Semaglutide enhances cognitive abilities and reduces Alzheimer’s pathology in mice and human brain models

Is this something your competent? doctor can do off label for your post stroke dementia risk?

 Semaglutide is an antidiabetic medication used for the treatment of type 2 diabetes and an anti-obesity medication used for long-term weight management. It is a peptide similar to the hormone glucagon-like peptide-1, modified with a side chain. It can be administered by subcutaneous injection or taken orally.

Semaglutide enhances cognitive abilities and reduces Alzheimer’s pathology in mice and human brain models

Research shows that Semaglutide not only improves memory and learning in Alzheimer's models, but also reduces harmful plaques and proteins, while restoring the neuroprotective effects of oxytocin.Study: Semaglutide ameliorates Alzheimer's disease and restores oxytocin in APP/PS1 mice and human brain organoid models. Image Credit: Marko Aliaksandr / Shutterstock

In a recent study published in the journal Biomedicine & Pharmacotherapy, a group of researchers investigated the therapeutic effects of Semaglutide in Alzheimer's Disease (AD) and identified its molecular targets in both mouse and human brain organoid models.

Background

Semaglutide’s GLP-1 receptor agonist mechanism helps reduce inflammation and supports insulin production, a factor that might be relevant in addressing brain glucose metabolism dysregulation in Alzheimer’s.

AD is a global neurodegenerative disorder that primarily affects older adults, leading to cognitive decline, memory loss, and reduced functional abilities.

Despite significant advancements in research, there is currently no cure, and existing treatments only manage symptoms without halting disease progression. AD's prevalence is increasing with the aging population, making it a critical public health concern.

Recent research suggests that glucagon-like peptide-1 (GLP-1) receptor agonists, including Semaglutide, show neuroprotective potential in AD models by reducing inflammation, amyloid-beta (Aβ) accumulation, and tau hyperphosphorylation. These effects may be mediated through key pathways such as the PI3K/Akt/mTOR signaling pathway, which is involved in cellular survival and neuroprotection. Further research is needed to confirm their therapeutic efficacy in humans.

About the study

All animal experiments were conducted following the National Institutes of Health Guide for the Care and Use of Laboratory Animals in the study. Five-month-old male Amyloid Precursor Protein/Presenilin 1 (APP/PS1) transgenic mice, bred from Prion Protein Promoter-human Amyloid Precursor Protein with K595N and M596L mutations (PrP-hAPPK595N/M596L) and Prion Protein Promoter-human Presenilin 1 with a deletion of exon 9 (PrP-hPS1dE9) transgenic lines, were used. Age-matched wild-type (WT) C57BL/6J mice served as controls. The animals were housed under controlled conditions with a 12-hour light/dark cycle and had ad libitum access to food and water.

APP/PS1 mice were randomly divided into three groups: vehicle-treated, Donepezil-treated, and Semaglutide-treated. Donepezil was administered orally, while Semaglutide was given subcutaneously for six months. WT mice received double-distilled water as controls.

To evaluate cognitive function, the Morris water maze and Barnes maze tests were used. These tests measured learning and memory abilities with hidden platform trials and spatial memory assessments. Performance was recorded using video tracking systems.

Semaglutide also suppresses appetite and slows digestion, potentially reducing obesity-related risk factors that are increasingly linked to neurodegenerative conditions.

Other behavioral tests, such as nest-building behavior and active avoidance tests, were also performed to assess general cognitive and memory abilities.

Tissue samples from treated mice were collected for biochemical analysis, including protein and Ribonucleic Acid (RNA) assays. Statistical analyses were conducted using SPSS, and results were considered significant when P-values were less than 0.05.

Study results

Semaglutide was shown to improve learning ability and memory in APP/PS1 mice, which are known to exhibit cognitive decline and develop amyloid plaques by 6 months of age.

To assess the cognitive effects of Semaglutide, several behavioral tests were conducted on 6-month-old APP/PS1 mice after 3 and 6 months of treatment.

In the Barnes maze test, the untreated model mice took significantly longer to find the target box compared to WT mice, indicating cognitive impairment.

However, mice treated with Semaglutide or Donepezil showed improved performance, with shorter latencies to reach the target box, suggesting enhanced learning ability.

Similarly, in the Morris water maze test, the APP/PS1 model group displayed a longer latency to find the hidden platform, but Semaglutide-treated mice demonstrated faster performance, indicating improvements in spatial learning and memory.

Semaglutide-treated mice also demonstrated improvements in their daily functioning, as assessed by nest-building behavior. Mice treated with Semaglutide significantly outperformed untreated APP/PS1 mice in building nests, suggesting enhanced abilities in daily activities.

Despite these cognitive improvements, the memory performance during the retention phase of the Morris water maze test remained unchanged.

Semaglutide also reduced amyloid plaque burden and Tau protein levels in the brain tissues of APP/PS1 mice. Immunohistochemical analysis revealed that the untreated APP/PS1 mice had significantly larger amyloid plaques and higher levels of Aβ1–40 and Aβ1–42 proteins compared to WT mice.

Semaglutide treatment significantly decreased the amyloid plaque area and reduced the levels of both Aβ1–40 and Aβ1–42 in brain tissues.

Although Semaglutide reduced overall Tau protein levels, the study noted that phosphorylated Tau (p-Tau) levels remained unchanged in the hippocampus, indicating that the reduction may primarily affect total Tau levels. These findings suggest Semaglutide can reduce amyloid pathology and Tau accumulation in APP/PS1 mice.

Furthermore, Semaglutide was found to reduce neuroinflammation by decreasing the expression of the glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule 1 (Iba1) in brain tissues, markers of astrocyte and microglia activation, respectively. This indicates that Semaglutide attenuates the neuroinflammatory response associated with AD.

The researchers also measured the levels of BACE1, an enzyme involved in amyloid production, and found no significant changes in its serum concentration after treatment, indicating that Semaglutide's effects might not involve BACE1 modulation.

Lastly, RNA sequencing of hippocampal tissue from Semaglutide-treated mice revealed an upregulation of oxytocin (OXT) expression, which was significantly reduced in untreated APP/PS1 mice. This novel finding suggests that oxytocin may play a key role in the neuroprotective effects of Semaglutide and may interact with GLP-1 signaling pathways in the brain.

