blood-brain barrier and achieve wide distribution in the brain, which is critical for CNS effects. (Wu et al 2010)

Considering that multifactorial and progressive pathophysiological processes are involved in cerebral ischemia; using natural compounds which are able to exert pleiotrophic effects by acting on multiple targets or using combinations of natural compounds that act on single targets may prove to be effective strategies in treating ischemia and related cerebral injury as well as neurodegenerative diseases.

Natural Compounds Helpful in the Prevention and/or Recovery from Stroke
α-Tocotrienol (a member of the family of vitamin E compounds), but not natural vitamin E, offered protection in stroke models by suppressing glutamate-induced cell death mediated through early activation of c-Src kinase and 12-lipoxygenase pathways.  (Adibhatia & Hatcher 2009)

Baicalein – One group of multi-target compounds that may meet the criteria for the treatment of stroke are plant-derived polyphenolics. Our laboratories have recently shown that two flavones, fisetin and baicalein, improve clinical function in a rigorous rabbit embolic stroke model. (Lapchak et al 2011)

Berberine – Our study also demonstrates that berberine reduces brain ischemic-hypoxic injury dose-dependently. Therefore, beberine may be considered as useful anti-stroke agent. (Benaissa et al 20090

Berberine and palmatine – Use of voltage-gated calcium channels (VGCC) blockers has been considered a therapeutic approach for post-stroke neuroprotection in humans for many years. Previous studies have shown that some isoquinoline alkaloids contained in medicinal herbs such as berberine (an alkaloid derived from the herbal medicine Rhizoma coptidis and palmatine (a flavonoid in propolis) exhibit significant and rapid inhibition of voltage-gated calcium currents in many native cells. (Wu et al 2010)

Bromelain – Results suggested that bromelain could be used for treating acute thrombophlebitis, as it decreases aggregation of blood platelets, has a cardio-protective effect, ameliorates rejection-induced arterial wall remodelling, prevents thrombin-induced human platelet aggregation as well as reduces thrombus formation. (Ley et al 2011)

Caffeic acid – The antioxidant activities of caffeic acid may provide neuroprotection against H₂O₂-induced toxicity. (Jeong et al 2011)

Cinnamophilin – extracted from Cinnamomum philippinense, has been demonstrated to reduce brain infarction and improve neurobehavioral outcome when administered either 15 min before (pretreatment) or 2 h after the onset of middle cerebral artery occlusion (MCAO) (postischemic treatment). (Wu et al 2010)

Curcumin and curcuminoids – are neuroprotective in a variety of preclinical stroke models. The novel multi-target curcuminoid, CNB-001 (a pyrazole derivative of curcumin), has a superior safety and pharmacokinetic profile and should be further developed as an acute monotherapy or to be used in conjunction with thrombolytics for acute ischemic stroke. (Lapchak 2011)

DHA (docosahexaenoic acid) diet-induced accumulation of DHA in the brain protects against postischemicinflammation and injury. Because DHA is widely available at low cost and has an excellent safety profile, our data suggest that increased DHA intake may provide protection against acute immune response/brain damage inischemic stroke. (Lalancette-Hebert et all 2011)

DHEA and allopregnanolone stimulate neurogenesis. (Adibhatia & Hatcher 2009)

EPA (eicosapentaenoic acid) – treatment in patients in the chronic phase of cerebral infarction leads to a decrease in ADMA in the blood, suggesting that EPA improves vascular endothelial function and therefore supports the protective efficacy against cerebral infarction. (Hagiwara et al 2011)

Ginkgo biloba extract (EGB761) – had significant therapeutic effects on ischemic stroke and it perhaps worked through activating the Akt-CREB-BDNF pathway. (Zhang et al 2011)

Ginseng total saponins (GTS) – can improve neurological deficits after focal cerebral ischemia by inducing endogenous neural stem cells activation and thereby enhance adult central nervous system regeneration. (Zheng et al 2011)

Green and Black Tea – Natural plant polyphenols (flavonoids and non-flavonoids) are the most abundant antioxidants in the diet and as such, are ideal nutraceuticals for neutralizing stress-induced free radicals and inflammation. Human epidemiological and new animal data suggest that green and black tea drinking (enriched in a class of flavonoids named catechins) may help protecting the aging brain and reduce the incidence of dementia, AD, and PD. Mechanistic studies on the neuroprotective/neuroregenerative effects of green tea catechins revealed that they act not only as antioxidants metal chelators, but also as modulators of intracellular neuronal signaling and metabolism, cell survival/death genes, and mitochondrial function. (Mandel et al 2011)

