Ursolic Acid Ameliorates Inflammation in Cerebral Ischemia and Reperfusion Injury Possibly via High Mobility Group Box 1/Toll-Like Receptor 4/NFκB Pathway

WHOM do we talk to to get this tested in humans? 

How do you get ursolic acid?

Ursolic acid is available over the counter as a supplement. It is also present in food, such as apple peel, cranberry juice, grape skin, holy basil, rosemary, thyme, oregano, sage, and other herbs. Rosemary and sage have the highest content of ursolic acid, 3.0% and 1.8%, respectively.

Grape skin; good, that means your doctor should be prescribing red wine.

Don't do this! I'm not medically trained and thus know nothing. Nothing here suggests it travels thru the digestive system unchanged and is useful afterwards.

 

Ursolic Acid Ameliorates Inflammation in Cerebral Ischemia and Reperfusion Injury Possibly via High Mobility Group Box 1/Toll-Like Receptor 4/NFκB Pathway

Yanzhe Wang, Lei Li, Shumin Deng, Fang Liu and Zhiyi He*

• Department of Neurology, The First Affiliated Hospital of China Medical University, Shenyang, China

Toll-like receptors (TLRs) play key roles in cerebral ischemia and reperfusion injury by inducing the production of inflammatory mediators, such as interleukins (ILs) and tumor necrosis factor-alpha (TNF-α). According to recent studies, ursolic acid (UA) regulates TLR signaling and exhibits notable anti-inflammatory properties. In the present study, we explored the mechanism by which UA regulates inflammation in the rat middle cerebral artery occlusion and reperfusion (MCAO/R) model. The MCAO/R model was induced in male Sprague–Dawley rats (MCAO for 2 h, followed by reperfusion for 48 h). UA was administered intragastrically(not orally) at 0.5, 24, and 47 h after reperfusion. The direct high mobility group box 1 (HMGB1) inhibitor glycyrrhizin (GL) was injected intravenously after 0.5 h of ischemia as a positive control. The degree of brain damage was estimated using the neurological deficit score, infarct volume, histopathological changes, and neuronal apoptosis. We assessed IL-1β, TNF-α, and IL-6 levels to evaluate post-ischemic inflammation. HMGB1 and TLR4 expression and phosphorylation of nuclear factor kappa-light-chain-enhancer of activated B cell (NFκB) were also examined to explore the underlying mechanism. UA (10 and 20 mg/kg) treatment significantly decreased the neurological deficit scores, infarct volume, apoptotic cells, and IL-1β, TNF-α, and IL-6 concentrations. The infarct area ratio was reduced by (33.07 ± 1.74), (27.05 ± 1.13), (27.49 ± 1.87), and (39.74 ± 2.14)% in the 10 and 20 mg/kg UA, GL, and control groups, respectively. Furthermore, UA (10 and 20 mg/kg) treatment significantly decreased HMGB1 release and the TLR4 level and inactivated NFκB signaling. Thus, the effects of intragastric administration of 20 mg/kg of UA and 10 mg/kg of GL were similar. We provide novel evidence that UA reduces inflammatory cytokine production to protect the brain from cerebral ischemia and reperfusion injury possibly through the HMGB1/TLR4/NFκB signaling pathway.

Introduction and Background

Ischemic stroke, which occurs as a result of the sudden occlusion of a blood vessel by a thrombus or embolism, is a common cause of death and disability worldwide (1). Currently, thrombolysis therapy within the therapeutic window and mechanical thrombectomy in stroke patients are widely accepted for the treatment of sudden cerebral ischemia (2, 3). However, an inflammatory response has been shown to occur after thrombolysis, exacerbating the reperfusion injury (4–6). Therefore, studies aiming to identify an effective adjunct to treatments for cerebral ischemia and reperfusion injury deserve more attention.

Toll-like receptor 4 (TLR4) plays a key role in cerebral ischemia and reperfusion injury by inducing the production of inflammatory mediators, such as interleukins (ILs) and tumor necrosis factor-alpha (TNF-α) (7, 8). TLR4 were initially identified as receptors for endogenous ligands known as damage-associated molecular patterns (DAMPs), particularly high mobility group box 1 (HMGB1), during brain injury. HMGB1 is a ubiquitous DNA-binding nuclear protein that is either passively released from necrotic cells or actively secreted in response to inflammatory signals (9, 10). In addition, overactive microglia and reactive astrocytes in the ischemic region can aggravate ischemic damage after activation of the TLR4 signaling pathways (11). Therefore, strategies that modulate post-ischemic TLR4 signaling in the brain may suppress inflammation induced by cerebral ischemia and provide new therapies for stroke.

Ursolic acid (UA: 3b-hydroxy-urs-12-ene-28-oic acid), a natural pentacyclic triterpenoid, has been reported to exhibit biological activities in the brain, including anti-oxidative, anti-tumor, anti-rheumatic, anti-viral, and anti-inflammatory effects (12). Furthermore, UA also inhibited microglial and astrocyte activation and decreased the levels of TNF-α, IL-1β, and IL-6 in lipopolysaccharide-induced brain inflammation in mice with cognitive deficits (13). However, researchers have not determined whether UA protects against ischemia and reperfusion injury by antagonizing the HMGB1/TLR4 signaling pathway. In this study, we used glycyrrhizin (GL) as a positive control drug. GL is a direct HMGB1 inhibitor and the effective dose for treating cerebral ischemia and reperfusion injury has been established (14).

