Conference News Update—Federation of American Societies for Experimental Biology

Antioxidant Therapy May Have Promising Potential in Concussion Treatment
A study conducted by investigators at West Virginia University suggests that antioxidants may play a key role in reducing the long-term effects of concussions and could potentially offer a unique new approach for treatment.

It is estimated that 3.4 million concussions occur each year in the United States, and concussions are common among athletes and soldiers. The development of a readily available oral supplement would have the potential to improve brain function in a percentage of individuals with concussion.

The study adds to recent findings that concussions can lead to chronic traumatic encephalopathy. Head injuries often result in chronic traumatic encephalopathy, a disease associated with long-term brain damage and behavioral symptoms including memory loss, impulsive behavior, depression, and aggression. The number of retired athletes and veterans diagnosed with chronic traumatic encephalopathy has climbed in recent years.

“Concussions can contribute to long-term changes within the brain, and these changes are the result of cell death, which may be caused by oxidative stress,” said Brandon Lucke-Wold, an MD and PhD student at West Virginia University’s Medical School in Morgantown. “This study shows that antioxidants such as lipoic acid can reduce the long-term deficits when given after a concussion.”

In Mr. Lucke-Wold’s research, rats were separated into three groups: a nonconcussed control group, a group that experienced concussive injury, and another concussed group that received lipoic acid supplementation. Seven days after the concussion, the rats were tested for seemingly impulsive behavior through an elevated maze. The rats exposed to concussion without lipoic acid had increased impulsive behavior and spent more time exploring open spaces, which indicates risk-taking behavior.

“This increase in impulsive behavior was an indication of underlying brain damage,” said Mr. Lucke-Wold. Analysis of the brains of the group receiving supplementation showed markedly decreased impulsive behavior. “These findings make sense because lipoic acid works to help reduce toxic free radicals that can damage cells.

“By understanding the mechanisms behind brain injury following concussion, we can more effectively target treatment interventions to reduce these damaging effects,” Mr. Lucke-Wold concluded.

New Compounds Could Offer Therapy for Various Diseases
Newly developed compounds safely prevented harmful protein aggregation in preliminary tests using animals, according to an international team of more than 18 research groups. The research findings suggest that a new class of drugs may be on the horizon for the more than 30 diseases and conditions that involve protein aggregation, including spinal cord injury, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, diabetes, and cancer.

“Diseases caused by protein aggregation affect millions of people around the world,” said Gal Bitan, PhD, Associate Professor of Neurology at the David Geffen School of Medicine at the University of California, Los Angeles. “We hope that the new compounds will provide therapy for diseases caused by protein aggregation, many of which have no treatment at all.”

The researchers call the compounds that they developed molecular tweezers because of the way they wrap around the lysine amino acid chains that make up most proteins. The compounds are unique in their ability to attack only aggregated proteins, leaving healthy proteins alone.

To develop a new drug, researchers typically screen large libraries of compounds to find ones that affect a protein involved in a disease. Dr. Bitan’s team used a fundamentally different approach to develop the molecular tweezers.

“We looked at the molecular and atomic interactions of proteins to understand what leads to their abnormal clumping,” Dr. Bitan said. “Then we developed a tailored solution. So, unlike many other drugs, we understand how and why our drug works.”

The team is in the process of testing multiple versions of the tweezers, each with a slightly different molecular makeup. For CLR01, one of the most promising versions, the researchers have demonstrated therapeutic benefits in two rodent models of Alzheimer’s disease, two fish and one mouse model of Parkinson’s disease, a fish model of spinal cord injury, and a mouse model of familial amyloidotic polyneuropathy, a rare disease in which protein aggregation affects the nervous system, heart, and kidneys.

“Our data suggest that CLR01 or a derivative thereof may become a drug for a number of diseases that involve protein aggregation,” Dr. Bitan said. “We also found a high safety window for CLR01.”

In one of the safety tests, mice receiving a daily dose of CLR01 that was 250 times higher than the therapeutic dose for one month showed no behavioral or physiologic signs of distress or damage. In fact, blood cholesterol in the mice decreased by 40%, a possible positive side effect of CLR01.

