A Review of Neuroinflammatory Mechanisms in Ischemic Stroke: Background and Therapeutic Approaches

It seems to me that this should have been totally unnecessary. A summary of all the processes involved in neuronal death should be publicly available. Then we would all be speaking to the same problems needing to be solved. But it seems we have no one in stroke with any sense of business processes.
This just needs updating which will never occur since we have NO stroke leadership.
Dr. Michael A. Moskowitz in 2010 had some great ideas needing followup;

The Science of Stroke: Mechanisms in Search of Treatments

 

A Review of Neuroinflammatory Mechanisms in Ischemic Stroke: Background and Therapeutic Approaches

research-article

Attila Sas^1∗, László Horváth¹, Csaba Oláh^{2, 3} and Attila Valikovics¹

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Abstract

In this review, we will discuss the relevant clinical details of acute ischemic stroke and its currently very limited therapeutic opportunities, sequentially emphasizing its populational and economical burden. Based on our increasing knowledge in molecular and cell biology of immunological mechanisms of ischemic stroke, we will introduce the main processes in the background of arterial vessel occlusion, ensuing tissue damage and following reparation. After that, we will compare the obtained results from animal models with clinical studies and thus the possible causes of foregoing failures. Following this, we will demonstrate the most important drugs tested and/or being tested in human or animal studies from the field of neuroprotection. Finally, we raise possible opportunities that can be considered in development or clinical applications of neuroprotectants.

Keywords: acute ischemic stroke, stroke induced immunodepression, neuro-inflammation, neuroprotection, future perspectives

1. Introduction

In 2013, the Stroke Council of the American Heart Association/American Stroke Association laid an up-to-date definition of ischemic stroke. According to this, it is defined as brain, spinal cord or retinal cell death attributable to ischemia, based on neuropathological, neuroimaging and/or clinical evidence of permanent injury. In a clinical spectrum, it can be accompanied by symptoms or can be asymptomatic. Transient ischemic attack (TIA) is defined as a transient episode of neurological dysfunction caused by focal brain, spinal cord or retinal ischemia, without acute infarction [1].

Estimates from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD 2010) ranked stroke as the second most common cause of death [2] and the third most common cause of disability-adjusted life-years (DALYs) [3] worldwide in 2010. Expressed by numbers, roughly 10% of the 52,769,700 deaths [2] and about 4% of the 2,490,385,000 DALYs [3] worldwide were due to stroke. Further analysis of the GBD study showed that although stroke mortality rates and mortality-to-incidence ratios have decreased in the past two decades, the global burden of stroke in terms of the absolute number of people affected every year, stroke survivors, related deaths, and DALYs lost are great and increasing, with most of the burden in low-income and middle-income countries. If these trends in stroke incidence, mortality, and DALYs continue, by 2030, there will be almost 12 million stroke deaths, 70 million stroke survivors, and more than 200 million DALYs lost globally [4]. Furthermore, stroke changes the lives not only of those who experience a stroke but also of their family and other caregivers [5].

We can classify the stroke subtypes by aetiology. According to this, 80–85% of all stroke events are ischemic, the other 15–20% are of haemorrhagic origin [6]. The theme of our review is about ischemic stroke, so from now on, we will discuss only this subtype—means, that if ‘stroke’ is written, it refers to ischemic stroke automatically.

The ischemic stroke has its well-known risk factors, some of them are the common vascular risk factors. Among these, we can find so called non-modifiable ones: genetics, age, ethnicity/race, and low birth weight. Fortunately an international case-control study of 6000 individuals found that 10 potentially modifiable risk factors explained 90% of the risk of stroke [7]. These are—with no purpose of detailed description—physical inactivity with or without diet and nutrition failure (containing dyslipidaemia, obesity and body fat distribution, metabolic syndrome, diabetes mellitus) hypertension, cigarette smoking, atrial fibrillation and other cardiac conditions, carotid artery stenosis, sickle cell disease, migraine, alcohol consumption, drug abuse, sleep-disordered breathing [8].

Despite the intensive populational stroke education of these methods of primary prevention, the number of stroke patients increases to date.

After so many years of unsuccessful therapeutic approaches, recombinant tissue plasminogen activator (rtPA) was approved by the U.S. Food and Drug Administration (FDA) in 1996 for the treatment of acute ischemic stroke [9]. Since then, scores of stroke patients have been treated worldwide with this drug, managed by comprehensive stroke centres.