In the present study, we used the rat middle cerebral artery occlusion and reperfusion (MCAO/R) model with UA and GL to examine the mechanism by which UA regulates the inflammation response induced by ischemia and reperfusion. We investigated whether UA reduced inflammatory cytokine production to protect the brain from cerebral ischemia and reperfusion injury possibly though the HMGB1/TLR4/NFκB signaling pathway.

More at link.

The Delta-Subunit Selective GABAA Receptor Modulator, DS2, Improves Stroke Recovery via an Anti-inflammatory Mechanism

I guess you are just going to have to wait until human followup is done. Maybe 50 years from now unless WE destroy the existing stroke associations and run them like the Michael J. Fox Foundation which is dedicated to finding a cure for Parkinson's disease. 

The Delta-Subunit Selective GABA_A Receptor Modulator, DS2, Improves Stroke Recovery via an Anti-inflammatory Mechanism

Silke Neumann^1,2†, Lily Boothman-Burrell^2†, Emma K. Gowing², Thomas A. Jacobsen³, Philip K. Ahring⁴, Sarah L. Young¹, Karin Sandager-Nielsen³ and Andrew N. Clarkson^2*

• ¹Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
• ²Department of Anatomy, Brain Health Research Centre, Brain Research New Zealand, University of Otago, Dunedin, New Zealand
• ³Saniona A/S, Copenhagen, Denmark
• ⁴School of Pharmacy, University of Sydney, Sydney, NSW, Australia

Inflammatory processes are known to contribute to tissue damage in the central nervous system (CNS) across a broad range of neurological conditions, including stroke. Gamma amino butyric acid (GABA), the main inhibitory neurotransmitter in the CNS, has been implicated in modulating peripheral immune responses by acting on GABA_A receptors on antigen-presenting cells and lymphocytes. Here, we investigated the effects and mechanism of action of the delta-selective compound, DS2, to improve stroke recovery and modulate inflammation. We report a decrease in nuclear factor (NF)-κB activation in innate immune cells over a concentration range in vitro. Following a photochemically induced motor cortex stroke, treatment with DS2 at 0.1 mg/kg from 1 h post-stroke significantly decreased circulating tumor necrosis factor (TNF)-α, interleukin (IL)-17, and IL-6 levels, reduced infarct size and improved motor function in mice. Free brain concentrations of DS2 were found to be lower than needed for robust modulation of central GABA_A receptors and were not affected by the presence and absence of elacridar, an inhibitor of both P-glycoprotein and breast cancer resistance protein (BCRP). Finally, as DS2 appears to dampen peripheral immune activation and only shows limited brain exposure, we assessed the role of DS2 to promote functional recovery after stroke when administered from 3-days after the stroke. Treatment with DS2 from 3-days post-stroke improved motor function on the grid-walking, but not on the cylinder task. These data highlight the need to further develop subunit-selective compounds to better understand change in GABA receptor signaling pathways both centrally and peripherally. Importantly, we show that GABA compounds such as DS2 that only shows limited brain exposure can still afford significant protection and promote functional recovery most likely via modulation of peripheral immune cells and could be given as an adjunct treatment.

Introduction

Stroke is the leading cause of lasting disability, with patients experiencing varied levels of functional recovery, and with more than 50% of survivors being discharged into care (Dobkin, 2008; Go et al., 2014). Changes in neuronal excitability, loss of gamma amino butyric acid (GABA) inhibition, enhanced glutamatergic signaling, and changes in neuronal connections and plasticity all contribute to impairment after stroke (Wittenberg and Schaechter, 2009; Clarkson et al., 2010, 2011, 2015, 2019; Carmichael, 2012; Krakauer et al., 2012). In addition, it is well documented that the full expansion of the infarction and ongoing impairment in the weeks to months following a stroke is underpinned by inflammation and the infiltration of peripheral immune cells that cross the blood–brain-barrier (BBB) (Gelderblom et al., 2009, 2015; Doyle et al., 2015). To date, drug therapies have attempted to minimize the extent of cell death, however, all drug therapies that have been trialled have failed to translate into the clinic. Therefore, new drug therapies need to be developed in order to support the recovery of stroke patients.

Changes in inflammatory processes is a hallmark for many pathologies including obesity, diabetes and stroke. Although acute inflammation is beneficial for the repairing and healing process, chronic inflammation contributes to tissue damage. Immune cells play a critical role in contributing to brain damage initiated by ischemic stroke. As a consequence of stroke, immune cells migrate to the brain in response to danger signals (damage-associated molecular patterns, DAMPs), in an effort to repair the damage (Brait et al., 2010; Gelderblom et al., 2015). However, these cells can also promote further inflammation and damage. In addition, the injured brain has an immune-suppressive effect that promotes life-threating infections, which threaten the survival of stroke patients (Liesz et al., 2015).