Hesperetin – a flavanone derived from citrus fruits, suppresses NF-κB activation in both young and old rats through multiple signal transduction pathways. (Kim et al 2006)

Ligusticum chuanxiong (LCX) – is a commonly used traditional Chinese medicine (TCM) for empiric treatment of cerebrovascular and cardiovascular diseases for many centuries. Two compounds with inhibition on neuroinflammation were isolated from LCX. both compounds protected Neuro-2a cells from neuroinflammatory toxicity. Senkyunolide A and Z-ligustilide isolated from LCX may be considered as potential complementary drug candidates for treating inflammatory processes associated with cerebrovascular diseases. (Or et al 2011)

Lumbrokinase – It is concluded that lumbrokinase is beneficial to the treatment of cerebral infarction. The effect of lumbrokinase is related to the inhibition of intrinsic coagulation pathway and the activation of fibrinolysis via an increase of t-PA activity. (Jin et al al 2000)

Ocimum basilicum (sweet basil) – Pre-treatment with standardized ethyl acetate extract of Ocimum basilicum markedly reduced cerebral infarct size and lipid peroxidation, restored GSH content, and attenuated impairment in short-term memory and motor coordination. The results of the study suggest that Ocimum basilicum could be useful clinically in the prevention of stroke. (Bora et al 2011)

Oleanolic acid – These results demonstrate that oleanolic acid effectively alleviates cerebral ischemic damage in vivo and oxidative injury in vitro, which may be in part due to the modulation of endogenous antioxidants and the improvement of mitochondrial function. Oleanolic acid may be a potential medicine for attenuating ischemic stroke. Oleanolic acid, a triterpenoid compound, exists in many plants. (Rong et al 2011)

Panax notoginseng – In conclusion, we showed that the PN extract exhibited significant neuroprotective effects in rats with transient focal ischemia, and that the neuroprotective effect of the PN extract appears to involve the inhibition of the induction of iNOS and COX-2 up-regulation by activation of NF-κB in the ischemic brain. Our findings suggest that the roots of P. notoginseng have a neuro- protective effect in the ischemic brain, which is due to the inhibition of inflammation and of microglial activation, and can be used as potential therapeutic agent against inflammation in ischemic stroke. (Son et al 2008)

Polygonum multiflorum – Tetrahydroxystilbene glucoside (TSG), an active component of the rhizome extract fromPolygomum multiflorum, has been reported to attenuate intracellular ROS generation and mitochondrial membrane potential dissipation caused by ischemia/reperfusion. Interestingly, it can directly upregulate the expression of sirt1, which is a class III histone deacetyltransferase that promotes cell survival and subsequently reduces the expression and activity of iNOS. TSG also protected against brain injury at 2 h after cerebral ischemia. (Wu et al 2010)

Resveratrol – has neuroprotective features both in vitro and in vivo in models of Alzheimer’s disease (AD), but it has proved to be beneficial also in ischemic stroke, Parkinson’s disease, Huntington’s disease, and epilepsy. (Albani et al 2010)

Saffron – In addition, we show that among these saffron’s constituents, crocin most effectively promotes mRNA expression of gamma-glutamylcysteinyl synthase (gamma-GCS), which contributes to GSH synthesis as the rate-limiting enzyme, and that the carotenoid can significantly reduce infarcted areas caused by occlusion of the middle cerebral artery (MCA) in mice. (Ochiai et al 2007)

Scutellaria – A recent study reveals that Baicalein (Bai), one flavonoid extracted from Scutellaria baicalensisGeorgi, when administered either prior to or after ischemia, can significantly protect against brain injury. (Wu et al 2010)

Silymarin, a naturally occurring flavone from the milk thistle (Silybum marianum), may be helpful in slowing down the progression of neurodegeneration in focal cerebral ischemia. These results suggest that the neuroprotective potential of silymarin is mediated through its anti-oxidative and anti-apoptotic properties. (Raza et al 2011)

Sulforaphane – activates the  Anti-oxidant Response Element ARE/Nrf2 pathway of antioxidant defense and protects immature neurons from death caused by stress paradigms relevant to those associated with ischemic and traumatic injury to the immature brain. Due to its broad-based antioxidant effects resulting from induction of multiple antioxidant systems through the ARE/Nrf2 pathway, sulforaphane might offer an effective approach toward protection against heme toxicity. (Soane et al 2010) 

Blood Markers in Stroke
ADMA (asymmetric dimethylarginine) – An increase of both ADMA and SDMA plasma levels within the first 72 hours after the onset of ischemic stroke predicts a poor outcome. (Worthmann et al 2011)