Conclusions

To summarize, behavioral analysis in mice demonstrated improved cognitive abilities, particularly in learning and memory. Biochemical assessments revealed a reduction in amyloid plaque deposition, modulation of Tau protein levels, and downregulation of GFAP and Iba1 in mouse brain tissues.

In human organoid models, Semaglutide increased OXT expression and reduced p-Tau, Aβ, and GFAP levels. These effects were found to be dose-dependent, with higher concentrations of Semaglutide yielding more pronounced reductions in AD markers. These findings suggest that Semaglutide may exert its neuroprotective effects through the GLP-1 receptor and OXT interaction, highlighting OXT’s potential as a therapeutic target for AD.

Journal reference:

• Yinbing Zhang, Cheng Tang, Yao He, et al. Semaglutide ameliorates Alzheimer's disease and restores oxytocin in APP/PS1 mice and human brain organoid models, Biomedicine & Pharmacotherapy (2024), DOI - 10.1016/j.biopha.2024.117540, https://www.sciencedirect.com/science/article/pii/S0753332224014264

SGLT2 Inhibitor Use Associated With Reduced Risk of Dementia, Parkinson Disease

 With your increased risk of Parkinsons and dementia post stroke, what is your doctor's position on this for off-label use? Does your competent? doctor even know and think about these issues?

With your elevated chances of dementia post stroke,  your competent? doctor is responsible for preventing that! Have they taken on that responsibility? Or are they DOING NOTHING?

With your chances of getting dementia post stroke you need solutions. YOUR DOCTOR IS RESPONSIBLE FOR PREVENTING THIS!

1. A documented 33% dementia chance post-stroke from an Australian study?   May 2012.

2. Then this study came out and seems to have a range from 17-66%. December 2013.`    

3. A 20% chance in this research.   July 2013.

4. Dementia Risk Doubled in Patients Following Stroke September 2018 

Parkinson’s Disease May Have Link to Stroke March 2017

 

The latest here:

SGLT2 Inhibitor Use Associated With Reduced Risk of Dementia, Parkinson Disease

Use of sodium-glucose cotransporter-2 (SGLT2) inhibitors among patients with type 2 diabetes significantly reduced the risk of neurodegenerative disorders, independent of various factors including comorbidities and bioclinical parameters, according to a nationwide population-based study published in the journal Neurology.

“We know that these neurodegenerative

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article continues here

diseases like dementia and Parkinson’s disease are common and the number of cases is growing as the population ages, and people with diabetes are at increased risk of cognitive impairment, so it’s encouraging to see that this class of drugs may provide some protection against dementia and Parkinson’s disease,” said Minyoung Lee, MD, Yonsei University College of Medicine, Seoul, South Korea.

The retrospective study looked at people with type 2 diabetes who started diabetes medication between 2014 and 2019 in South Korea. Patients taking SGLT2 inhibitors were matched with patients taking other oral diabetes drugs. Those taking the SGLT2 inhibitors were followed for an average of 2 years and those taking the other drugs were followed for an average of 4 years.

Among the 358,862 participants with an average age of 58, a total of 6,837 people developed dementia or Parkinson’s disease during the study.

For Alzheimer’s disease, the incidence rate for people taking SGLT2 inhibitors was 39.7 cases per 10,000 person-years, compared with 63.7 cases for those taking other diabetes drugs. For vascular dementia, the incidence rate was 10.6 cases per 10,000 versus 18.7, respectively. For Parkinson’s disease, the incidence rate for those taking the SGLT2 inhibitors was 9.3 cases per 10,000, compared with 13.7 for those taking the other drugs.

After researchers adjusted for other factors that could affect the risk of dementia or Parkinson’s disease, such as complications from diabetes and medications, they found that SGLT2 inhibitor use was associated with a 20% reduced risk of Alzheimer’s disease and a 20% reduced risk of Parkinson’s disease. Those taking SGLT2 inhibitors had a 30% reduced risk of developing vascular dementia.

“The results are generally consistent even after adjusting for factors like blood pressure, glucose, cholesterol, and kidney function,” Dr. Lee said. “More research is needed to validate the long-term validity of these findings.”

He noted that since participants were followed for less than 5 years at the most, it’s possible that some participants would later develop dementia or Parkinson’s disease.

Reference: https://www.neurology.org/doi/10.1212/WNL.0000000000209805

SOURCE: American Academy of Neurology

Is reverse aging already possible? Drugs that could treat aging might already be on the pharmacy shelves

What has your doctor done with this senolytic research? ANYTHING AT ALL? Or are you allowing incompetence to continue to exist until it affects your children and grandchildren?

• senolytic (1 post to December 2022)

• senolytic drugs (1 post to July 2021)

• Senolytics (3 posts to March 2015)

• senotherapeutics (1 post to September 2017)

Is reverse aging already possible? Drugs that could treat aging might already be on the pharmacy shelves

At 67 years old, Dr. Nir Barzilai looks about the same as, if not younger than, he did 10 years ago. It’s apparent in side-by-side photographs, and it’s what most people who know him say. Barzilai lives a healthy lifestyle. He exercises every day, eats right, and practices intermittent fasting.

He’s also been taking the diabetes drug metformin off label for 10 years. He has never been diagnosed with diabetes or prediabetes—the conditions for which the drug is approved and prescribed—but takes it for a different off-label reason.

“We know that it targets aging,” said Barzilai, who is a professor of medicine and genetics at Albert Einstein College of Medicine and director of the American Federation for Aging Research.

“People on metformin have 30% lower rates of almost every kind of cancer. It delays cognitive decline. Even people with diabetes who are obese and have more disease to start with but are on metformin have lower mortality rates than people without diabetes who aren’t on the drug.”

What he says is born out in numerous studies. Overall, this safe, super-cheap, decades-old drug not only treats diabetes, but it also seems to delay and compress the years of chronic illness associated with the final stage of life and extend what geroscientists call the “healthspan.”

Metformin is just one of many medications, including other old ones and some brand new inventions, that academic researchers and biotech startups are exploring to slow, stop, or perhaps even reverse aging.

What is aging

All sorts of processes are happening in our bodies as we age. Some of which make us more vulnerable to the diseases most linked to old age: cancer, dementia, heart disease, stroke, macular degeneration and so forth.

Doctors and scientists in the longevity field are trying to determine which of those processes is the strongest hallmark of overall aging and declining health and how to target that process with a drug in the same way that current drugs target specific diseases.