Traditionally considered a disease refined to the brain, it is becoming increasingly clear that the immune system heavily impacts the pathology of stroke. Local microglia, endothelial cells, neurons, and astrocytes recognize danger signals released from dying cells, which in turn stimulate the production of pro-inflammatory cytokines that attract circulating immune cells to migrate to the central nervous system (Offner et al., 2006; Gelderblom et al., 2009). Together, local and infiltrating cells, contribute to further neural cell death by producing pro-inflammatory cytokines, reactive oxygen species and by activating matrix metalloproteinases (Amantea et al., 2015). In particular, microglia have been shown to be chronically activated even when the initial DAMPs have been cleared (Huh et al., 2003; McGeer et al., 2003). This results in prolonged neuroinflammation that is associated with delayed recovery in stroke patients (Liguz-Lecznar and Kossut, 2013), and impaired memory, sensory learning and plasticity (Greifzu et al., 2011; Doyle et al., 2015).

Gamma amino butyric acid, known for its role as inhibitory neurotransmitter in the CNS, has a similar inhibiting effect on immune cells thereby creating a link between the CNS and the peripheral inflammatory response (Reyes-Garcia et al., 2007). Both, innate and adaptive immune cells express functional GABA receptors and possess enzymes to synthesize and catabolize GABA (Wheeler et al., 2011; Fuks et al., 2012). This includes microglia, macrophages, dendritic cells and T-cells. GABA signals through GABA_A and GABA_B receptors, both of which are expressed on immune cells (Kuhn et al., 2004; Wheeler et al., 2011; Fuks et al., 2012). The composition of the five subunits that make up GABA_A receptors likely varies for the various immune cells, which in turn will account for differences in potency and efficacy of drug treatments targeting GABA receptors and GABA itself (Fuks et al., 2012). GABA is known to act on GABA_A receptors in both millimolar and nanomolar to micromolar concentrations depending on the location (synaptic versus extrasynaptic) and functional composition of the receptors (Mody, 2001; Semyanov et al., 2003; Glykys and Mody, 2007). Of importance, submicromolar GABA concentrations have not only been found around neurons in the brain, but have also been detected in blood and hormone-producing cells in the intestine (Petty et al., 1999; Braun et al., 2004; Wendt et al., 2004). In addition to being exposed to chronic low levels of GABA, these peripheral tissues and receptors are likely to also be modulated following treatment with various GABA modulators. With the development of subunit specific GABA modulators, we may be able to find and develop compounds that could selectively regulate the function of peripheral immune cells.

Extrasynaptic GABA_A receptors, which are located outside the synapse typically contain either the δ- or α5-subunit and are highly sensitive to low GABA concentrations (Mody, 2001). Recent evidence has shown that modulation of extrasynaptic GABA_A receptors plays an important role in minimizing the extent of damage when given early (within hours) to increase tonic GABA currents after a stroke. In addition, this modulation can also facilitate an improvement in motor function when treatment is initiated at a delay (days) to dampen tonic GABA currents after the initial insult (Clarkson et al., 2010, 2019). As little is known about the role of δ-containing GABA_A receptor after stroke, we were interested in testing the therapeutic effects of the δ-subunit-selective GABA_A receptor modulator DS2 (4-chloro-N-[2-(2-thienyl)imidazo[1,2-a]pyridin-3-yl]benzamide). DS2 positively modulates δ-containing GABA_A receptors (Wafford et al., 2009), however, DS2 has not been investigated in a clinical disease model. Therefore, we aimed to assess the potential of DS2 to improve stroke recovery and to modulate inflammatory responses in innate immune cells. Herein, we show that positive allosteric modulation of δ-containing GABA_A receptors with DS2 affords significant protection and improves motor function in a mouse model of stroke. Investigation into a potential mechanism of action revealed that DS2 reduces the activation of NF-κB in LPS-stimulated macrophages and reduces the expression of activation markers on bone marrow-derived dendritic cells (BMDCs). Interestingly, we show that DS2 only has limited brain exposure, indicating that DS2-mediated effects in vivo are most likely attributed to modulation of peripheral immune cells.

More at link. 

Anti-inflammatory psoriasis agents could prevent heart disease

Ask your doctor if this treatment could vastly reduce your chances of getting another stroke or heart attack.
What other treatments does your doctor have you on to reduce atherosclerosis? Any of these? Or is your doctor not treating your vascular inflammation at all?

VIP-U: Psoriasis treatment reduces vascular inflammation Feb. 2018

 

Researchers develop new biomedical polymer to treat atherosclerosis May 2017 

 

Vitamin D and cardiovascular disease: From atherosclerosis to myocardial infarction and stroke Jan. 2017 

 

Watermelon juice reverses hardening of the arteries Nov. 2011 

 

New study shows aged garlic extract can reduce dangerous plaque buildup in arteries  Jan. 2016 

The latest here:

 

Anti-inflammatory psoriasis agents could prevent heart disease

Elnabawi YA, et al. Cardiovasc Res. 2019;doi:10.1093/cvr/cvz009.