D-Dimer & fibrinogen – Cardioembolic stroke patients showed increased D-dimer, fibrinogen and D-dimer/fibrinogen ratio. Patients with atherothrombotic stroke showed raised fibrinogen and erythrocyte sedimentation rate. Patients with lacunar and undetermined stroke showed intermediate values of markers. Totalanterior cerebral infarction syndrome was related to D-dimer. (Alvarez-Perez et al 2011)

Homocysteine – Hyperhomocysteinemia is a risk factor for cardiovascular disease and stroke. Like many other cardiovascular risk factors, hyperhomocysteinemia produces endothelial dysfunction due to impaired bioavailability of endothelium-derived nitric oxide (NO). (Dayal & Lentz 2005)

hs-CRP – Eighty-seven percent of patients had an antihypertensive regimen, but hypertension control was achieved in 34.1% of patients. Neither use of six different antihypertensive drug regimens nor the change in blood pressure levels showed any difference on new atherothrombotic events, outcomes or survival rates. On the other hand, the higher levels of hs-CRP at baseline were found to be associated with higher mortality rates(p = 0.020).Our findings emphasize the predictive role of inflammation in future cardiovascular mortality in patients with acute ischemic stroke, indicating that inflammatory mediators underlying the atherothrombotic process play a more important role than it is assumed. (Benbir et al 2011)

Neutrophils – Sufficient evidence has indicated that neutrophils play a key role in the development of ischemic brain damage, and the depletion of circulating neutrophils or inhibition of neutrophil infiltration is demonstrated to ameliorate ischemic cerebral injury. (Wu et al 2010)

Triglycerides – Hypertriglyceridemia may be a possible predictor for early neurological deterioration (END) inacute lacunar stroke. Thrombogenecity and microcirculatory disturbance augmented by hypertriglyceridemia may be suggested as potential mechanisms. (Kwon et al 2011)

Biomarkers Elevated in Stroke
COX-2 – Several proinflammatory genes or mediators, such as inducible nitric oxide synthase (iNOS), cycloxygenase-2 (COX-2), and pro-inflammatory cytokines, are strongly expressed in the ischemic brain. (Son et al 2008)

iNOS – Several proinflammatory genes or mediators, such as inducible nitric oxide synthase (iNOS), cycloxygenase-2 (COX-2), and pro-inflammatory cytokines, are strongly expressed in the ischemic brain. (Son et al 2008)

MMPs – Stroke initiates the immune response, activating inflammatory cells including microglia/macrophages and generating ROS. ROS can further stimulate release of cytokines that cause upregulation of adhesion molecules, mobilization and activation of leukocytes, platelets, and endothelium. These activated inflammatory cells also release cytokines, MMPs, nitric oxide, and additional ROS in a feedback fashion. Inflammatory response after stroke suggests that cytokines (TNF-α, IL-1α/β, and IL-6) affect the phospholipid metabolism and subsequent production of eicosanoids, ceramide, and ROS that may potentiate stroke injury. (Adibhatia & Hatcher 2009)

NFkappaB  – There is ample evidence indicating that NF-κB is activated in cerebral ischemia and reperfusion (I/R), especially in neurons. This suggests that inhibition of NF-κB may represent a treatment strategy in ischemic stroke. (Jiang et al 2010)

PPAR – The three peroxisome-proliferator-activated receptor (PPAR) subtypes (α, β/δ, and γ) are nuclear receptors that are recently recognized to play an important role in CNS disorders and injuries. Recent studies using neuron-specific PPARγ null mice reinforce the neuroprotective function of PPARγ and the growing body of evidence recognizing activation of PPARγ as a possible target for neuroprotection in CNS disorders and injuries where oxidative stress is a major player. These studies also indicate that PPARγ in neurons is not essential for normal neuronal well being, but it plays an important role in protecting neurons from damage by ischemic and oxidative injury. (Adibhatia & Hatcher 2009)

Sirt1 – Recently, sirt1 has been introduced for the therapy of neurodegenerative diseases. Many natural compounds such as resveratrol, butein and quercetin, which are known as anti-aging agents, have been found to directly activate sirt1, suggesting that sirt1 may be the direct target of many herbal components that exhibit anti-aging effects. (Wu et al 2010)

TNF-alpha – During ischemia, inflammatory mediators including tumor necrosis factor-alpha (TNF-α) and nitric oxide are produced by microglia, which play a central role in the pathogenesis of the disease. (Or et al 2011)