The researchers are continuing to study CLR01 in animal models of various diseases and are working to secure funding for more animal studies. The investigators are also making improvements that would allow CLR01 to be administered in a pill or capsule rather than requiring an injection.

Neurologic Diseases Share Common Blood–Brain Barrier Defects
Although stroke, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis (ALS), and traumatic brain injury each affect the CNS differently, they share common defects in the blood–brain barrier that can be traced to a single set of genes, according to a new study. The findings could yield new approaches for treating brain diseases.

To protect the brain from harm, endothelial cells lining the blood vessels around the brain form a barrier that lets only specific molecules move from the blood to the brain. In people with certain diseases or brain injuries, the barrier doesn’t work properly and can allow dangerous molecules or pathogens into the brain.

“Our goal is to identify the mechanisms that lead to this disruption of the blood–brain barrier in stroke, multiple sclerosis, epilepsy, ALS, and traumatic brain injury,” said Richard Daneman, PhD, fellow at the University of California, San Diego, and leader of the research team. “For these diseases, the blood–brain barrier dysfunction is a significant contributor to symptoms and disease progression, so if we can stop the endothelial cells from going down this path, we could possibly limit the progression and the severity of these diseases.”

To identify molecular pathways and genes that are important for blood–brain barrier dysfunction, Dr. Daneman developed a way to isolate blood–brain barrier endothelial cells and compare gene expression in cells from healthy brain tissue to cells from the brains of mouse models of stroke, multiple sclerosis, epilepsy, traumatic brain injury, and ALS.

“Even though the diseases we looked at all have different triggers, we see very similar genes changing in all the different diseases within the brain endothelial cells,” said Dr. Daneman. “The fact that we found a common pathway means we could potentially find a single therapeutic target that could stop these different neurological diseases from occurring or progressing.”

To learn more about the exact function of genes that they identified as being involved in blood–brain barrier dysfunction, the researchers plan to create genetically modified mice with brain endothelial cells that either overexpress or lack a given gene. “If we can develop methods to stop these genes from being turned on, we may be able to limit the blood–brain barrier dysfunction,” Dr. Daneman said.

Genetic Variability in the Platelet Linked to Increased Risk for Clotting
Coronary heart disease and stroke, two of the leading causes of death in the United States, are associated with heightened platelet reactivity. An underlying reason for the variability in the risk of clotting may result from a genetic variation in a receptor on the surface of the platelet, according to researchers. In addition, people with this genetic variant may be less protected from clotting and thrombosis when taking current antiplatelet therapies such as aspirin and other blood-thinning medications.

Antiplatelet therapy has helped to reduce mortality associated with heart attacks and strokes significantly. Some individuals taking antiplatelet drugs are not fully protected from platelet clot formation, however. For example, black individuals are disproportionately affected by these diseases, compared with white individuals, even after adjusting for clinical and demographic factors.

Benjamin Tourdot, PhD, a postdoctoral fellow on a research team led by Michael Holinstat, PhD, Associate Professor of Pharmacology at the University of Michigan in Ann Arbor, recently discovered a genetic variant in a key platelet receptor, PAR4, that enhances platelet reactivity and is more frequently expressed in blacks than whites.

Although the genetic variation is more common in blacks than in whites, it is relatively common in both races. Approximately 76% of blacks and 36% of whites express at least one copy of the gene responsible for the hyper-responsiveness.

To determine whether individuals with the hyper-responsive form of PAR4 may be less protected following a myocardial infarction or stroke even after receiving recommended antiplatelet therapy, the investigators compared healthy individuals and cardiac patients with and without the mutation for their responsiveness to PAR4. Participants were taking standard-of-care antiplatelet therapy (ie, aspirin and Plavix). The preliminary data demonstrated that, independent of race, individuals with a copy of the hyperactive variant of PAR4 have an increase in PAR4-mediated platelet reactivity, compared with individuals without the variant, even in the presence of antiplatelet therapy.