In a selected patient population (see detailed inclusion and exclusion criteria as per applied protocol), intravenous or intra-arterial thrombolysis can be a reliable choice. With this method of recanalisation, the treatment physician must calculate certain complications and a relatively poor outcome in several cases [10].

Most of these severely disabled stroke patients have intra- or extra-cranial large arterial vessel occlusion. In the past decade, a new form of acute revascularisation treatment, the endovascular stroke treatment (EST), appeared. After the failure of the first ‘unhappy’ trials with first-generation devices; in the past few years, smashing successes were achieved with the newer stent retrievers. These results—especially combined with iv thrombolysis—were comparably better than iv thrombolysis alone, and patient safety with risk/benefit ratio is also very promising [11].

Although several patients can benefit from the above mentioned methods of acute stroke treatment, they still have a few significant weak spots, above all, the narrow therapeutic time window.

Even in the countries with the best achievements, just like Austria with about 10% of stroke patients, can receive either or other treatment, the others, with wider stroke onset-to-treatment time have no or minimal chance of revascularisation, thus of good clinical outcome.

There is an urgent need to aim this enormous patient population with an effective treatment.

Neuroprotection would be a promising choice for this group, but until now, controversial results came to light in this field.

Hereinafter, we will introduce the main known reactions, immune responses in the brain following acute arterial vessel occlusion and potential therapeutic targets in this process.

More at link.

Myeloperoxidase inhibition increases neurogenesis after ischemic stroke

What protocol does your doctor have to increase your neurogenesis? How does s/he know that neurogenesis is working? Does your doctor know ONE DAMN THING ABOUT NEUROGENESIS?
http://jpet.aspetjournals.org/content/early/2016/08/22/jpet.116.235127.abstract

1. HyeonJu Kim1,
2. Ying Wei1,
3. Ji Yong Lee1,
4. Yue Wu1,
5. Yi Zheng1,
6. Michael A. Moskowitz2, and
7. John W. Chen1,*

+ Author Affiliations

1. ¹ MGH;
2. ² Massachusetts General Hospital

1. ↵^*Address correspondence to: jwchen@mgh.harvard.edu

Abstract

The relationship between inflammation and neurogenesis in stroke is currently not well understood. Focal ischemia enhances cell proliferation and neurogenesis in the neurogenic regions including the subventricular zone (SVZ), dentate gyrus (DG) as well as non-neurogenic striatum, cortex in the ischemic hemisphere. Myeloperoxidase (MPO) is a potent oxidizing enzyme secreted during inflammation by activated leukocytes and its enzymatic activity is highly elevated after stroke. In this study, we investigated whether inhibition of MPO activity by a specific irreversible inhibitor, 4-aminobenzoic acid hydrazide (ABAH) or MPO-/- mice can increase neurogenesis after transient middle cerebral artery occlusion (tMCAO) in mice. ABAH administration increased the number of proliferating 5-bromo-2' deoxyuridine (BrdU)-positive cells expressing markers for neural stems cells, astrocytes, neuroprogenitors (Nestin), and neuroblasts (doublecortin) in the ischemic SVZ, anterior SVZ (aSVZ), striatum and cortex. MPO inhibition also increased levels of brain-derived neurotrophic factor (BDNF), phospho-cAMP response element-binding protein (pCREB Ser133), acetylated H3 (AcH3), and NeuN to promote neurogenesis in the ischemic SVZ. ABAH treatment also increased chemokine CXC receptor 4 (CXCR 4) expression in the ischemic SVZ. MPO-deficient mice treated with vehicle or ABAH both showed similar effects on the number of BrdU+ cells in the ischemic hemisphere, demonstrating that ABAH is specific to MPO. Taken together, our results underscore a detrimental role of MPO activity to post-ischemia neurogenesis and that a strategy to inhibit MPO activity can increase cell proliferation and improve neurogenesis after ischemic stroke.

The Role of Monocytes in Ischemic Stroke Pathobiology: New Avenues to Explore

Someplace in here a smart person could figure out what further research is needed to make something useful out of this. But since we don't have anyone in our stroke associations with two functioning neurons the answers will not be coming from there.