February 5, 2019

Anti-inflammatory biologic therapy for treatment of severe psoriasis reduced coronary artery plaque, raising questions about whether such agents could have a role in prevention of CHD, researchers reported in Cardiovascular Research.
“Classically a heart attack is caused by one of five risk factors: diabetes, hypertension, high cholesterol, family history or smoking,” Nehal N. Mehta, MD, chief of inflammation and cardiometabolic diseases at the NHLBI, said in a press release from the NIH. “Our study presents evidence that there is a sixth factor, inflammation; and that it is critical to both the development and the progression of atherosclerosis to heart attack.”

Mehta and colleagues conducted a prospective observational study of 121 patients with moderate to severe psoriasis and low risk for CVD (mean age, 51 years; 58% men; median Framingham risk score, 3), who completed 1-year follow-up and had not had biologic treatment at baseline. During the study period, 89 patients were treated with biologic therapy.
All patients underwent coronary CTA at baseline and 1 year to quantify total plaque coronary burden and plaque subcomponents in three coronary vessels of at least 2 mm in diameter.
According to the researchers, biologic therapy was associated with reductions in noncalcified plaque burden (6%; P = .005) and necrotic core (57%; P = .03), but not in fibrous burden (P = .71).
Compared with patients who were not treated with biologics, those who were had a greater decrease in noncalcified plaque burden (–0.07 mm² vs. 0.06 mm²; P = .02), which persisted after adjustment for traditional CV risk factors (beta = 0.2; P = .02), Mehta and colleagues wrote.
The group treated with biologics had a reduction in C-reactive protein at 1 year (P < .001), but the untreated group did not (P = .21).
The treatment effect was greatest in patients treated with , according to the researchers.
“We found that these anti-inflammatory drugs commonly used to treat severe psoriasis also improve plaque in the coronary artery, making them more stable and less likely to cause a heart attack. This occurred in the absence of changes in traditional cardiovascular risk factors including blood pressure and blood lipids,” Mehta said in a press release from the European Society of Cardiology. “This preliminary study provides the first evidence that biologic therapy is associated with coronary plaque reduction and stabilization, and provides strong rationale for conduct of a randomized trial testing the impact of biologic therapy on the progression of coronary disease in patients with psoriasis.” – by Erik Swain
Disclosures: Mehta reports he received research grants to his employer, the NHLBI, from AbbVie, Celgene, Janssen and Novartis. Please see the study for all other authors’ relevant financial disclosures.

New drug beats heart disease by reducing inflammation

How much would this help in preventing stroke?
Hopefully you can use this off-label.  They would rather pay for your heart attack or stroke.  
http://www.foxnews.com/health/2017/09/27/new-drug-beats-heart-disease-by-reducing-inflammation.html
By Dr. Manny Alvarez, Fox News

About every 40 seconds, an American has a heart attack, and almost 15 percent of those heart attacks are fatal. As the leading cause of death in the U.S., heart disease has been the subject of thousands of studies in the last several decades, and breakthroughs in the last 50 years have been significant.

First, diet, exercise, and smoking cessation were all proven to play an enormous role in heart health, helping physicians guide patients to less risky lifestyle choices.

Then, in the 1980s, the first commercial statin was approved by the FDA, ushering in an era in which medication could be used alongside lifestyle changes to lower cholesterol levels, potentially reducing heart attack risk by over a third for some high risk patients.
STDS HIT RECORD HIGH IN US, 2M CASES REPORTED IN 2016
Despite these gains and the fact that statins are one of the most frequently prescribed drugs, heart disease is still the number one killer of Americans, but researchers are excited about the results of a study published last month in the New England Journal of Medicine that investigates the impact of a new drug on cardiovascular risk.
The trial is the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), and the drug, called Canakinumab, may be able to bring heart attack risk to an all-time low by targeting inflammation.
This study is the first in which a systemic anti-inflammatory, a drug that reduces inflammation throughout the body, has been shown to lower heart attack risk independent of cholesterol-lowering medications.
The purpose of the trial was to see whether reducing inflammation could reduce the risk of recurring cardiovascular events among people who had already had a heart attack and who had elevated levels of high sensitivity C-reactive protein (hsCRP), an indication of systemic inflammation.
The study was the culmination of more than 25 years of research. By treating all patients in the trial with standard care (high doses of statins) and then dividing them into groups that would receive either 50, 150, or 300 mg of Canakinumab (or a placebo), the researchers were able to accurately assess the impact of the new drug. More than 10,000 patients took part in the trial, some of whom were monitored for up to four years.

The results showed a 15 percent reduction in heart attacks and strokes for patients taking either 150 or 300 mg of the of Canakinumab, proving for the first time that inflammation plays a role in heart disease risk independent of cholesterol levels.
This discovery may change therapeutic practice for patients at high risk of heart attack or stroke. More studies are underway to establish the best strategies for using Canakinumab – which patients benefit most and how the drug can be used in combination with other therapies.
“These findings represent the end game of more than two decades of research, stemming from a critical observation: Half of heart attacks occur in people who do not have high cholesterol," Paul M. Ridker, M.D., the study's lead author, said. "For the first time, we’ve been able to definitively show that lowering inflammation independent of cholesterol reduces cardiovascular risk. This has far-reaching implications. It tells us that by leveraging an entirely new way to treat patients — targeting inflammation — we may be able to significantly improve outcomes for certain very high-risk populations.”
The need for invasive and expensive interventions, like bypass surgery and angioplasty, were reduced by more than 30 percent in patients taking Canakinumab, a far greater reduction than is usually found with the use of statins alone.