“We can target aging,” Barzilai said. “We can delay it. And in several instances, we can stop and reverse it. At one point we had hope. Then we moved to promise. Now, we need to move to realize that promise. That’s where we are.”

Dr. Nir Barzilai has been taking the diabetes drug metformin off label to treat aging.

Targeting undead cells

Dozens of biotechs want to be the first to realize that promise through drugs called senolytics. In certain diseases, these pharmaceuticals can clear out toxic, old, dysfunctional cells and leave only young, healthy, well functioning ones behind. Senolytic Dasatinib (Sprycel) is FDA-approved for certain types of chronic myelogenous leukemia.

Here’s why researchers think senolytics could do more than treat one specific disease.

Your cells constantly reproduce and divide throughout their lifespan to create new, healthy cells. When they stop doing this, they die. But with some cells, even though they’ve stopped reproducing, they don’t die off like they should. These undead cells, called senescent cells, stick around and give off toxic substances that can harm the healthy cells around them—like the one bad apple that spoils the whole bunch.

As you get older, your aging body becomes less efficient at clearing out senescent cells, so they accumulate, especially around the sites where chronic diseases develop, like macular degeneration.

Unity Biotechnology has a senolytic, dubbed UBX1325, in phase 2 clinical trials for diabetic macular edema (DME) and age-related macular degeneration (AMD). In both conditions, damage to the retina can lead to vision loss.

Preliminary findings in DME patients in the trial suggest that the drug clears out problem-causing senescent cells in the eye and allows the remaining healthy cells to repair and regenerate the retina and bring lost vision back.

“It takes about 8 weeks to kick in, and at 24 weeks, you can see that the tissue has dramatically remodeled,” said Anirvan Ghosh, PhD, Unity CEO. “We had patients who had big gains in vision and big improvements in retinal structure.”

As incredible as these results are, vision restoration isn’t the endgame for Unity or most any company invested in senolytics development. The idea is to develop another drug that will have this same effect on another progressive disease and another and another until, ideally, researchers can figure out how to make a drug that would clear out all senescent cells, not just the one type behind a certain disease.

“In different tissues, it’s not always the same cell type that becomes senescent. I think next we will have tissue-specific senolytics for a specific disease or if you’re high-risk for that disease.” But to target aging, rather than just individual diseases, he says, “We’d have to have something that clears these cells from multiple tissue types.” That’s the long-term goal. And it may still be a long road to get there.

Understanding biological age

While zombie cells build up in the aging body, wreaking havoc as their numbers grow, critical changes are taking place on the surface of DNA, too. That is, in the epigenome, a landscape of proteins and chemicals that sits atop your genetic material.

These changes over time are the result of your environment, behaviors and exposures throughout your lifetime. Think: pollution, trauma, diet, exercise, and secondhand smoke. They don’t change your DNA, but they change the way your DNA acts. Genes that once functioned perfectly may at some point in life slow down, speed up, shut off, or just go generally haywire. Any dysregulation can cause disease or the signs and symptoms of old age.

Epigenetic changes are like scratches on a record: You can still hear the music, but it’s not what it used to be.

Led by Harvard Medical School professor and molecular geneticist David Sinclair, PhD, Tally Health is already bringing epigenetic approaches to aging directly to consumers. The company offers a cheek swab test that estimates customers’ biological age—how old they seem based on their epigenetics rather than their birth year.

“Biological age is a much better representation of health status than birthday candles,” Sinclair says. “Birthday candles don’t tell you how well you’ve been living and they certainly don’t tell you how many years you’ve got left.”

Tally Health creates personalized recommendations based on customers’ biological age for how they might reduce that age because, as Sinclair points out, “Your biological clock is not unidirectional.”

For now, the means to turn back the clock are mostly lifestyle changes. But Sinclair, who has founded several biotechs, and others are researching and developing drugs that might slow or restart the clock so genes will act like they are young again.

Sinclair and his collaborators have shown that this is possible in the eyes of blind mice. In newborn mice, if the optic nerve – the nerve that carries messages from the retina to the brain—is damaged, it will recover. But in old mice, it can no longer heal.

In Sinclair’s lab, they crushed the optic nerves of mice to blind them. The serious injury to the eye caused epigenetic changes that resemble those that happen in old age. They then injected the nerves with genes that contained factors they expected would reprogram the genes to behave like they were young again.

The treatment reversed the age-related epigenetic changes in the eyes, rescued retinal cells, and led to regeneration of neurons. Since then, Sinclair and his colleagues have corrected similar age-related epigenetic changes in muscle and kidney tissue. Other researchers have successfully used the technique to extend the overall lifespan of mice. Sinclair expects to release results of his study which tests this concept in primates in a few months.

The holy grail, of course, is to erase the scratches that time puts on our own epigenetic records. Sinclair says that’s coming.

“Resetting the whole human body in this way is a different matter,” he says. “Are we one day going to be able to turn ourselves back 20 years? I don’t see any reason why that won’t be possible. It’s just a question of when.”

Drugs that treat aging

But some drugs that could lower risk for multiple age-related diseases at once and, perhaps, treat aging as a whole, might already be on the shelves of the pharmacy.

Rapamycin, an mTOR inhibitor, got FDA approval in 1991 as an immune suppressor that prevents organ recipients from rejecting a new organ. By shutting off the mTOR protein, it prevents immune system cells from proliferating to attack the donated organ.

“But in every species that’s been studied to date – yeast, worms, flies, mice – when they are given rapamycin, healthspan and lifespan are extended. No other therapeutic has that degree of validation,” says Joan Mannick, MD, CEO of Tornado Therapeutics.

Mannick and other mTOR researchers believe that, among the other deleterious processes of aging, mTOR proteins might start to malfunction, too. In a healthy, young person, mTOR, which supports cell growth, is active when we eat. That’s critical for growth, development and reproduction. When we fast, like during the night, mTOR is inactive, which allows for cell repair.

This, by the way, is probably one of the reasons intermittent fasting has so many health benefits, Mannick says, because it blocks mTOR and allows for more cell repair.

As we get older, mTOR may stay active all the time—opening the door to out-of-control cell growth that can lead to cancer and closing the door on cell repair. In older adults, low doses of rapamycin, an mTOR inhibitor, seem to set mTOR activity back to its youthful state: on when you need it, off when you don’t.

