Reviving drugs with anti-stroke potential, minus side effects

In the 1990s, neuroscientists identified a class of drugs that showed promise in the area of stroke. NMDA receptor antagonists could limit damage to the brain in animal models of stroke. But one problem complicated testing the drugs in a clinical setting: the side effects included disorientation and hallucinations.

(Image caption: Schematic representation of the NMDA receptor complex. NMDA receptor antagonists can have beneficial effects in animal models of stroke, but also have pronounced side effects such as disorientation and hallucinations)

Now researchers have found a potential path around this obstacle. The results were published in Neuron.

"We have found neuroprotective compounds that can limit damage to the brain during ischemia associated with stroke and other brain injuries, but have minimal side effects," says senior author Stephen Traynelis, PhD, professor of pharmacology at Emory University School of Medicine.

"These compounds are most active when the pH is lowered by biochemical processes associated with injury of the surrounding tissue. This is a proof of concept study that shows this mechanism of action could potentially be exploited clinically in several conditions, such as stroke, traumatic brain injury and subarachnoid hemorrhage."

In a mouse model of ischemic stroke, a NMDA receptor antagonist called 93-31 can reduce the volume of damaged brain tissue by more than half, researchers found. At the same time, giving mice 93-31 does not seem to lead to the side effects seen with other NMDA receptor antagonists.

The drugs phencyclidine (also known as PCP) and ketamine are NMDA receptor antagonists; their ability to block all subtypes of NMDA receptors is thought to account for their psychoactive side effects. NMDA receptors are abundant on the surfaces of brain cells and play key roles in healthy processes such as memory formation.

In brain tissue affected by stroke or traumatic injury, the environment becomes more acidic because of the lack of oxygen and the buildup of metabolites such as lactic acid. In addition, NMDA receptors get overstimulated by an increase in the neurotransmitter glutamate — enough to kill cells. Researchers reasoned that NMDA receptor antagonists whose activity is dependent on acidic conditions should, at the right dose, be active only in the injured areas of the brain.

To identify the new pH-dependent drugs, Emory pharmacologists led by Traynelis and Ray Dingledine, PhD collaborated with chemists Dennis Liotta, PhD and James Snyder, PhD. The co-first authors of the Neuron paper are pharmacology instructor Hongjie Yuan PhD, chemistry postdoctoral fellow Gordon Wells, PhD and Scott Myers, PhD, director of drug discovery at Atlanta-based pharmaceutical company NeurOp.

In medicinal chemistry terms, 93-31 is ten times more potent at pH 6.9, typical for ischemic tissue with an insufficient blood supply, than at pH 7.6, close to the value for healthy brain tissue.

In collaboration with Katherine Nicholson, PhD at Virginia Commonwealth University, the researchers tested 93-31 on mice trained to press a lever when they detect low levels of PCP. When researchers substituted 93-31 for PCP, the mice did not perceive 93-31’s subjective effects to be similar enough to PCP’s to respond by pressing levers in the same way.

Doses of 93-31 that had a positive effect in the stroke model did not seem to impair coordination or motor function. The mice could still hold onto a turning rod, in contrast with mice dosed with other NMDA receptor antagonists.

The research that led to 93-31’s identification has been a platform for further drug discovery efforts by NeurOp, according to the company’s CEO, Barney Koszalka, PhD. However, 93-31’s pharmaceutical profile may not be optimal for further development, he says. In mouse experiments in the Neuron paper, 93-31 was either injected directly into the brain or into the body cavity.

NeurOp is developing a related candidate drug as a potential preventive measure for people who experience subarachnoid hemorrhage, because they have a high risk of a secondary stroke-like event for days after the initial hemorrhage. NeurOp is completing safety studies and is planning to file an Investigational New Drug application with the FDA later in 2015.

"We are taking an analogue of the compound identified in the Neuron paper forward as a post-surgical treatment for individuals that have suffered a subarachnoid hemorrhage,” Koszalka says. “The pH boost we see with this series of subunit specific NMDA modulators is expected to provide an additional safety advantage.”