Study: Omega-3 fatty acids fight inflammation via cannabinoids

Since your doctor will never prescribe marijuana no matter how much it helps you, you could go down this secondary route.
So ask your doctor specifically how much omega-3 you need to consume to get these anti-inflammation properties.
https://www.mdlinx.com/internal-medicine/medical-news-article/2017/07/20/omega-3-fatty-acids-inflammation-cannabinoids/7240860/?

University of Illinois Urbana-Champaign Health News

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Chemical compounds called cannabinoids are found in marijuana and also are produced naturally in the body from omega–3 fatty acids. A well–known cannabinoid in marijuana, tetrahydrocannabinol, is responsible for some of its euphoric effects, but it also has anti–inflammatory benefits. A new study in animal tissue reveals the cascade of chemical reactions that convert omega–3 fatty acids into cannabinoids that have anti–inflammatory benefits – but without the psychotropic high.

The findings were published in the Proceedings of the National Academy of Sciences journal.

Foods such as meat, eggs, fish and nuts contain omega–3 and omega–6 fatty acids, which the body converts into endocannabinoids – cannabinoids that the body produces naturally, said Aditi Das, a University of Illinois professor of comparative biosciences and biochemistry, who led the study. Cannabinoids in marijuana and endocannabinoids produced in the body can support the body’s immune system and therefore are attractive targets for the development of anti–inflammatory therapeutics, she said. In 1964, the Israeli chemist Raphael Mechoulam was the first to discover and isolate THC from marijuana. To test whether he had found the compound that produces euphoria, he dosed cake slices with 10 milligrams of pure THC and gave them to willing friends at a party. Their reactions, from nonstop laughter, to lethargy, to talkativeness, confirmed that THC was a psychotropic cannabinoid.

It wasn’t until 1992 that researchers discovered endocannabinoids produced naturally in the body. Since then, several other endocannabinoids have been identified, but not all have known functions.

Cannabinoids bind to two types of cannabinoid receptors in the body – one that is found predominantly in the nervous system and one in the immune system, Das said. “Some cannabinoids, such as THC in marijuana or endocannabinoids can bind to these receptors and elicit anti–inflammatory and anti–pain action,” she said.

“Our team discovered an enzymatic pathway that converts omega–3–derived endocannabinoids into more potent anti–inflammatory molecules that predominantly bind to the receptors found in the immune system,” Das said. “This finding demonstrates how omega–3 fatty acids can produce some of the same medicinal qualities as marijuana, but without a psychotropic effect.”

The study was an interdisciplinary effort led by recent comparative biosciences alumnus Daniel McDougle and supported by current biochemistry graduate student Josephine Watson. The team included U. of I. animal sciences professor Rodney Johnson; U. of I. bioengineering professor Kristopher Kilian; Michael Holinstat, of the University of Michigan; and Lucas Li, the director of the Metabolomics Center at the Roy J. Carver Biotechnology Center at Illinois.

Targeting nitric oxide to treat aneurysm

Since nitric oxide is pretty good for you you'll have to have your doctor get the protocol for administering it.

76 posts on nitric oxide for blood pressure and anti-inflammation.

http://science.sciencemag.org/content/355/6324/491.3?utm_campaign=ec_sci_2017-02-02&et_rid=17139052&et_cid=1140907

1. Priscilla Kelly

Science  03 Feb 2017:
Vol. 355, Issue 6324, pp. 491-492
DOI: 10.1126/science.355.6324.491-c

• Article
• Figures & Data
• Info & Metrics
• eLetters
• PDF

Could nitric oxide inhibitors help prevent cardiac aneurysm?

PHOTO: SUSUMU NISHINAGA/SCIENCE SOURCE

Aneurysms are the abnormal enlargement of arteries and can lead to death if the artery wall bursts. Oller et al. studied patients with Marfan syndrome, an inherited genetic condition in which individuals are prone to cardiac aneurysms. They discovered lower levels of ADAMTS1 in the heart tissue of Marfan syndrome patients compared with that of organ transplant donors. Genetic inactivation of ADAMTS1 in mice resulted in a Marfan syndrome-like disease, which included low blood pressure, aortic dilation, and aneurysm development. These effects were driven by enhanced activity of nitric oxide, and treatment with a nitric oxide inhibitor reduced blood vessel size and reversed the clinical signs of aneurysm formation.

Nat. Med. 10.1038/nm.4266 (2017).