“When they get rapamycin, their immune systems, which have already been damaged by old age, start to function better,” Mannick says. “There’s research to suggest that when you rejuvenate the immune system, you make a lot of other organ systems function better. But we need well-powered, placebo-controlled clinical trials to find out the dose, what conditions it improves, and who responds best.”

To carry out that research, Tornado Therapeutics has acquired a portfolio of rapamycin derivatives, or “rapalogs,” from Novartis, which they are studying as treatments for aging. If it can increase the lifespan of every plant and animal that’s been exposed to it, Mannick and the company’s investors, such as Cambrian Bio, bet it might increase the human lifespan, too.

“I think in the next 5 to 10 years, FDA will have approved the first drug to target aging biology,” Mannick says. “It very well could be a new rapalog that is going to have benefits for an aging-related condition as our first step to a much broader aging medicine advance.”

Type 2 diabetes is an age-related condition. Numerous studies show that metformin, a drug that’s FDA-approved to treat it, may also lower risk for cancer, heart disease, stroke, dementia, or death for any other reason, including COVID-19.

The benefits, researchers suspect, are a result of metformin’s ability to control blood sugar, blunt the effects of a lifetime of oxidative stress on the body, and protect cardiovascular function. That is, it may meet a host of needs that grow greater as we age.

Of course, the overwhelming majority of data on metformin’s benefits comes from people with diabetes. Numerous clinical trials currently underway are looking at its effects on specific diseases in people who don’t have diabetes. But longevity researchers, like Barzilai, want to prove to the FDA that it doesn’t have to be taken for a specific disease. Older adults should simply take it for aging.

Barzilai’s TAME (Targeting Aging with Metformin) trial, which will last six years, aims to prove that anyone between the ages of 65 and 79 can extend their healthspan with metformin.

“We’re using metformin as a tool,” he says, “to show the FDA that aging itself can be targeted.”

Targeting the healthspan

No matter which approach becomes the first prescription drug for aging, researchers in the area tend to agree it’s coming soon. It would be expected to improve and extend life not only for average older adults, but also for those who currently tend to get chronic diseases and die sooner: childhood cancer survivors, people living with HIV, people living in poverty.

Researchers predict the implications will be huge when the healthy years of life last longer for everyone.  Economist Andrew Scott calculated that a slowdown in aging that increases life expectancy by just one year would be worth $38 trillion. A ten-year increase would be worth $367 trillion.

“That’s because with this kind of increase in life expectancy, we are not spending that time in the hospital, we are not sick,” Barzilai says. “We’re shopping, we’re traveling, we are participating in society. We are living life. And that’s what we want.”

This story was originally featured on Fortune.com

At-Home Vagus Nerve Stimulation Promising for Postpartum Depression

With all the benefits on stroke recovery, does your doctor have enough functioning brain cells to prescribe this off-label? Don't listen to me, I'm not medically trained. Is your doctor? 

• vagus nerve (58 posts to July 2012)

At-Home Vagus Nerve Stimulation Promising for Postpartum Depression

At-home, noninvasive auricular vagus nerve stimulation (aVNS) therapy is well-tolerated and associated with a significant reduction in postpartum depressive and anxiety symptoms, new research suggests.

In a small proof-of-concept pilot study of 25 women with postpartum depression receiving 6 weeks of daily aVNS treatment, results showed that 74% achieved response and 61% achieved remission, as shown in reduced scores on the Hamilton Rating Scale for Depression (HAM-D17).

Dr Kristina M. Deligiannidis

Although invasive electrical stimulation of the vagus nerve was approved by the US Food and Drug Administration for treatment-resistant depression in 2005, it involves risk for implantation, infection, and significant side effects, coinvestigator Kristina M. Deligiannidis, MD, director, Women's Behavioral Health, Zucker Hillside Hospital, Northwell Health, Glen Oaks, New York, told Medscape Medical News.

"This newer approach, transcutaneous auricular VNS, is non-invasive, is well tolerated, and has shown initial efficacy in major depression in men and women," she said.

The findings were presented at the virtual American Society of Clinical Psychopharmacology (ASCP) 2022 Annual Meeting.

Potential Alternative to Meds

"Given that aVNS is a non-invasive treatment which can be administered at home, we wanted to test if this approach was safe, feasible, and could reduce depressive symptoms in women with postpartum depression, as many of these women have barriers to accessing current treatments," Deligiannidis said.

Auricular VNS uses surface skin electrodes to stimulate nerve endings of a branch of the vagus nerve, located on the surface of the outer ear. Those nerve endings travel to the brain where they have been shown to modulate brain communication in areas important for mood and anxiety regulation, she said.

Deligiannidis noted that evidence-based treatments for postpartum depression include psychotherapies and antidepressants. However, some women have difficulty accessing weekly psychotherapy, and, when antidepressants are indicated, many are reluctant to take them if they are breastfeeding because of concerns about the medications getting into their breast milk, she said.

Although most antidepressants are safe in lactation, many women postpone antidepressant treatment until they have finished breastfeeding, which can postpone their postpartum depression treatment, Deligiannidis added.

"At home treatments reduce many barriers women have to current treatments, and this intervention [of aVNS] does not impact breastfeeding, as it is not a medication approach," she said.

The researchers enrolled 25 women (mean age, 33.7 years) diagnosed with postpartum depression. Ten of the women (40%) were on a stable dose of antidepressant medication.

 

Cannabis-Based Products in a Neurological Setting: A Clinical and Pharmacokinetic Survey

I suppose you could ask your doctor to get Sativex from the UK off label for your spasticity.

Sativex, a cannabis based spray, was approved in England in 2019 for use in moderate to severe spasticity(only MS) when other treatments haven’t worked.

Currently, Sativex is not approved for any indication in the US, so you are totally screwed unless you are in a legal marijuana state and want to experiment on your own. But you can't, that would only be allowed if prescribed by your doctor. And your doctor will never prescribe marijuana.

 

Cannabis-Based Products in a Neurological Setting: A Clinical and Pharmacokinetic Survey

Susan Mohamed¹, Giovanna Lopane¹, Loredana Sabattini¹, Cinzia Scandellari¹, Diletta Zardi², Vincenzo Donadio¹, Giovanni Rizzo¹, Alessandro Perrone¹, Alessandra Lugaresi^1,2† and Manuela Contin^1,2*†

• ¹IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
• ²Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy

Background and Aim: Limited data are available in clinical settings on the pharmacokinetics of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). We investigated the use of cannabis-based products in neurological practice, monitoring patients' steady-state cannabinoids (CBs) plasma concentrations matched with different preparations.