Natural Compounds that Target Biomarkers Involved in Stroke
COX-2 (Cyclooxygenase-2) – is a key enzyme that catalyses the biosynthesis of prostaglandins from arachidonic acid and plays a critical role in some pathologies including inflammation, neurodegenerative diseases and cancer. (Weber et al 2010)

Natural Compounds that Inhibit or Down-Regulate COX-2:Curcumin (Lin et al 2010) (Moon et al 2010) (Leite et al 2009) 
Honokiol – Nitric oxide (NO) and COX-2 are the key targets of honokiol in the inhibition of breast cancercell migration, an essential step in invasion and metastasis. (Singh & Katiyar 2011)
Parthenolide (Weng et al 2009)
Amla (Indian Gooseberry) (Br J Nutr 2007)
Cinnamon (Food Chem Toxicol 2007)
Curcumin (Adv Exp Med Biol 2007) (Ajaikumar 2008)
Resveratrol (Leuk Res 2004)
Scutellaria baicalensis extract – has strong anti-inflammatory properties by inhibition of iNOS, COX-2, PGE2, IL-1beta, IL-2, IL-6, IL-12 and TNF-alpha expression in animal cells. (Kim et al 2009)
Pterostilbene – inhibits MMP-9 – (Pan et al 2009)
Salvia miltiorrhiza – downregulates MMP-2 (Huang et al 2009)
Turmeric – curcuminoids – 95% (Ajaikumar 2008) 
Ursolic Acid (Holy Basil) 2-3% – (Huang et al 2008) – downregulates MMP-9 expression
Vitamin D3 – reduced the expression of MMP-2 and MMP-9 in metastatic lung carcinoma. (Nakagawa et al 2005)
Chinese skullcap (Scutellaria) (Piao et al 2008) (Peng et al 2008)
Curcumin – (Rafiee et al 2010) (Kamat et al 2009) 
DIM – significantly inhibited Akt activation, NF-kappaB DNA binding activity and PSA targeting multiple pathways involved in prostate cancer. (Bhuiyan et al 2006) (Banerjee et al 2009)
Diosgenin – in fenugreek seeds – inhibits NF-kappaB activity (Wargovich et al 2010)
Ginger treatment resulted in inhibition of NF-kB activation as well as diminished secretion of VEGF and IL-8 in ovarian cancer cells. (Rhode et al 2007)Carnosic acid, carnosol and ursolic acid (Phenolic diterpene compounds from rosemary and sage.) 
Curcumin (Ajaikumar 2008) 
EGCG 
Andrographolide (J. Immunol 2004)
ITCs downregulate TNFα (Nitric Oxide 2007)
Scutellaria baicalensis extract – has strong anti-inflammatory properties by inhibition of iNOS, COX-2, PGE2, IL-1beta, IL-2, IL-6, IL-12 and TNF-alpha expression in animal cells. (Kim et al 2009)

Andrographis – increases glutathione.  It is also liver protective against oxidative damage in the liver.  Andrographolide was found to be even more potent than silymarin. (Visen et al 1993) 

Milk thistle (Silymarin) – spares glutathione degradation. Milk Thistle has also demonstrated an ability to replenish glutathione levels. (Lucena 2002)  Milk Thistle binds tightly to the receptors of liver cell membranes that allow toxins in thus locking them out.

NAC (N-acetyl cysteine) – increases the level of glutathione produced in the body. (NAC) is the most bioavailable precursor of glutathione.  NAC helps with natural chelation.  

Spinach, kale, asparagus, broccoli, avocado and parsley – are rich in constituents which form glutathione precursors. Raw eggs, garlic and fresh unprocessed meats contain high levels of sulfur-containing amino acids and help to maintain optimal glutathione levels.

Whey protein has been shown to increase glutathione content within the cell
Following a stroke there is a need for blood moving plants – both general and specific plant extracts – that specifically target the brain.  
There is also a need for nourishing and building (adaptogenic and anabolic) herbs and nutrients – in order to nourish and rebuild the damaged nerve cells, tissues and blood vessels.  
Essential fatty acids are necessary to help in the restoration of nerve function, and enzymes are necessary in order to dissolve clots.  
We also need to target any blood work abnormalities that may be revealed in the blood work such as fibrinogen and d-dimer (blood clotting pathways) homocysteine, ADMA, C-reactive protein (CRP), etc.

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Compassionate Acupuncture and Healing Arts, providing craniosacral acupuncture, herbal and nutritional medicine in Durham, North Carolina. Phone number 919-475-1005.