Stroke treatment: Miracle drug limits brain damage and promotes repair

Dr. Heather is late, this came out Nov. 25, 2016.
I bet our fucking failures of stroke associations won't lead the charge to get this into general use. In fact I bet they do absolutely nothing. I wonder if they know which of these 5 causes of neuronal cascade of death this intervention ameliorates? Or was this just pure luck rather than following any sort of strategy?
http://www.medicnewsweb.com/stroke-treatment/
By Dr. Heather on January 18, 2017 

Researchers at The University of Manchester have discovered that a potential new drug for stroke treatment reduces the number of brain cells destroyed by stroke and then helps to repair the damage.A reduction in blood flow to the brain caused by stroke is a major cause of death and disability, and there are few effective treatments.A team of scientists at The University of Manchester has now found that a potential new stroke drug not only works in rodents by limiting the death of existing brain cells but also by promoting the birth of new neurons (so-called neurogenesis).

This finding provides further support for the development of this anti-inflammatory drug, interleukin-1 receptor antagonist (IL-1Ra in short), as a new stroke treatment. The drug is already licensed for use in humans for some conditions, including rheumatoid arthritis. Several early stage clinical trials in stroke with IL-1Ra have already been completed in Manchester, though it is not yet licensed for this condition.In the research, published in the biomedical journal Brain, Behavior and Immunity, the researchers show that in rodents with a stroke there is not only reduced brain damage early on after the stroke, but several days later increased numbers of new neurons, when treated with the anti-inflammatory drug IL-1Ra.Previous attempts to find a drug to prevent brain damage after stroke have proved unsuccessful and this new research offers the possibility of a new treatment.Importantly, the use of IL-1Ra might be better than other failed drugs in stroke as it not only limits the initial damage to brain cells, but also helps the brain repair itself long-term through the generation of new brain cells.

These new cells are thought to help restore function to areas of the brain damaged by the stroke. Earlier work by the same group showed that stroke treatment with IL-1Ra does indeed help rodents regain motor skills that were initially lost after a stroke. Early stage clinical trials in stroke patients also suggest that IL-1Ra could be beneficial.The current research is led by Professor Stuart Allan, who commented: “The results lend further strong support to the use of IL-1Ra in the stroke treatment, however further large trials are necessary.”

New drug limits and then repairs brain damage in stroke

I bet our fucking failures of stroke associations won't lead the charge to get this into general use. In fact I bet they do absolutely nothing. I wonder if they know which of these 5 causes of neuronal cascade of death this intervention ameliorates? Or was this just pure luck rather than following any sort of strategy?
http://medicalxpress.com/news/2016-11-drug-limits-brain.html
Researchers at The University of Manchester have discovered that a potential new drug reduces the number of brain cells destroyed by stroke and then helps to repair the damage.

A reduction in blood flow to the brain caused by stroke is a major cause of death and disability, and there are few effective treatments.
A team of scientists at The University of Manchester has now found that a potential new stroke drug not only works in rodents by limiting the death of existing brain cells but also by promoting the birth of new neurones (so-called neurogenesis).
This finding provides further support for the development of this anti-inflammatory drug, interleukin-1 receptor antagonist (IL-1Ra in short), as a new treatment for stroke. The drug is already licensed for use in humans for some conditions, including rheumatoid arthritis. Several early stage clinical trials in stroke with IL-1Ra have already been completed in Manchester, though it is not yet licensed for this condition.
In the research, published in the biomedical journal Brain, Behavior and Immunity, the researchers show that in rodents with a stroke there is not only reduced brain damage early on after the stroke, but several days later increased numbers of new neurones, when treated with the anti-inflammatory drug IL-1Ra.
Previous attempts to find a drug to prevent brain damage after stroke have proved unsuccessful and this new research offers the possibility of a new treatment.
Importantly, the use of IL-1Ra might be better than other failed drugs in stroke as it not only limits the initial damage to brain cells, but also helps the brain repair itself long-term through the generation of new brain cells.
These new cells are thought to help restore function to areas of the brain damaged by the stroke. Earlier work by the same group showed that treatment with IL-1Ra does indeed help rodents regain motor skills that were initially lost after a stroke. Early stage clinical trials in stroke patients also suggest that IL-1Ra could be beneficial.
The current research is led by Professor Stuart Allan, who commented: "The results lend further strong support to the use of IL-1Ra in the treatment of stroke, however further large trials are necessary."
The paper, 'Reparative effects of interleukin-1 receptor antagonist in young and aged/co-morbid rodents after cerebral ischemia', was published in the journal Brain, Behavior and Immunity.

Explore further: Outcome of stroke worse for people with infection

More information: Jesus.M. Pradillo et al, Reparative Effects of Interleukin-1 Receptor Antagonist in Young And Aged/Co-Morbid Rodents After Cerebral Ischemia, Brain, Behavior, and Immunity (2016). DOI: 10.1016/j.bbi.2016.11.013

Journal reference: Brain, Behavior, and Immunity
Provided by: University of Manchester

Resolvins, generated naturally from fish oil, show promise as anti-inflammation treatment

Would this also prevent the inflammation in our arteries? Stop the need for statin treatment?