Methods: This was a prospective, single-center, observational study. Patients underwent venous blood withdrawal before the CBs' morning dose and then 2.5 h post-dosing. Spasticity or pain were patient self-assessed by the Numeric Rating Scale (NRS) before the morning CB's administration and 2.5 h post-dosing.

Results: Thirty-three patients were enrolled. Main indications for CBs were spasticity and chronic pain. Sixteen patients were treated with oromucosal spray formulation Sativex^® and 17 with oil-based solutions. Both CBs trough plasma concentrations were ≤ limit of detection (0.1 ng/ml) in 45% of patients. Intrasubject CB's plasma levels significantly increased over baseline values in patients treated with Bediol^® oil (p < 0.05) and Sativex^® (p < 0.01). Post-dosing CB's bioavailability did not significantly differ between oral oil and oromucosal spray. NRS scores decreased (p < 0.01), matching the increase (p < 0.01) in CB's plasma concentrations.

Conclusion: This is the first study investigating CB's plasma concentrations of oral and oromucosal preparations in real-world neurological practice. Findings of similar bioavailability for both CBD and THC after galenic oil compared with oromucosal spray dosing may be clinically relevant and deserve additional research in larger cohorts.

Introduction

The cannabis plant contains several substances, such as more than one hundred cannabinoids (CBs) (1). There is great interest in the use of cannabis for the management of many diseases and symptoms (2) and the attention has been focused in particular on the two CBs, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) (3).

Two types of CB receptors have been identified, CB1 and CB2, which are parts of the human endocannabinoid system, involved in various functions, such as muscle spasticity, analgesic activity, anticonvulsant properties, vasodilatory and hypotensive action, and appetite (3).

THC is a partial agonist of CB1 and CB2 receptors. The main pharmacological effects of THC are psychoactivity, analgesia, muscle relaxation, anti-vomiting, and stimulation of appetite (3). Muscle relaxant effects are also recognized for hyper-reflexic bladder (4, 5).

Cannabidiol does not have a direct effect on the CB1 or CB2 receptors responsible for cannabis psychoactivity but it has been shown to have a negative allosteric activity on CB1 (6). From experimental models of epilepsies, different CBD mechanisms have emerged, such as antagonism of G protein-coupled receptor 55 (GPR55), desensitization of transient receptor potential of vanilloid type 1 (TRPV1) channels, and interactions with voltage-gated sodium and potassium channels (7). Other mechanisms associated with anti-inflammatory pathways include direct agonistic activity on serotonin 1A and adenosine A2A receptors (8). The main pharmacological effects of CBD are antiseizure, muscle relaxant, anxiolytic, and anti-inflammatory (1).

In the literature, several works have examined the efficacy and safety of CB's preparations in the treatment of a series of symptoms associated with neurological diseases, such as multiple sclerosis (MS), epilepsies, Huntington's disease, Parkinson's disease, cervical dystonia, and Tourette's syndrome. These applications were reviewed by an ad hoc guideline development subcommittee of the American Academy of Neurology (9). Chronic pain is another field of use of therapeutic cannabis, although few rigorous studies have evaluated its effectiveness (10).

Available data on CB's safety from clinical trials and real-world experience show that the most common adverse effects (AEs) associated with THC are dizziness, drowsiness, dry mouth, nausea/vomiting, impairment in cognitive function (perception disorders, euphoria, and confusion) and psychomotor skills, balance, and coordination problems (11). Studies on recreational cannabis have suggested a link between early, frequent use of high potency THC, and earlier onset of psychosis in subjects with a personal or family history of schizophrenia or psychotic disorders (12). CBD's common AEs include diarrhea, somnolence, pyrexia, decreased appetite, vomiting, and upper respiratory tract infection (11).

In Italy, two cannabis medicinal products are authorized: one based on THC and CBD, in the approximate 1:1 dose ratio (2.7 mg THC and 2.5 mg for CBD), in a spray for oral mucosa (Sativex^®, GW Pharmaceuticals, UK), indicated to relieve symptoms in adult patients who suffer from moderate to severe spasticity due to MS. The other, marketed from the end of June 2021, is based on purified plant-based CBD, in an oil oral formulation (Epidiolex, GW Pharmaceuticals, UK), indicated as an adjunct treatment of seizures associated with two rare, severe forms of epilepsy with childhood onset, the Lennox-Gastaut and Dravet syndromes. Furthermore, there are several available cannabis galenical preparations (i.e., oil extracts, decoctions) characterized by different percentages of THC and CBD (Supplementary Table 1), which can be prescribed by physicians to users registered on the Italian Ministry of Health database (13). Eligible indications of medical cannabis include the management of the chronic pain associated with MS and spinal cord injury, the control of nausea and vomiting due to chemotherapy, radiotherapy, or HIV therapy, the handling of appetite loss in oncologic and HIV-positive patients. Medical cannabis is also indicated for its appetite stimulant effect in cachexia and anorexia, its hypotensive effect in glaucoma, and as antispasmodic in Tourette's syndrome (14).

Despite the substantial number of published studies, data on the pharmacokinetics of THC and CBD are limited (15, 16). In particular, the pharmacokinetics of CBs from oral galenical preparations has not been extensively studied in clinical settings (17). CB's posological protocols for physicians are missing (14), thus, currently the management of dosing is largely empirical, based on a balance between the desired therapeutic effects and the prevention of the adverse ones. Knowledge of CB's pharmacokinetics from different available formulations could help the prescribers in optimizing therapeutic regimens.

The purpose of this study was to investigate the use of cannabis-based products at the Institute of Neurological Sciences of Bologna (ISNB), such as indications, type of patients treated, formulations, dosages, evidence of efficacy, and AEs, and to monitor steady-state CB's plasma concentrations matched with different cannabis-based products.

More at link.

Stroke Lytic(tPA) May Help Lungs in Severe COVID-19

Interesting off-label use of tPA. You as a stroke survivor might want to inform your doctor of your stroke, ischemic or hemorrhagic. But since I'm not medically trained this is obviously not medical advice, just common sense.