The Role of Monocytes in Ischemic Stroke Pathobiology: New Avenues to Explore

Ayman ElAli^1,2* and Noëmie Jean LeBlanc²

• ¹Neuroscience Axis, CHU de Québec Research Center (CHUL), Québec City, QC, Canada
• ²Department of Psychiatry and Neuroscience, Faculty of Medicine, Laval University, Québec City, QC, Canada

Ischemic stroke accounts for the majority of stroke cases and constitutes a major cause of death and disability in the industrialized world. Inflammation has been reported to constitute a major component of ischemic stroke pathobiology. In the acute phase of ischemic stroke, microglia, the resident macrophages of the brain, are activated, followed by several infiltration waves of different circulating immune cells into the brain. Among these circulating immune cells, monocytes have been shown to play a particularly important role. Following their infiltration, monocytes differentiate into potent phagocytic cells, the monocyte-derived macrophages (MDMs), in the ischemic brain. Initially, the presence of these cells was considered as marker of an exacerbated inflammatory response that contributes to brain damage. However, the recent reports are suggesting a more complex and multiphasic roles of these cells in ischemic stroke pathobiology. Monocytes constitute a heterogeneous group of cells, which comprises two major subsets in rodent and three major subsets in human. In both species, two equivalent subsets exist, the pro-inflammatory subset and the anti-inflammatory subset. Recent data have demonstrated that ischemic stroke differentially regulate monocyte subsets, which directly affect ischemic stroke pathobiology and may have direct implications in ischemic stroke therapies. Here, we review the recent findings that addressed the role of different monocyte subsets in ischemic stroke pathobiology, and the implications on therapies.

Introduction

Stroke is the third leading cause of death and the first cause of disability in industrialized world. Ischemic stroke accounts for the majority of stroke cases, whereas the remaining stroke cases are hemorrhagic (Dirnagl et al., 1999). Regional blood supply disruption initiates the ischemic cascade that leads to neuronal death and rapid loss of neuronal function (Dirnagl et al., 1999). The ischemic cascade is characterized by the activation of several signaling pathways that compromise cell survival and function (Mehta et al., 2007). Ischemic stroke triggers blood-brain barrier (BBB) breakdown, thus contributing to the secondary progression of ischemic injury by increasing brain edema and exacerbating the inflammatory response in the sub-acute phase (hours to days after ischemic stroke onset; Dirnagl et al., 1999; Fagan et al., 2004). The severity of these early events reduces the capacity of neurons to recover in the chronic phase (days to weeks after ischemic stroke onset), thus significantly worsening stroke outcomes (Moskowitz et al., 2010).

Inflammation plays a central role in ischemic stroke pathobiology (Jin et al., 2010). Following ischemic stroke, microglia, which are brain resident macrophages, are activated and circulating immune cells, such as monocytes, neutrophils and lymphocytes are recruited to injury site (Jin et al., 2010). Among these immune cells, monocytes that give rise to macrophages play a particularly important role (Chiba and Umegaki, 2013). Initially, the presence of monocytes at the injury site has been suggested to contribute to ischemic injury exacerbation in the acute phase (minutes to hours after ischemic stroke onset; Chen et al., 2003). However, the experimental approaches that aimed at depleting these cells in ischemic stroke animal models worsened ischemic injury by destabilizing brain microvasculature (Gliem et al., 2012). These reports outline the complex and multifaceted role of monocytes in ischemic stroke pathobiology. As such, this mini-review aims to summarize and discuss the recent findings that addressed the role of different monocyte subsets in ischemic stroke pathobiology, which may have direct implication on stroke therapies.

Does your doctor know who the thought leaders are in stroke?

I have no clue who they might be. When your neurologist has a stroke whom will they be going to to get 100% recovered? It's a simple question, demand an answer. But I would suggest some;
Dr. Michael Tymianski, of the Toronto Western Hospital Research Institute in Canada.
Dr. Michael A. Moskowitz in 2010 had some great ideas needing followup.
I'm sure our stroke associations have not called these people together to establish a strategy to solve all the f*cking problems in stroke. Because everyone in the world is waiting for SOMEONE ELSE TO SOLVE THE PROBLEM.

Seth Godin has a good discussion on this;

You don't know Lefsetz? 