This research could identify the PAR4 T120A variant as a potential risk factor for thrombosis and would require a new approach to treating patients with this genetic variant, including the development of PAR4 antagonists. A greater understanding of which patients benefit the most from current therapeutic strategies and which patients remain at elevated risk for a thrombotic event will aid in the development of new therapeutic targets for at-risk populations.

This study illustrates potential benefits of the personalized medicine approach to therapeutic intervention and challenges the one-size-fits-all approach, which often leaves at-risk populations without adequate protection from thrombotic events and stroke.

More Reasons Why Getting a Good Night’s Sleep Is Important
Not getting enough sleep not only makes our minds less alert, but our bodies, too. Studies have suggested that losing several hours of sleep can slow the body’s metabolism. A team of researchers from the University of South Carolina and Arizona State University found that metabolic effects are seen even when sleep is shortened by two hours.

In this study, 15 healthy nonobese young adult volunteers completed two oral glucose tolerance tests. One was after three days of sleep restricted by two hours each day, and the other was after three days of ad libitum sleep. Plasma samples were collected before and 30, 60, 90, and 120 minutes after consumption of a glucose drink to determine glucose and insulin concentrations. Fasting C-peptide concentration was also determined.

The researchers observed that glucose concentrations before and 30, 60, 90, and 120 minutes following consumption of glucose were not different during the two glucose tolerance tests. Glucose area under the curve was also similar. Insulin concentrations before and 60, 90, and 120 minutes following consumption of glucose were not different, but insulin concentration 30 minutes following consumption of glucose was higher after restricted sleep (31.4 uIU/mL) than ad libitum sleep (23.7 uIU/mL). Insulin area under the curve and fasting C-peptide concentration were also greater following restricted sleep than ad libitum sleep. Sleeping two hours less thus increased insulin concentration, suggesting that cutting sleep even a little can alter metabolism.

“Our study was conducted in a group of young healthy adults after only three days of shortened sleep by two hours,” said Xuewen Wang, PhD, Assistant Professor of Exercise Science at the University of South Carolina in Columbia. “The study findings are important because this amount of shortened sleep is often seen in real life. Our next step is to find out whether the sleep pattern of shortened sleep during the week and catching-up sleep during the weekend affects glucose metabolism in the longer term. We are also interested in finding out the responses in individuals who already have impaired glucose metabolism.”

Antioxidant Therapy May Have Promising Potential in Concussion Treatment
A study conducted by investigators at West Virginia University suggests that antioxidants may play a key role in reducing the long-term effects of concussions and could potentially offer a unique new approach for treatment.

It is estimated that 3.4 million concussions occur each year in the United States, and concussions are common among athletes and soldiers. The development of a readily available oral supplement would have the potential to improve brain function in a percentage of individuals with concussion.

The study adds to recent findings that concussions can lead to chronic traumatic encephalopathy. Head injuries often result in chronic traumatic encephalopathy, a disease associated with long-term brain damage and behavioral symptoms including memory loss, impulsive behavior, depression, and aggression. The number of retired athletes and veterans diagnosed with chronic traumatic encephalopathy has climbed in recent years.

“Concussions can contribute to long-term changes within the brain, and these changes are the result of cell death, which may be caused by oxidative stress,” said Brandon Lucke-Wold, an MD and PhD student at West Virginia University’s Medical School in Morgantown. “This study shows that antioxidants such as lipoic acid can reduce the long-term deficits when given after a concussion.”

In Mr. Lucke-Wold’s research, rats were separated into three groups: a nonconcussed control group, a group that experienced concussive injury, and another concussed group that received lipoic acid supplementation. Seven days after the concussion, the rats were tested for seemingly impulsive behavior through an elevated maze. The rats exposed to concussion without lipoic acid had increased impulsive behavior and spent more time exploring open spaces, which indicates risk-taking behavior.

“This increase in impulsive behavior was an indication of underlying brain damage,” said Mr. Lucke-Wold. Analysis of the brains of the group receiving supplementation showed markedly decreased impulsive behavior. “These findings make sense because lipoic acid works to help reduce toxic free radicals that can damage cells.