Stroke Lytic(tPA) May Help Lungs in Severe COVID-19

Case series and anecdote suggestive, but clotting may quickly overtake the effect

by Crystal Phend, Senior Editor, MedPage Today April 14, 2020

Off-label use of tissue plasminogen activator (tPA) for COVID-19 patients with acute respiratory distress syndrome (ARDS) improved lung function in a case series.
Among three patients treated with an intermediate dose of alteplase (Activase), the ratio of partial pressure of arterial oxygen to percentage of inspired oxygen (PaO2/FiO2, or P/F) improved by 38% to almost 100%, found Christopher Barrett, MD, of Beth Israel Deaconess Medical Center and Harvard in Boston, and colleagues.
However, those improvements proved temporary and were lost over time after completion of tPA despite maintenance on heparin, the group reported in the Journal of Thrombosis and Haemostasis.
Other groups have also described using tPA in desperate cases in recent days, to mixed success.
Mount Sinai Hospital physicians in New York City saw oxygenation levels rise rapidly soon after starting the bolus but then diminish again, presumably as clots reformed, for one patient treated there with tPA, while another three saw a more durable improvement in oxygenation.
Sukh Nijjer, MD PhD, of Imperial College London, tweeted about his "N of 1" experience giving alteplase to an ST-segment elevation myocardial infarction patient with COVID-19 when emergency angioplasty and stenting was not possible: "Amazingly O₂ requirements also reduced & improved clinical status."
A higher dose of tPA, like that used in heart attacks or for pulmonary embolism, might be reasonable, Barrett's group suggested.
Using a "larger bolus-dose tPA (50 mg or 100 mg bolus) without holding anticoagulation in order to prevent recurrence of the suspected pulmonary microvascular thrombosis underlying COVID-19 ARDS is worthy of further consideration and study," they wrote.
Coagulopathy has emerged as a hallmark of severe COVID-19. One study showed that 71.4% who died from the virus met ISTH criteria for disseminated intravascular coagulation, compared with only 0.6% of survivors.
The same group had argued the rationale for tPA in COVID-19 in the Journal of Trauma and Acute Care Surgery last month, noting that clotting problems have been seen in ARDS from other causes.
"A consistent finding in ARDS is the deposition of fibrin in the airspaces and lung parenchyma, along with fibrin-platelet microthrombi in the pulmonary vasculature, which contribute to the development of progressive respiratory dysfunction and right heart failure," they noted.
They had used 25-mg IV tPA bolus over 2 hours, followed by a 25-mg infusion over the subsequent 22 hours for the critically-ill, mechanically-ventilated COVID-19-positive patients with ARDS. Extracorporeal membrane oxygenation capabilities, staffing, and resources were extremely limited at the center due to pandemic, the group noted.
They are using the early results to move forward with a compassionate use clinical trial, along with looking for biomarkers of enhanced response.
"We're hearing anecdotally that a subset of patients with COVID-19 induced ARDS are clotting abnormally around their catheters and IV lines," co-author Michael Yaffe, MD, PhD, of Beth Israel Deaconess, said in a press release. "We suspect these patients with aggressive clotting are will show the most benefit from tPA treatment, and this new clinical trial will reveal whether that's the case."
However, now is not the time to start widely using tPA for COVID-19, cautioned Stephan Moll, MD, of the University of North Carolina at Chapel Hill Hemophilia and Thrombosis Center.
"We are always concerned about the risk of bleeding," he told MedPage Today. Critically-ill COVID-19 patients can have prolongation of partial thromboplastin time, renal failure, and other risk factors for bleeding, he noted, so giving them thrombolysis needs to be weighed carefully.
The temporary benefits seen in Barrett's case series might suggest more aggressive anticoagulation to prevent recurrence of clots after tPA dissolves those already present, Moll noted.

Disclosures

Barrett and several co-authors disclosed patents pending related to both coagulation/fibrinolysis diagnostics and therapeutic fibrinolytics, and are passive co-founders and hold stock options in Thrombo Therapeutics.

Primary Source

Journal of Thrombosis and Haemostasis

Source Reference: Wang J, et al "Tissue Plasminogen Activator (tPA) Treatment for COVID‐19 Associated Acute Respiratory Distress Syndrome (ARDS): A Case Series" J Thromb Haemost 2020; DOI: 10.1111/jth.14828.

Brain study paves way for therapy for common cause of dementia

Now our researchers need to find out whether this is the cause of most stroke related dementia. But since we have NO leadership to go to and NO strategy to update nothing will be done.  Without naming the drug you are totally reliant on your doctor figuring out if this can possibly be treated off label. 

Brain study paves way for therapy for common cause of dementia

July 4, 2018, University of Edinburgh

The authors discovered more proliferating dysfunctional endothelial cells (red arrows) in diseased human brains compared to controls. Credit: R.M. Rajani et al., Science Translational Medicine (2018)

Scientists have uncovered a potential approach to treat one of the commonest causes of dementia and stroke in older people.

Studies with rats found the treatment can reverse changes in blood vessels in the brain associated with the condition, called cerebral small vessel disease.
Treatment also prevents damage to brain cells caused by these blood vessel changes, raising hope that it could offer a therapy for dementia.
Small vessel disease, or SVD, is a major cause of dementia and can also worsen the symptoms of Alzheimer's disease. It is responsible for almost half of all dementia cases in the UK and is a major cause of stroke, accounting for around one in five cases.
Patients with SVD are diagnosed from brain scans, which detect damage to white matter—a key component of the brain's wiring.
Until now, it was not known how changes in small blood vessels in the brain associated with SVD can cause damage to brain cells.
A team led by the University of Edinburgh found that SVD occurs when cells that line the small blood vessels in the brain become dysfunctional. This causes them to secrete a molecule into the brain.
The molecule stops production of the protective layer that surrounds brain cells—called myelin—which leads to brain damage.
Treating rats with drugs that stop blood vessel cells from becoming dysfunctional reversed the symptoms of SVD and prevented brain damage, tests found.
Researchers say that further studies will need to test whether the treatment also works when the disease is firmly established. They will also need to check if the treatment can reverse the symptoms of dementia.
Dementia is one of the biggest problems facing society, as people live longer and the population ages. Estimates indicate there are almost 47 million people living with dementia worldwide and the numbers affected are expected to double every 20 years, rising to more than 115 million by 2050.
The research, published in Science Translational Medicine, was carried out at the Medical Research Council Centre for Regenerative Medicine and the UK Dementia Research Institute at the University of Edinburgh. It was funded by the MRC, Alzheimer's Research UK and Fondation Leducq.
Professor Anna Williams, Group Leader at the University of Edinburgh's MRC Centre for Regenerative Medicine, said: "This important research helps us understand why small vessel disease happens, providing a direct link between small blood vessels and changes in the brain that are linked to dementia. It also shows that these changes may be reversible, which paves the way for potential treatments."
Dr. Sara Imarisio, Head of Research at Alzheimer's Research UK said: "Changes to the blood supply in the brain play an important role in Alzheimer's disease as well as being a direct cause of vascular dementia. This pioneering research highlights a molecular link between changes to small blood vessels in the brain and damage to the insulating 'white matter' that helps nerve cells to send signals around the brain.
"The findings highlight a promising direction for research into treatments that could limit the damaging effects of blood vessel changes and help keep nerve cells functioning for longer. There are currently no drugs that slow down or stop Alzheimer's disease and no treatments to help people living with vascular dementia. Alzheimer's Research UK is very pleased to have helped fund this innovative research, which is only possible thanks to the work of our dedicated supporters."
Dr. Nathan Richardson, the MRC's Head of Molecular and Cellular Medicine, commented: "This study is a great example of how innovative discovery science into regenerative mechanisms can be applied to improve our understanding of how vascular changes contribute to dementia. This research in rats opens up new possibilities for developing therapies for cerebral small vessel disease."

