NMDA receptors are saddled with an unwieldy name, but they are some of the most important* signaling molecules in the brain, both for learning and memory and in neurological and psychiatric diseases.
Kasper Hansen, a postdoc from Stephen Traynelis' lab who is establishing his own at the University of Montana, is lead author on a recent paper in Neuron, which could spur research on NMDA receptors' pharmacological properties.
The NMDA receptors in the brain are actually mix-and-match assemblies of four subunits, and most of the time in the brain, three different proteins come together to make one receptor, the authors explain. In the laboratory, it has been easier to study simpler, more homogenous, but also more artificial constructs. Hansen and his colleagues developed a way to build replicas of the more complicated NMDA receptors found in the brain and probe their distinct responses to drugs.*Want back-up for that sweeping statement? Check out the connections between NMDA receptors and complex diseases such as autism, schizophrenia and Parkinson's. The antidepressant effects of the NMDA receptor antagonist ketamine has been a recent bright spot in the study of depression. To be sure, NMDA receptor antagonists like ketamine have dissociative/hallucinatory effects, which get in the way of their utility vs excitotoxicity, a source of damage in stroke/brain injury. Developing more selective approaches could unlock the potential of drugs that act on NMDA receptors.
Informed consent is a basic principle of clinical research. Doctors are required to make sure that patients understand what’s involved with experimental treatments, and patients should only participate if they provide consent.
However, an important area of clinical research takes place outside of this general rule, because some life-threatening conditions – seizures, traumatic brain injury and cardiac arrest, as examples — make it impossible for the patient to learn about a clinical trial and make a decision about whether to participate. The urgency of treatment can also mean that seeking proxy consent from a relative is impractical.
A recent editorial in USA Today highlights this area of research, called EFIC (exception from informed consent). The author, Katherine Chretien from George Washington University, cites research from Emory investigators Neal Dickert and Rebecca Pentz.
Biomarkers circulating in the bloodstream may serve as a predictive window for recurrent stroke risk and also help doctors accurately assess what is happening in the brains of patients with acute traumatic brain injury (TBI).
Michael Frankel, MD
Researchers at Emory University School of Medicine, led by principal investigator Michael Frankel, MD, Emory professor of neurology and director of Grady Memorial Hospital’s Marcus Stroke & Neuroscience Center, are studying biomarkers as part of two ancillary studies of blood samples using two grants from the National Institutes of Health.
In the $1.47 million, four-year grant called “Biomarkers of Ischemic Outcomes in Intracranial Stenosis” (BIOSIS), Emory researchers are analyzing blood samples from 451 patients from around the country who were enrolled in a study known as SAMMPRIS (Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis), the first randomized, multicenter clinical trial designed to test whether stenting intracranial arteries would prevent recurrent stroke.
Researchers in the SAMMPRIS study recently published their results in the New England Journal of Medicine, showing that medical management was more effective than stenting in preventing recurrent strokes in these patients. Frankel’s BIOSIS research team is using blood samples from these same patients to continue learning more about the molecular biology of stroke to predict risk of a stroke occurring in the future.
“Our goal is to learn more about stroke by studying proteins and cells in the blood that reflect the severity of disease in arteries that leads to stroke. If we can test blood samples for proteins and cells that put patients at high risk for stroke, we can better tailor treatment for those patients,” says Frankel.
Patients with narrowed brain arteries, known as intracranial stenosis, have a particularly high risk of disease leading to stroke. At least one in four of the 795,000 Americans who have a stroke each year will have another stroke within their lifetime. Within five years of a first stroke, the risk for another stroke can increase more than 40 percent. Recurrent strokes often have a higher rate of death and disability because parts of the brain already injured by the original stroke may not be as resilient.
The other study, “Biomarkers of Injury and Outcome in ProTECT III” (BIO-ProTECT)” is a $2.6 million, five-year NIH grant in which Frankel’s team will use blood to determine what is happening in the brain of patients with acute TBI. The blood samples are from patients enrolled in the multicenter clinical trial ProTECT III (Progesterone for Traumatic brain injury, Experimental Clinical Treatment), led by Emory Emergency Medicine Professor, David Wright, MD, to assesses the use of progesterone to treat TBI in 1,140 patients at 17 centers nationwide.
In the BIO-ProTECT study, Emory is collaborating with the Medical University of South Carolina, the University of Pittsburgh, the University of Michigan and Banyan Biomarkers.
TBI is the leading cause of death and disability among young adults in the US and worldwide. According to the Centers for Disease Control and Prevention, approximately 1.4 million Americans sustain a traumatic brain injury each year, leading to 275,000 hospitalizations, 80,000 disabilities, and 52,000 deaths.
Acute TBI leads to a cascade of cellular events set in motion by the initial injury that ultimately lead to cerebral edema (swelling of the brain), cellular disruption and sometimes death. Tissue breakdown leads to the release of proteins into the bloodstream. These proteins may serve as useful biomarkers of the severity of the injury and perhaps provide useful information about response to treatment.
Using the large patient group in the ProTECT III trial, the researchers hope to validate promising TBI biomarkers as predictors of clinical outcome and also evaluate the relationship between progesterone treatment, biomarker levels and outcome.
“If we can better determine the amount of brain injury with blood samples, we can use blood to help doctors better assess prognosis for recovery, and, hopefully whether a patient will respond to treatment with progesterone,” says Frankel.
Georgia Tech biomedical engineer Steve Potter explained his work harnessing the behavior of neurons grown on a grid of electrodes. The neurons, isolated from rats, produce bursts of electrical signals in various patterns, which can be “tuned” by the inputs they receive.