Brain’s iconic seat of speech goes silent when we actually talk

For 150 years, the iconic Broca’s area of the brain has been recognized as the command center for human speech, including vocalization. Now, scientists at UC Berkeley and Johns Hopkins University in Maryland are challenging this long-held assumption with new evidence that Broca’s area actually switches off when we talk out loud.

The findings, reported in the Proceedings of the National Academy of Sciences journal, provide a more complex picture than previously thought of the frontal brain regions involved in speech production. The discovery has major implications for the diagnoses and treatments of stroke, epilepsy and brain injuries that result in language impairments.

“Every year millions of people suffer from stroke, some of which can lead to severe impairments in perceiving and producing language when critical brain areas are damaged,” said study lead author Adeen Flinker, a postdoctoral researcher at New York University who conducted the study as a UC Berkeley Ph.D. student. “Our results could help us advance language mapping during neurosurgery as well as the assessment of language impairments.”

Flinker said that neuroscientists traditionally organized the brain’s language center into two main regions: one for perceiving speech and one for producing speech.

“That belief drives how we map out language during neurosurgery and classify language impairments,” he said. “This new finding helps us move towards a less dichotomous view where Broca’s area is not a center for speech production, but rather a critical area for integrating and coordinating information across other brain regions.”

In the 1860s, French physician Pierre Paul Broca pinpointed this prefrontal brain region as the seat of speech. Broca’s area has since ranked among the brain’s most closely examined language regions in cognitive psychology. People with Broca’s aphasia are characterized as having suffered damage to the brain’s frontal lobe and tend to speak in short, stilted phrases that often omit short connecting words such as “the” and “and.”

Specifically, Flinker and fellow researchers have found that Broca’s area — which is located in the frontal cortex above and behind the left eye — engages with the brain’s temporal cortex, which organizes sensory input, and later the motor cortex, as we process language and plan which sounds and movements of the mouth to use, and in what order. However, the study found, it disengages when we actually start to utter word sequences.

“Broca’s area shuts down during the actual delivery of speech, but it may remain active during conversation as part of planning future words and full sentences,” Flinker said.

The study tracked electrical signals emitted from the brains of seven hospitalized epilepsy patients as they repeated spoken and written words aloud. Researchers followed that brain activity – using event-related causality technology – from the auditory cortex, where the patients processed the words they heard, to Broca’s area, where they prepared to articulate the words to repeat, to the motor cortex, where they finally spoke the words out loud.

My mom created a gofundme, and I know a lot of you don’t have the money to help, but to those of you who have even $5 to help her, please send me a message on Tumblr. I will give promote your blog, I will do whatever you need me to do, my mom just really needs help.

Thank you c:

I’m trying to be as positive as I can in the current situation I am in, but I can’t. I’m trying to be happy for my mom, though she cries all day, but I just can’t. This just sucks, good people don’t deserve bad things to happen to them. I know life isn’t a wish granting factory, but can he please just live, not just for me, or my mom, or our whole family, but for the people he inspired every single day.

Recovering Attention After a Stroke: Brain’s Right Hemisphere May Be More Valuable

A new study conducted by a researcher at the George Washington University suggests that the right hemisphere of the brain may be able to assist a damaged left hemisphere in protecting visual attention after a stroke.

Summer Sheremata, a postdoctoral research fellow in the Attention and Cognition Laboratory in the Columbian College of Arts and Sciences, led the study. The paper, “Hemisphere-Dependent Attentional Modulation of Human Parietal Visual Field Representations,” was published in the Journal of Neuroscience in January.

“Patients with damage to the right hemisphere often fail to visually perceive objects on their left, but the reverse is much less common. That is, damage to the left hemisphere does not typically lead to deficits in attention,” Dr. Sheremata said. “Psychologists have hypothesized that the right hemisphere could help out the left hemisphere in attending to objects on the right, both in healthy individuals and patients recovering from stroke, but until now it remained an assumption.”