Explore further: Vascular dementia trial of Viagra-type drug nears closing stages

More information: R.M. Rajani el al., "Reversal of endothelial dysfunction reduces white matter vulnerability in cerebral small vessel disease in rats," Science Translational Medicine (2018). stm.sciencemag.org/lookup/doi/ … scitranslmed.aam9507

Journal reference: Science Translational Medicine
Provided by: University of Edinburgh

A review of vagus nerve stimulation as a therapeutic intervention

So your doctor could use this as a off-label treatment for stroke since it already is FDA approved, but then I know nothing since I'm not medically trained.
33 posts on vagus nerve for your doctor to review. 

A review of vagus nerve stimulation as a therapeutic intervention

 

Authors Johnson RL, Wilson CG
Received 20 January 2018
Accepted for publication 15 March 2018
Published 16 May 2018 Volume 2018:11 Pages 203—213
DOI https://doi.org/10.2147/JIR.S163248
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Amy Norman
Peer reviewer comments 2
Editor who approved publication: Dr Ning Quan

Rhaya L Johnson,¹ Christopher G Wilson<sup>1,2

1</sup>Lawrence D Longo MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University, Loma Linda, CA, USA; ²Department of Pediatrics, Loma Linda University, Loma Linda, CA, USA

Abstract: In this review, we provide an overview of the US Food and Drug Administration (FDA)-approved clinical uses of vagus nerve stimulation (VNS) as well as information about the ongoing studies and preclinical research to expand the use of VNS to additional applications. VNS is currently FDA approved for therapeutic use in patients aged >12 years with drug-resistant epilepsy and depression. Recent studies of VNS in in vivo systems have shown that it has anti-inflammatory properties which has led to more preclinical research aimed at expanding VNS treatment across a wider range of inflammatory disorders. Although the signaling pathway and mechanism by which VNS affects inflammation remain unknown, VNS has shown promising results in treating chronic inflammatory disorders such as sepsis, lung injury, rheumatoid arthritis (RA), and diabetes. It is also being used to control pain in fibromyalgia and migraines. This new preclinical research shows that VNS bears the promise of being applied to a wider range of therapeutic applications.

Keywords: vagus nerve stimulation, pediatrics, inflammation, peripheral nerve stimulation, autonomic circuits

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

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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. 

New drug beats heart disease by reducing inflammation 

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.

Mechanism of Action and Clinical Potential of Fingolimod for the Treatment of Stroke

Fingolimod already has this positive research needing more followup: Already approved for MS, so your doctor being an innovative sort will likely use this as an off-label use for stroke. That will never occur, you will just need to deal with the fact your doctor is doing nothing in the first week to save all your dying neurons.(neuronal cascade of death)

FTY720 Preserves Blood-Brain Barrier Integrity Following Subarachnoid Hemorrhage in Rats

The latest here:

Mechanism of Action and Clinical Potential of Fingolimod for the Treatment of Stroke

Wentao Li¹, Haoliang Xu² and Fernando D. Testai¹*

• ¹Department of Neurology and Rehabilitation, University of Illinois College of Medicine, Chicago, IL, USA
• ²Department of Pathology, University of Illinois College of Medicine, Chicago, IL, USA

Fingolimod (FTY720) is an orally bio-available immunomodulatory drug currently approved by the FDA for the treatment of multiple sclerosis. Currently, there is a significant interest in the potential benefits of FTY720 on stroke outcomes. FTY720 and the sphingolipid signaling pathway it modulates has a ubiquitous presence in the central nervous system and both rodent models and pilot clinical trials seem to indicate that the drug may improve overall functional recovery in different stroke subtypes. Although the precise mechanisms behind these beneficial effects are yet unclear, there is evidence that FTY720 has a role in regulating cerebrovascular responses, blood–brain barrier permeability, and cell survival in the event of cerebrovascular insult. In this article, we critically review the data obtained from the latest laboratory findings and clinical trials involving both ischemic and hemorrhagic stroke, and attempt to form a cohesive picture of FTY720’s mechanisms of action in stroke.

Introduction

Fingolimod (FTY720) is an orally bio-available immunomodulatory drug unique for its reversible leukocyte sequestration properties. In 2010, it was approved by the FDA for the treatment of multiple sclerosis (MS) (1, 2).

Given the current understanding of the role of the immune system in the pathophysiology of brain injury in cerebrovascular diseases, there is now significant interest in the potential benefits of FTY720 on stroke outcomes. Several groups have independently evaluated its effects in rodent models of brain ischemia and intracerebral hemorrhage (ICH). More recently, pilot clinical trials have been conducted demonstrating promising results, albeit in small populations (3–5). Taken together, these studies seem to indicate that administration of FTY720 results in overall improved functional recovery in different stroke subtypes.