“The cells want to form circuits and wire themselves up,” he said.
As for future opportunities, he cited the technique of deep brain stimulation as well as clinical trials in progress, including one testing technology developed by the company Neuropace that monitors the brain’s electrical activity for the purpose of suppressing epileptic seizures. Similar technology is being developed to help control prosthetic limbs and could also promote recovery from brain injury or stroke, he said. Eventually, electrical stimulation that is not modulated according to feedback from the brain will be seen as an overly blunt instrument, even “barbaric,” he said.
Mike Kuhar, a neuroscientist at Yerkes National Primate Research Center, introduced the topic of cognitive enhancers or “smart drugs.” He described one particular class of proposed cognitive enhancers, called ampakines, which appear to improve functioning on certain tasks without stimulating signals throughout the brain. Kuhar questioned whether “smart drugs” pose unique challenges, compared to other types of drugs. From a pharmacology perspective, he said there is less distinction between therapy and enhancement, compared to a perspective imposed by regulators or insurance companies. He described three basic concerns: safety (avoiding toxicity or unacceptable side effects), freedom (lack of coercion from governments or employers) and fairness.
“Every drug has side effects,” he said. “There has to be a balance between the benefits versus the risks, and regulation plays an important role in that.”
He identified antidepressants and treatments for attention deficit-hyperactivity disorder or the symptoms of Alzheimer’s disease as already raising similar issues. The FDA has designated mild cognitive impairment associated with aging as an open area for pharmaceutical development, he noted.
James Hughes, a sociologist from Trinity College and executive director of the Institute for Ethics and Emerging Technologies, welcomed new technologies that he said could not only treat disease, but also enhance human capabilities and address social challenges such as criminal rehabilitation. However, he did identify potential “Ulysses problems”, where users of new technologies would need to exercise control and judgment.
In contrast, historian and Judaic scholar Hava Tirosh-Samuelson, from Arizona State University, decried an “overly mechanistic and not culturally-based understanding of what it means to be human.” She described transhumanism as a utopian extension of 19th century utilitarianism as expounded by thinkers such as Jeremy Bentham.
“Is the brain simply a computational machine?” she asked.
The use of military metaphors – such as “the war on cancer” – in the context of mental illness creates the false impression that everything is correctable or even perfectable, she said.
Representative Gabrielle Giffords. Photo courtesy Giffords’ House office.
As we watch the daily progress of Representative Gabrielle Giffords, many close observers have commented that her recovery has been moving along more quickly than expected, and took a big leap after the visit from President Obama. Related? Perhaps.
Emory Psychologist, Dr. Nadine Kaslow, says there is no question that love and support from family, friends, and others individuals a patient is close to, can make an enormous difference in the recovery process.
She explains that after people come out of a coma, they often seem to have a special connection to those who were there for them during the coma, even if they don’t actually remember anything in a conscious way. Efforts to communicate with the patient, she says, whether those be verbal or physical, can reinforce linking and communication. She adds patients who have physical contact from a loved one seem to visibly relax and engage more.
At Emory, as we move more and more to patient and family centered health care, we actively encourage loved ones to talk with the patient, read to the patient, touch and stroke the patient. Additionally, beds and shower facilities are provided so that family members can be with their loved ones around the clock.
Owen Samuels, MD, director of Emory University Hospital’s neuroscience critical care unit, reiterates that patient families are now recognized as central to the healing process and their presence can even reduce a patient’s length of stay. He says that in a neurology ICU, where the average length of stay is 13 days, but is often many, many more, this can be especially beneficial.
One of the Emory SFN presentations covered efforts to find progesterone analogues that are more water soluble. This work comes from Stein and his colleagues in collaboration with the laboratory of Dennis Liotta, PhD, Emory professor of chemistry.
Currently, the lack of water solubility limits delivery of progesterone, in that the hormone must be prepared hours ahead and cannot be kept at room temperature. Small chemical modifications may allow similar compounds with the same effects as progesterone to be given to patients closer to the time of injury.
According to the results, two compounds similar to progesterone showed an equivalent ability to reduce brain swelling in an animal model of traumatic brain injury.
The second Emory report described evidence that adding vitamin D to progesterone enhances the hormone’s effectiveness when applied to neurons under stress in the laboratory. Like progesterone, vitamin D is a steroid hormone that is inexpensive, has good safety properties and acts on many different biochemical pathways.
David Wright, MD
The authors showed that a low amount of vitamin D boosted the ability of progesterone to protect neurons from excito-toxicity , a principal cause of brain injury and cell death.
A new study at Emory, slated to begin early 2010, will evaluate progesterone’s effectiveness for treating traumatic brain injury in a multisite phase III clinical trial called ProTECT III.
The study follows earlier findings that showed giving progesterone to trauma victims shortly after brain injury appears to be safe and may reduce the risk of death and long-term disability.
David Wright, MD, assistant professor of emergency medicine at Emory School of Medicine is the national study’s lead investigator.
Michael Frankel, MD, Emory professor of neurology, will serve as site principal investigator of the clinical trial at Grady Memorial Hospital.
You or a loved one is suffering severe brain trauma in the wake of an accident. Imagine if doctors told you there was a treatment available that could up your chances of survival and even your chances at recovery. This isn’t just theoretical, because that’s an option some Emory patients have had, thanks to the availability of PROTECT, a progesterone-based treatment developed at Emory University and being administered by Emory trauma doctors.