I was talking to someone dedicating his career to working in newspapers. I asked him what he thought of the work of Jeff Jarvis. He had no idea what I was talking about.
I met a musician the other day, and asked her how her work without a label was going, and referenced something by Bob Lefsetz. She didn't know who I meant.
The last time I was at an event for librarians, I mentioned Maria Popova. Blank stares.
A podcaster asked me a question, and I wondered if he admired the path Krista Tippett had taken. He had no clue.
A colleague was explaining his work in memetics to me. I asked about Dawkins and Blackmore. You guessed it...
Or Kenji on food, Cader on publishing, Underhill on retail, Lewis on direct mail copywriting and on and on...
We would never consent to surgery from a surgeon who hadn't been to medical school, and perhaps even more important, from someone who hadn't kept up on the latest medical journals and training. And yet there are people who take pride in doing their profession from a place of naivete, unaware or unlearned in the most important voices in their field.
The line between an amateur and professional keeps blurring, but for me, the posture of understanding both the pioneers and the state of the art is essential. An economist doesn't have to agree with Keynes, but she better know who he is.
If you don't know who the must-reads in your field are, find out before your customers and competitors do.
Too much doing, not enough knowing.

Stroke - The way forward

Since I haven't seen any strategy or planning from any stroke association or person I figure I'm more qualified than most to provide a step by step plan for solving the f*cking problems in stroke. I was going to call this a manifesto but that would recall the Unabomber.
1. No fast, easy, accurate and objective way to diagnose a stroke, both ischemic and hemorrhagic. This is easy to solve; you fund researchers to test out these 17 possibilities to find out which one is the best. Or maybe the Qualcomm Xprize for the tricorder. No installing scanners in the ambulance, that is a waste of money.
The goal is to deliver tPA while still in the ambulance. None of this lazy door-to-needle time.
2. Replace tPA. It only completely works to clear the stroke 12% of the time. This has been known almost since the beginning  but no one was willing to identify the emperor as naked. As a result we've wasted 19 years trying to make the world believe tPA works. And lost 19 years of research time. What a FUCKING waste. Everyone associated with this failure should have their medical license removed.
3. Solve the neuronal cascade of death. I bet this is more important than replacing tPA. We know the 
5 causes of neuronal cascade of death We just need to fund researchers to solve them. Maybe a good start would be to talk to Dr. Michael Tymianski, of the Toronto Western Hospital Research Institute in Canada who talked about 1000+ failed neuroprotective drugs years ago. That talk could establish a basis for why those drugs failed and speed up the solutions needed.  Dr. Michael A. Moskowitz in 2010 had some great ideas needing followup;
The Science of Stroke: Mechanisms in Search of Treatments This is not rocket science, you state exactly the problem and fund researchers to solve that problem. Maybe a few billionaires might want to chip in a few bucks for their self preservation in case they have a stroke.
I will be asking my doctor to do  these 31 hyperacute possibilities I'm going to insist my doctor give me the first week after my next stroke. I don't give a shit if they haven't been clinically proven. I want the kitchen sink and all the mice and rats that gave their lives for stroke research to be thrown at my stroke.  These 177 hyperacute therapies that need more research.
4.  Get an accurate 3d damage diagnosis both dead brain and penumbra. Without this it will be impossible to correlate stroke protocols to recovery. And finally have physiatrists stop giving out stupid prescriptions like ET(Evaluate and treat).  I expect my doctor to know what protocols to prescribe to fix the damage that was just accurately diagnosed rather than throwing every bit of recovery responsibility onto the therapists.  A 3d MRI mapping of dead brain is possible, I had one from James R. Carey, PhD, PT, FAPTA at the University of Minnesota in a research program.  Penumbra damage can be evaluated via PET scans
5. Establish stroke protocols for everything in the first weeks. This requires that our stroke medical professionals have to become professional and drop this blastedly stupid idea that 'All strokes are different, all stroke recoveries are different'' This has been used as a crutch for too fucking long as to why stroke survivors can't be helped to recover.
   a. Diet protocols. Stroke prevention, dementia prevention and stroke recovery. There is plenty of research out there that this should be easy to compile. These are my ideas.

What would a post-stroke diet look like?

  b.  Music protocols. This is a complete no-brainer, your doctor is completely incompetent if this hasn't already been implemented in their hospital.