Resolvins, generated naturally from fish oil, show promise as anti-inflammation treatment

Roswell Park Cancer Institute News

Excessive inflammation contributes to a variety of diseases, including cancer. The class of molecules known as resolvins appears to modify disease progression by decreasing inflammation, offering a potential therapeutic option, according to a recent review article published in the World Journal of Clinical Cases and co–authored by Kazuaki Takabe, MD, PhD, FACS, Clinical Chief of Breast Surgery at Roswell Park Cancer Institute. Resolvins are produced when the body metabolizes omega–3 fatty acids, which are found naturally in fish oil and vegetable oil. The scientists examined a number of studies evaluating the role of these molecules in reducing acute and chronic inflammation, which has been associated with diseases including gastroenteritis, hepatitis, diabetes, neurological diseases and cancer. “Resolvins have been shown to play a central anti–inflammatory role, and may have the clinical potential to slow the progression of diseases related to inflammation, including cancer,” says Dr. Takabe. “Currently, there are only a small number of studies that investigate the correlation between resolvins and cancer in humans. Given their unique function with minimal side effects, resolvins could represent a new class of anti–inflammatory drugs.” The authors note that further study will be required in order to develop therapies that take advantage of this anti–inflammatory capability of resolvins.

Systems Biology of Immunomodulation for Post-stroke Neuroplasticity: Multimodal Implications of Pharmacotherapy and Neurorehabilitation

It would seem that this should have been broken into multiple trials. Putting anti-inflammation drugs, tDCS, and rTMS into the same trial  is a recipe for not knowing which intervention did what.  A good mentor would have known that and changed the trial appropriately.
http://journal.frontiersin.org/article/10.3389/fneur.2016.00094/abstract

Mohammed A. Alam¹, V.P. S. Rallabandi¹ and Prasun K. Roy^1*

• ¹National Brain Research Centre, India

AIMS: Recent studies indicate that anti-inflammatory drugs, act as a double-edged sword, not only exacerbating secondary brain injury but also contributing to neurological recovery after stroke. Our aim is to explore whether there is a beneficial role for neuroprotection and functional recovery using antiinflammatory drug along with neurorehabilitation therapy using transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS), so as to improve functional recovery after ischemic stroke.
METHODS: We develop a computational systems biology approach from preclinical data using ordinary differential equations, to study the behavior of both phenotypes of microglia such as M1 type (pro-inflammatory) vis-à-vis M2 type (anti-inflammatory) under anti-inflammatory drug action (minocycline). We explore whether pharmacological treatment along with cerebral stimulation using tDCS and rTMS is beneficial or not. We utilize the systems pathway analysis of minocycline in NF-κB (nuclear factor kappa beta) signaling and neurorehabilitation therapy using tDCS and rTMS which act through brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) signaling pathways.
RESULTS: We demarcate the role of neuroinflammation and immunomodulation in post-stroke recovery, under minocycline activated microglia and neuroprotection together with improved neurogenesis, synaptogenesis and functional recovery under the action of rTMS or tDCS. We elucidate the feasibility of utilizing rTMS/tDCS to increase neuroprotection across the reperfusion stage during minocycline administration. We delineate that the signaling pathways of minocycline by modulation of inflammatory genes in NF-κB and proteins activated by tDCS and rTMS through BDNF, Trk-B and Calmodulin kinase (CaMK) signaling. Utilizing systems biology approach, we show the activation pathways for pharmacotherapy (minocycline) and neurorehabilitation (rTMS applied to ipsilesional cortex and tDCS) results into increased neuronal and synaptic activity that commonly occur through activation of N-methyl-D-aspartate (NMDA) receptors. We construe that considerable additive neuroprotection effect would be obtained and delayed reperfusion injury can be remedied, if one uses multimodal intervention of minocycline together with tDCS and rTMS.
CONCLUSION: Additive beneficial effect is thus noticed for pharmacotherapy along with neurorehabilitation therapy, by maneuvering the dynamics of immunomodulation using anti-inflammatory drug and cerebral stimulation for augmenting the functional recovery after stroke, which may engender clinical applicability for enhancing plasticity, rehabilitation and neurorestoration.

Keywords: Stroke, Neuroprotection, Rehabilitation, Minocycline, direct current stimulation, Transcranial magnetic stimulation.
Citation: Alam MA, Rallabandi VS and Roy PK (2016). Systems Biology of Immunomodulation for Post-stroke Neuroplasticity: Multimodal Implications of Pharmacotherapy and Neurorehabilitation. Front. Neurol. 7:94. doi: 10.3389/fneur.2016.00094

Received: 22 Jan 2016; Accepted: 07 Jun 2016.

Edited by:
Anirban Dutta, Leibniz-Institut für Arbeitsforschung an der TU Dortmund, Germany

Reviewed by:
Raju S. Bapi, University of Hyderabad, India
Mamta Naidu, GRI/ CCSB-Tufts Sch Med, USA  

Copyright: © 2016 Alam, Rallabandi and Roy. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Prof. Prasun K. Roy, National Brain Research Centre, NH-8, Nainwal Road, Manesar, Grgaon, 122051, Haryana, India, pkroy@nbrc.ac.in

Surgeons test stroke patients(SAH) drug based on chemical in broccoli

You had better hope your stroke hospital has been reading and applying research if you have a SAH.
http://www.dailymail.co.uk/wires/pa/article-3603931/Surgeons-test-stroke-patients-drug-based-chemical-broccoli.html
Surgeons are trialling a new drug based on a chemical found in broccoli to try to improve outcomes for stroke patients.
Diederik Bulters, a consultant neurosurgeon at Southampton General Hospital, and his team will assess the effect of experimental drug SFX-01 on patients who have received treatment for a bleed on the brain known as a subarachnoid haemorrhage (SAH), which is a type of stroke.
SFX-01 is a synthetic form of sulforaphane, a small molecule that occurs naturally in the vegetable and is part of a group of chemicals found in plants - phytochemicals - that are strong antioxidants and can help regulate some of the body's functions.