The precise mechanisms behind these beneficial effects are still under investigation. FTY720 is a partial sphingosine-1-phosphate (S1P) agonist with immunomodulatory properties that regulates cerebrovascular responses, blood–brain barrier (BBB) permeability, and central nervous system (CNS) cell survival (6, 7). In this article, we will organize these elements and attempt to form a cohesive picture of FTY720’s mechanisms of action in stroke, and critically review the data obtained from recent clinical trials.

Role of the Immune System in Stroke Progression

Immunomodulation is a well-characterized effect of FTY720 and is thought to mediate some of the beneficial effects seen in stroke models. In order to understand the extent to which the immune system impacts the evolution of stroke outcomes, we will sketch a proposed model of the immune cascade following ischemic insult.

In the immediate aftermath of an ischemic event, complement activation, clot formation, and oxidative stress result in direct damage to local vasculature. Endothelial cells die and detach, interrupting the integrity of the BBB and exposing sub-endothelial antigens. Immune cells adhere to the vessel wall and upregulate the expression of chemoattractant and adhesion molecules that lead to the infiltration of the brain parenchyma by the innate immune system.

A combination of neutrophils, monocytes, and macrophages, this innate immune system further contributes to vascular compromise and early inflammation. One well-documented process is through the release of matrix metalloproteinases (MMPs) by the immune cells, particularly MMP-9, which contributes to the breakdown of the BBB with the resultant edema and growth of the infarcted area (8).

In the parenchyma, glial cells are also activated by the inflammation and damage-associated molecular patterns (DAMPs) released from dying neurons. These reactive astrocytes and microglia further stimulate the recruitment of leukocytes, which release their own pro-inflammatory chemokines, perpetuating a cycle of vascular damage, inflammation, and cell death (9).

The second, adaptive phase of the immune response is mediated predominantly by effector T cells, which are stimulated by DAMPS and brain-specific antigens released upon neuronal cell death (10). These T cells mobilize to the injured regions of the brain, infiltrating a compromised BBB to release pro-inflammatory cytokines, including IFN-γ, resulting in a delayed neurotoxic effect (11, 12). Of note, brain-specific antigens were identified in cervical nodes and palatine tonsils of animals with cerebral ischemia and stroke survivors. Interestingly, some of these antigens were associated with infarct volume and survival. While these studies need to be replicated in larger cohorts, they suggest the participation of peripheral lymphoid tissue in stroke-associated inflammation and outcomes.

Lastly, the inflammatory process is brought to an end via a combination of B cells and regulatory T cells. The latter acts through IL-10, which in combination with TGF-β produced by local macrophages, suppresses further helper T-cell-induced inflammation, and promotes the regeneration of remaining viable neurons (13, 14).

A reduction in various components of the innate and adaptive immune response have been associated with better stroke outcomes. Clinically, a lower ratio of CD14+ pro-inflammatory monocytes to CD16+ reparative monocytes has been correlated with better acute and long-term functional outcomes (15). Similarly, decreased complement activation, specifically the reduced expression of C3, C4, and C-reactive protein, has been associated with better recovery at 3 months post-stroke (16). Experimentally, inhibition of CD8+ and CD4+ T-cell migration into the CNS and direct disruption of CD8+ cytotoxicity has led to reduced infarct volume and post-ischemic inflammation (17). Disruption of the DAMPs-activated γδT cells have also resulted in decreased infarct size and better functional recovery in mice (18). Finally, direct delivery of B cells and IL-10 to the brain in animal models have resulted in a reduction of inflammatory cytokines produced by effector T cells and a reduction of infarct size (19, 20).

Fingolimod and Stroke-Related Mechanisms of Action

Pharmacology

Isaria sinclairii, otherwise known as “winter-insect and summer-plant,” is a fungus that has been used in traditional Chinese medicine for over 300 years. Classically prescribed as a panacea for multiple ailments, it produces an atypical amino acid myriocin (ISP-1) that blocks the synthesis of sphingolipids. This chemical compound has since been modified into fingolimod, also known as FTY720 (21). In Western Medicine, FTY720 initially showed promise in preventing ischemic–reperfusion injury following organ transplant, but failed clinical trials due to the development of acute macular edema in some patients (22, 23). In 2010, it became the first oral disease modifying drug approved for treatment of MS (6). In its base form, FTY720 is an orally bio-available, lipophilic molecule that readily crosses the BBB and steadily accumulates in the CNS white and gray matter (24). It bears a structural similarity to sphingosine and is reversibly phosphorylated primarily by Sphingosine-Kinase 2 (SphK2) and, to a lesser extent, by SphK1 (25). In its activated form, FTY720-phosphate is a sphingosine-1-phosphate (S1P) analog that binds to cell membrane G-coupled S1P receptors (S1PR) S1PR1, 3, 4, and 5, but not S1P2 (26). With the exception of S1PR4, these receptors are ubiquitously distributed in the CNS (Table 1). In addition to its action on cell surface receptors, FTY720 regulates the synthesis of different bioactive sphingolipids and, together with S1P, regulates gene expression via epigenetic mechanisms (Figure 1). The half-life of FTY720 averages ~9 days and its pharmacology is not sensibly affected by age, weight, sex, or ethnicity (27).

Despite Critics Dismissal - Off Label Prescribing May Benefit Patients

Great reading about the problems of on-the-ground use and reporting of off-label prescribing. You will need to see which camp your doctor falls into. I'm sure most doctors do not have time to write up research reports after they have given two patients the same off-label prescriptions. This means the knowledge may be out there but not being disseminated.
http://www.policymed.com/2013/10/despite-critics-dismissal-off-label-prescribing-may-benefit-patients.html?utm_source=feedburner&utm_medium=email&utm_campaign=Feed%3A+policymed+%28Policy+and+Medicine%29
This includes some reporting on amantadine which I have posted on here;
http://oc1dean.blogspot.com/2012/02/study-old-flu-drug-speeds-brain-injury.html

This basically proves that you will need to tell your doctor what you want done because they do not have the knowledge to know what to do. A great stroke association would be compiling all these off-label uses and assorted protocols for wider dissemination.

Off-Label Drug Use: What You Need to Know

You will need to study up on this if you want to insist on some of the items I pointed out here:
What I am going to insist I get after my next stroke
Botox is a good example. It was not approved for stroke spasticity until 2010, but even then only for arm/wrist/hand.  In 2006 I had it for leg and toe muscles also and was never told it was an off-label use.

http://www.webmd.com/a-to-z-guides/features/off-label-drug-use-what-you-need-to-know