      1.  Exploring a Neuroplasticity Model of Music Therapy

      2.  Revealed: The Type of Music That Makes You Feel Most Powerful

       3. 11 Problems Music Can Solve

       4. How playing an instrument benefits your brain - Anita Collins

        5. Why does music therapy work? The Science Behind the Music.

        6. Musical Training Can Increase Blood Flow in Bra/in

        7.  Listening to classical music ameliorates unilateral neglect after stroke

         8. Music brings memories back to the brain injured 

         9.  Plasticity in the sensorimotor cortex induced by Music-supported therapy in stroke patients: a TMS study

          10.  Moderating variables of music training-induced neuroplasticity: a review and discussion

           11. Hand-Clapping Songs Improve Motor and Cognitive Skills, Research Shows

         12. Music listening enhances cognitive recovery and mood after middle cerebral artery stroke

         13. Intensive musical therapy may help improve speech in stroke patients 

The classical music one;

           Classical Music’s Surprising Effect on Genes Vital to Memory and Learning

c. Cognitive training protocols.  Survivors need as much brain power as they can muster to recover so give them some training in this. 

Its been proven that smarter people die less from stroke.

        1. Mind expanding: 7 ways to fine-tune your brain

         2. Improving fluid intelligence with training on working memory

         3. Gaming improves multitasking skills Study reveals plasticity in age-related cognitive decline.

         4. NUS study revealed that Vajrayana meditation techniques associated with Tibetan Buddhism can enhance brain performance

         5. Rehabilitation for post-stroke cognitive impairment: an overview of recommendations arising from systematic reviews of current evidence 

         6. Video Game Training Improves Cognitive Control in Older Adults

         7. The Art and Science of Cognitive Rehabilitation Therapy

         8. Towards a Smart Population: A Public Health Framework for Cognitive Enhancement

          9. Want to Slow Mental Decay? Play a Video Game

d. Meditation protocols.   This is a no-brainer also, Amy has proven this multiple times. The breathwork will generate NO, nitric oxide. Breathing exercises create nitric oxide which relaxes the arterial walls  lowering your blood pressure.

If your doctor doesn't know this, run run far away.

See Amys' posts here:

        Kundalini Yoga

        Why I Do What I Do Part Two…..Meditation

         Meditation and Breathwork

         Meditation and Chanting

         Yoga Breathing

e.  Action observation protocol gifs for every possible muscle movement.

The actual amount of therapy each day is appallingly low, this could be used to fill those empty hours.

           1.  New research supporting stroke rehabilitation   Nov. 2014.

            2.  Plasticity and Response to Action Observation   Oct. 2014.

             3.  Motor imagery during action observation modulates automatic imitation effects in rhythmical actions   Mar. 2014.

            4.  Clinical feasibility of action observation training for walking function of patients with post-stroke hemiparesis: a randomized controlled trial   Mar. 2014.

             5.  Training Videos Help Restore Motor Function, May Aid in Stroke Rehabilitation Mar. 2014.

             6.  Using action observation to study superior motor performance: a pilot fMRI study  Jan. 2014.

              7.  Multiple roles of motor imagery during action observation  Jan. 2014.

              8.  Motor imagery ability in stroke patients: the relationship between implicit and explicit motor imagery measures  Dec. 2013.

               9.  From action representation to action execution: exploring the links between cognitive and biomechanical levels of motor control  Oct. 2013.

               10.  Action observation as a stroke therapy  June 2013.

   

                11.  Action-Observation In Stroke Rehabilitation  June 2013.

                12.  Exercise for stroke patients' brains  June 2013.

                 13.  Watching object related movements modulates mirror-like activity in parietal brain regions  March 2013.

                 14.  Watching object related movements modulates mirror-like activity in parietal brain regions  May 2012.

                  15.  Action observation and mirror neuron network: a tool for motor stroke rehabilitation.  April 2012.

                   16.  Modulating the motor system by action observation: Implications for stroke rehabilitation  Feb. 2012.

 I challenge the following with their staffs to produce something better than this without referring to my blog.
Matt Lopez, president of the NSA
Dr. Mariell Jessup, president of the ASA
WSO President - Steve Davis (Australia)

A separate followup post will delineate where research needs to be done for some physical problems.