The research was conducted at the University of California, Berkeley, with senior author Michael Silver, associate professor of optometry and vision science and neuroscience. Participants’ brain activity was measured using fMRI while they used their attention in two different ways: 

  • Paying attention to a central box, ignoring a moving object in the background, and
  • Ignoring the central box and paying attention to the moving object in the background.

The first scenario measures the visual response, confirming that the right side of the brain represents the left visual field and that the left side of the brain represents the right visual field. The second scenario tests the effects of visual attention and indicates that while the left side of the brain only focused on the right visual field, the right side of the brain was able to represent both sides of the visual field. Visual field representations are included in a figure in the study.

While the research was conducted on healthy, non-stroke patients, the results suggest a possible brain mechanism for how the visual field can be recovered if it is damaged by a stroke.

“The results demonstrate that the tasks we do every day change how the brain pays attention to the world around us. By understanding how these changes occur in healthy individuals, we can focus on behaviors that are impaired in stroke patients and provide a focus for rehabilitation,” Dr. Sheremata said.

To further the research, Dr. Sheremata plans to study how these effects influence behavior in stroke patients and healthy individuals during attention and memory. Her next round of studies is being conducted at the George Washington University. 

Could an injection stop brain damage in minutes?

Recent tests show that injectable nanoparticles can quickly neutralize a process that occurs after traumatic injuries, such as a stroke.

When such injuries occur, thousands of damaging reactive oxygen species molecules are overexpressed by the body’s cells. These molecules damage cells and cause mutations.

The nanoparticles, known as PEG-HCCs, appear to quickly stem the process of overoxidation by turning the dangerous molecules into less reactive substances.

Researchers hope an injection of PEG-HCCs as soon as possible after an injury, such as traumatic brain injury or stroke, can mitigate further brain damage by restoring normal oxygen levels to the brain’s sensitive circulatory system.

The results were reported in the Proceedings of the National Academy of Sciences.

Read more via Futurity »

Funding: The Mission Connect Mild Traumatic Brain Injury Consortium from the Department of Defense and the National Institutes of Health, the Alliance for NanoHealth, and UTHealth supported the research.

Ability to balance on one leg may reflect brain health, stroke risk

Struggling to balance on one leg for 20 seconds or longer was linked to an increased risk for small blood vessel damage in the brain and reduced cognitive function in otherwise healthy people with no clinical symptoms, according to new research in the American Heart Association’s journal Stroke.

"Our study found that the ability to balance on one leg is an important test for brain health," said Yasuharu Tabara, Ph.D., lead study author and associate professor at the Center for Genomic Medicine at Kyoto University Graduate School of Medicine in Kyoto, Japan. "Individuals showing poor balance on one leg should receive increased attention, as this may indicate an increased risk for brain disease and cognitive decline."

Yasuharu Tabara, Yoko Okada, Maya Ohara, Eri Uetani, Tomoko Kido, Namiko Ochi, Tokihisa Nagai, Michiya Igase, Tetsuro Miki, Fumihiko Matsuda, and Katsuhiko Kohara. Association of Postural Instability With Asymptomatic Cerebrovascular Damage and Cognitive Decline: The Japan Shimanami Health Promoting Program Study. Stroke, December 2014 DOI: 10.1161/STROKEAHA.114.006704

Investigators Develop Groundbreaking Technique to Measure Oxygen in Deep-Sited Tumor and Brain

A novel Electron Paramagnetic Resonance (EPR) oximetry technique will help clinicians directly measure oxygen and schedule treatments at times of high oxygen levels in cancer and stroke patients to improve outcomes, The EPR team at Dartmouth’s Geisel School of Medicine has found.

Led by Harold Swartz, MD, PhD, the team published their groundbreaking progress on the decades-old conundrum of how to measure oxygenation in deep-sited tissue in a paper titled, “Deep-Tissue Oxygen Monitoring in the Brain of Rabbits for Stroke Research,” published in Stroke.