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Surgeons at Southampton General Hospital are testing a drug based on a chemical found in broccoli to try to improve outcomes for stroke patients

Mr Bulters said: "It is essential we work to improve outcomes for patients who have a subarachnoid haemorrhage as many of those who survive are left disabled and suffer long term cognitive and emotional problems, changing their lives forever.
"Despite the need, there have been no significant clinical developments since the introduction of nimodipine more than 20 years ago, so we are absolutely delighted to offer patients the opportunity to be involved with this exciting new treatment."
He added: "This is also a significant moment for me and the team as, having researched the potential benefits of sulforaphane in this patient group, we were frustrated that there was no practical way to administer it - until the development of SFX-01."
More than 6,000 people in England - mainly aged between 45 and 70 - are admitted to neuro-intensive care units with the condition every year.
Around half of all cases are fatal, while 50% of survivors suffer some long-term impairment such as epilepsy, brain dysfunction or emotional issues.
Initially, patients who develop SAH, which is normally caused by a weakness in the wall of a blood vessel that bursts open, undergo a surgical procedure to repair the bleed.
They then receive medication in the form of drug nimodipine to prevent common complication cerebral ischaemia, which restricts blood flow to the brain through narrowing of the arteries and commonly occurs in the first few days after a haemorrhage.
Nimodipine, which was successfully trialled at Southampton General Hospital in a landmark study published in 1989(27 years and I've only seen one mention of this anyplace), is currently the only drug proven to improve outcomes for patients who have suffered SAH. (Is this in a protocol at your hospital?)
SFX-01 will be taken in capsule form, either by mouth or nasogastric tube, in 300mg doses in combination with nimodipine during the trial, which will involve 90 patients over two years.
It is hoped the drug could help to prevent complications after SAH by improving blood flow to the brain.
Ardalan Zolnourian, a neurosurgical clinical research fellow and part of the study team, said: "SFX-01 contains a synthetic and stable version of sulforaphane, a known antioxidant and anti-inflammatory that was first discovered in broccoli.
"With SFX-01, we now have a reliable way of delivering what we hope will be an effective dose in a pharmaceutical formulation."
He added: "We hope that, when used in conjunction with current treatment nimodipine, it will further reduce the complications by reducing inflammation and improving blood flow."

Anti-inflammatory and antioxidant effects of a combination of cannabidiol and moringin in LPS-stimulated macrophages

A reference to TNF which still has to be determined if reducing TNF will help stroke patients.
Dr. Tobinick could have solved this TNF question years ago if he had only actually run clinical tests on etanercept.
http://www.sciencedirect.com/science/article/pii/S0367326X16301150

• Thangavelu Soundara Rajan^a,
• Sabrina Giacoppo^a,
• Renato Iori^b,
• Gina Rosalinda De Nicola^b,
• Gianpaolo Grassi^c,
• Federica Pollastro^d,
• Placido Bramanti^a,
• Emanuela Mazzon^{a, ,}

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doi:10.1016/j.fitote.2016.05.008

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Abstract

Inflammatory response plays an important role in the activation and progress of many debilitating diseases. Natural products, like cannabidiol, a constituent of Cannabis sativa, and moringin, an isothiocyanate obtained from myrosinase-mediated hydrolysis of the glucosinolate precursor glucomoringin present in Moringa oleifera seeds, are well known antioxidants also endowed with anti-inflammatory activity. This is due to a covalent-based mechanism for ITC, while non-covalent interactions underlie the activity of CBD. Since these two mechanisms are distinct, and the molecular endpoints are potentially complementary, we investigated in a comparative way the protective effect of these compounds alone or in combination on lipopolysaccharide-stimulated murine macrophages. Our results show that the cannabidiol (5 μM) and moringin (5 μM) combination outperformed the single constituents that, at this dosage had only a moderate efficacy on inflammatory (Tumor necrosis factor-α, Interleukin-10) and oxidative markers (inducible nitric oxide synthase, nuclear factor erythroid 2-related factor 2, nitrotyrosine). Significant upregulation of Bcl-2 and downregulation of Bax and cleaved caspase-3 was observed in cells treated with cannabidiol-moringin combination. Treatment with the transient receptor potential vanilloid receptor 1 antagonist was detrimental for the efficacy of cannabidiol, while no effect was elicited by cannabinoid receptor 1 and cannabinoid receptor 2 antagonists. None of these receptors was involved in the activity of moringin. Taken together, our in vitro results testify the anti-inflammatory, antioxidative, and anti-apoptotic effects of the combination of cannabidiol and moringin.