Mechanisms of Stroke Induced Neuronal Death: Multiple Therapeutic Opportunities

It is nice to see a pretty complete writeup of of the neuronal cascade of death. Now if we just had a great stroke association pushing a strategy to solve these problems we might get somewhere. But we don't, we have press release organizations that believe their highest calling is unknown to survivors.
But this was mostly written about by Dr. Michael A. Moskowitz in 2010;

The Science of Stroke: Mechanisms in Search of Treatments Dr. Michael A. Moskowitz 

We shouldn't have to write up the same crap every couple of years. Create a damn strategy and plan and follow it to a complete solution. Does no one have two neurons to rub together?

http://scholar.google.com/scholar_url?hl=en&q=http://nexusacademicpublishers.com/uploads/files/Nexus_515.pdf&sa=X&scisig=AAGBfm3EtAC621Ef-8xBDqIZNvN-0lWSXA&oi=scholaralrt

Stroke Researchers Aim to Stem the “Ischemic Cascade”

What took them so long to figure this out?  How much shouting needs to be done before doctors finally come to an understanding of the basis of where research should go?  Dr.  Moskowitz wrote extensively about this earlier here:

The Science of Stroke: Mechanisms in Search of Treatments Dr. Michael A. Moskowitz

Stroke Researchers Aim to Stem the “Ischemic Cascade”

A stroke may be sudden, but much stroke damage is not. While brain cells completely deprived of blood at the core of an ischemic stroke (the most common kind)  die within minutes, in the broader “penumbra” where circulation is down but not out, the process is gradual—and reversible.
Neuroscientists speak of the “ischemic cascade:” Without the energy from oxygen and glucose required to maintain neurotransmitter storage, neurons release massive amounts of glutamate. The resulting excitotoxicity allows a flood of calcium, sodium, and water into the cell, producing excessive nitric oxide and leading to inflammation, free radical formation, and, ultimately, the death of the cell.
“Cells in the penumbra stay for hours, maybe days in a meta-stable state,” says Michael A. Moskowitz, professor of neurology at Harvard. “They don’t function normally and don’t carry impulses, but they are alive and rescuable.”
The one approved treatment for ischemic stroke, tissue plasminogen activator (tPA), saves brain in the penumbra in the most direct way:  by dissolving the clot and restoring circulation. The drug must  be given within 3-4 hours of symptoms to do any good, though, and restoring circulation can bring problems of its own, including hemorrhage. In practice only 5 percent of patients benefit.
In recent years, researchers have sought to widen the window of therapeutic opportunity by targeting the ischemic cascade itself—halting the destructive process through neuroprotective strategies. Their activity has been intense: More than a thousand compounds have been considered, and more than one hundred tested in clinical trials—but none has yet succeeded. What are they?
 “An enormous amount of energy has been put into this, but no one has hit pay dirt,” says Moskowitz. “It’s been a very bad time for people interested in neuroprotection.” More than the innate difficulty of the problem, he suggests, the failure reflects serious flaws in the science behind screening: “Proof of concept has been lacking for most drugs chosen for clinical trials. They were tested without any demonstration that they could actually get into the brain, bind to their receptors, and do what they were intended to do.”
 On the other hand, poor experimental design may have meant promising possibilities were overlooked. “We may have thrown the baby out with the bathwater in some previous studies,” Moskowitz says.
He emphasizes that this dismal history by no means discredits the concept of neuroprotection. “There shouldn’t be so much doom and gloom. This isn’t an easy business, but there’s no theoretical reason why we can’t do a better job of rescuing cells. We need to reinvent the field.”