"This is a major step forward," said first author Nadeem Khan, PhD, "It brings EPR oximetry technique to the forefront of biomedical research for clinical applications."

Oxygen is necessary to sustain life. A certain level of oxygen in a cell or tissue is necessary to maintain normal processes, such as the generation of energy by cells. Oxygen also plays a pivotal role in the development and treatment of various diseases. The effectiveness of several therapies also depends on the oxygen levels in a malignancy. For example, a very low level of oxygen in cancer (solid tumors) is known to develop aggressive phenotypes, varies with the growth of tumors, and also compromises the effectiveness of chemotherapy and radiation. Therefore, it is very important to directly measure oxygen levels to understand disease progression, develop strategies to improve oxygen levels, and optimize the efficacy of therapies.

Oxygen measurement in deep-sited tissue has been a challenge for several techniques, which has unfortunately limited the understanding of various pathologies in large animals and humans. To solve the problem, Dartmouth’s EPR team developed implantable resonators made of thin nonmagnetic copper wire to facilitate direct and repeated measurement of tissue oxygenation at any depth from the surface. In their most recent experiment, which demonstrated the efficacy of in vivo EPR oximetry, they used a one-time implementation of the oxygen probes in the brain of a rabbit and successfully monitored oxygen levels for several weeks.

"Other than the implantation, which is done under anesthesia, the rest of the procedure for oxygen measurements is entirely non-invasive," explained Khan. "We anticipate that a better understanding of oxygen levels in stroke, for instance, will guide the development of strategies to significantly improve oxygen levels in the ischemic regions of the brain and thereby improve outcomes."

The investigators conclude that real-time monitoring of tissue oxygenation using implantable resonators will be a powerful tool in stroke and cancer research. In clinics, physicians will ultimately use the measurement of oxygen in tumors, or the brain, to guide decisions about best times for therapy. Development of “oxygen-guided” protocols to improve treatment outcome in patients will continue with the EPR team’s latest National Cancer Institute funded multi-million dollar study, which will commence in March 2015 under the leadership of Dr. Swartz. A second line of research for the team is investigating the dynamics of cerebral oxygenation following stroke, making oxygenation of the brain a strategic therapy that will save vital brain tissue from dying.

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Along with sharing photos of the boys here on Tumblr we also post on Instagram, that is how we met Courtney Nealy. He was one of the first sphynx accounts we followed when we joined Instagram because my husband and I loved that he named his sphynx Zod. The Instagram sphynx community is very close, it is amazing how much you feel like you know people online based on what they share about their lives. I could tell that Court has a wide range of interests including craft beers, roller derby, his beautiful sphynx kitties, tattoos, and cosplay. He always seemed to be up to something, with a real zest for life. On December 9th Court suffered multiple strokes and almost died. He has been in the hospital since then. His beloved sphynx, Lex, Dio, and Zod are currently being fostered.  Court is unable to move his left arm, he has a breathing tube and a feeding tube. He lost his apt and may also lose his car. He has a long and hard road to recovery. On the positive side he still has all of his memories, personality, and intellect and his girlfriend, and our new friend Melissa, tells me he is a fighter. If you have the ability, please dig deep into your heart and make a contribution to his recovery fund set up by his close friends. If you have a kitty who might need a warm shirt you could help out by purchasing a Batman for Catman shirt from Sphynx Nudie Patootie before MIDNIGHT Central Time Saturday Feb 7! $20 from the sale of each shirt will go towards Court’s recovery fund. Also on Etsy, ICraftCafe is donating 50% of the sale of these beautiful had stamped pendants to the recovery fund. (Pendants can be customized to say something other than Sphynx Mom.)  (Photocollages by Court’s girlfriend Melissa, cat photo by Sphynx Nudie Patooti, pendent photo by ICraftCafe) If you made it to here thank you for reading our very long post. Please reblog. Love you guys!