A most promising study

Asked about current research, Moskowitz mentioned Michael Tymianski. “He’s a very good, thoughtful investigator. I’d say, from the excitement point of view, [his work] may be the most encouraging thing we’ve seen.”
Tymianski’s research involves the excessive release of glutamate that occurs early in the ischemic cascade, the first step toward catastrophic excitotoxicity. Attempts to abort this process by blocking the NMDA glutamate receptor itself haven’t worked because glutamate neurotransmission is essential to normal neuron function. Tymianski’s approach is more selective: to inhibit a protein, PSD-95, that links the receptor to molecular events within the cell that promote overproduction of nitric oxide and the influx of calcium.
Tymianski, a senior scientist at Toronto Western Research Institute, and his colleagues have been developing a PSD-95 inhibitor for 15 years, testing it in cell cultures and rodent models of stroke. In his most recent study, reported in the March 8 issue of Nature, they administered the compound, Tat-NR2B9, to macaques, non-human primates whose brain closely resemble ours.
Findings were encouraging: the drug reduced the area of brain loss, compared with placebo, when given 1-3 hours after a large cerebral artery was blocked to simulate a stroke. The animals also fared significantly better in tests of neurological function up to two weeks later, confirming that the simulated stroke had done less damage.
“Our results show that neuroprotection is unequivocably feasible in the complex brain,” Tymianski says. “The challenge now is to design a human trial to show clinical benefit.”
The compound has already been shown to be safe in a recent clinical trial in which it was given to patients just after surgery to repair a brain aneurysm, a procedure that carries a high risk of stroke. Although he could not discuss further results in detail, Tymianski called them favorable, suggesting that ischemic damage had been reduced in patients who had strokes after the procedure.
Next, he hopes to test the compound in patients with acute ischemic stroke. Because the drug is apparently safe even in the face of hemorrhagic stroke, it might be given by emergency medical personnel en route to the hospital without the expert screening needed for tPA, dramatically shortening the time to potential neuroprotection. [Tymianski heads a company established to develop the drug in question.]
Tymianski’s success has led researchers to seek other ways to block the PSD-95 pathway. “His work is really impressive, but we like to think we’ve made a better compound,” said Anders Bach, a postdoctoral fellow at University of Copenhagen. The molecule developed by his group has a much higher affinity for PSD-95, and results of a study in mice, published in Proceedings of the National Academy of Sciences in February 2012, suggests that this enhanced its ability to protect the brain.

Other routes to neuroprotection

Researchers elsewhere are addressing other parts of the ischemic cascade.
“In my lab we’ve used two approaches to promote survival in the penumbra,” says Nicolas G. Bazan, director of the Neuroscience Center of Excellence at Louisiana State University and a member of the Dana Alliance for Brain Initiatives. “We’ve devised new molecules that can cross the blood-brain barrier and block bad things happening. And we’ve looked inside the brain to piece out the intrinsic mechanisms that the brain sets in motion to protect itself.”
Much of his research over the past several decades has involved the release of free fatty acids in stroke, with a particular eye toward an endogenous molecule derived from the fatty acid DHA, neuroprotectin-D1, which appears to reduce the impact of ischemia.
A recent focus of his attention has been platelet activating factor (PAF), a compound that normally aids in blood clotting but when released in large amounts by ischemia apparently participates, along with glutamate, in the cascade of excitotoxicity and its consequences.
In a study reported in the March 2012 issue of Translational Stroke Research, Bazan and his colleagues showed that timely administration of a PAF antagonist, LAU-0901, to rats reduced the area of brain damage after experimental stroke, limited inflammation, and improved neuron survival. Animals treated with LAU-0901 showed significantly less behavioral and neurological impairment up to a week later, compared to those given placebo. [Louisiana State University holds the patent on LAU-0901]
Another conspicuously active area of neuroprotection research is hypothermia. Lowering body temperature by just a few degrees appears to slow multiple destructive processes unleashed by ischemia—excitotoxicity, inflammation, free radical release— simultaneously, according to Midori A. Yenari, professor of neurology at University of California, San Francisco.
Hypothermia has been shown to protect the brain against disrupted circulation in conditions other than stroke—it is recommended for resuscitation of cardiac arrest survivors, for example—and animal experiments have been encouraging.
 What’s more, its benefits may persist long after the immediate post-stroke period. “There are a few studies suggesting a positive downstream effect on recovery— when cooling [is initiated] the first day, restorative processes like neurogenesis are improved months later,” Yenari says.
Like other stroke interventions, hypothermia would probably be used along with thrombolytic therapy, but how the two interact remains an open question. “[Some] studies suggest that thrombolysis doesn’t work as well when the brain is cooled, but other research indicates that if  tPA is given, the risk of hemorrhage is reduced,” she says.
The most imposing barriers to hypothermia for acute stroke are practical: Lowering body temperature can induce uncomfortable shivering, disturb electrolyte balance, and raise the risk of pneumonia or cardiac complications, particularly in older patients with other illnesses.
Researchers have used surface cooling, circulating ice water to cool blood vessels internally, and measures like helmets to cool the brain selectively. “People are now trying to identify drugs to cool the body instead of mechanical measures” in hopes of avoiding complications, says Yenari.