“By understanding the mechanisms behind brain injury following concussion, we can more effectively target treatment interventions to reduce these damaging effects,” Mr. Lucke-Wold concluded.

New Compounds Could Offer Therapy for Various Diseases
Newly developed compounds safely prevented harmful protein aggregation in preliminary tests using animals, according to an international team of more than 18 research groups. The research findings suggest that a new class of drugs may be on the horizon for the more than 30 diseases and conditions that involve protein aggregation, including spinal cord injury, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, diabetes, and cancer.

“Diseases caused by protein aggregation affect millions of people around the world,” said Gal Bitan, PhD, Associate Professor of Neurology at the David Geffen School of Medicine at the University of California, Los Angeles. “We hope that the new compounds will provide therapy for diseases caused by protein aggregation, many of which have no treatment at all.”

The researchers call the compounds that they developed molecular tweezers because of the way they wrap around the lysine amino acid chains that make up most proteins. The compounds are unique in their ability to attack only aggregated proteins, leaving healthy proteins alone.

To develop a new drug, researchers typically screen large libraries of compounds to find ones that affect a protein involved in a disease. Dr. Bitan’s team used a fundamentally different approach to develop the molecular tweezers.

“We looked at the molecular and atomic interactions of proteins to understand what leads to their abnormal clumping,” Dr. Bitan said. “Then we developed a tailored solution. So, unlike many other drugs, we understand how and why our drug works.”

The team is in the process of testing multiple versions of the tweezers, each with a slightly different molecular makeup. For CLR01, one of the most promising versions, the researchers have demonstrated therapeutic benefits in two rodent models of Alzheimer’s disease, two fish and one mouse model of Parkinson’s disease, a fish model of spinal cord injury, and a mouse model of familial amyloidotic polyneuropathy, a rare disease in which protein aggregation affects the nervous system, heart, and kidneys.

“Our data suggest that CLR01 or a derivative thereof may become a drug for a number of diseases that involve protein aggregation,” Dr. Bitan said. “We also found a high safety window for CLR01.”

In one of the safety tests, mice receiving a daily dose of CLR01 that was 250 times higher than the therapeutic dose for one month showed no behavioral or physiologic signs of distress or damage. In fact, blood cholesterol in the mice decreased by 40%, a possible positive side effect of CLR01.

The researchers are continuing to study CLR01 in animal models of various diseases and are working to secure funding for more animal studies. The investigators are also making improvements that would allow CLR01 to be administered in a pill or capsule rather than requiring an injection.

Neurologic Diseases Share Common Blood–Brain Barrier Defects
Although stroke, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis (ALS), and traumatic brain injury each affect the CNS differently, they share common defects in the blood–brain barrier that can be traced to a single set of genes, according to a new study. The findings could yield new approaches for treating brain diseases.

To protect the brain from harm, endothelial cells lining the blood vessels around the brain form a barrier that lets only specific molecules move from the blood to the brain. In people with certain diseases or brain injuries, the barrier doesn’t work properly and can allow dangerous molecules or pathogens into the brain.

“Our goal is to identify the mechanisms that lead to this disruption of the blood–brain barrier in stroke, multiple sclerosis, epilepsy, ALS, and traumatic brain injury,” said Richard Daneman, PhD, fellow at the University of California, San Diego, and leader of the research team. “For these diseases, the blood–brain barrier dysfunction is a significant contributor to symptoms and disease progression, so if we can stop the endothelial cells from going down this path, we could possibly limit the progression and the severity of these diseases.”

To identify molecular pathways and genes that are important for blood–brain barrier dysfunction, Dr. Daneman developed a way to isolate blood–brain barrier endothelial cells and compare gene expression in cells from healthy brain tissue to cells from the brains of mouse models of stroke, multiple sclerosis, epilepsy, traumatic brain injury, and ALS.

“Even though the diseases we looked at all have different triggers, we see very similar genes changing in all the different diseases within the brain endothelial cells,” said Dr. Daneman. “The fact that we found a common pathway means we could potentially find a single therapeutic target that could stop these different neurological diseases from occurring or progressing.”

To learn more about the exact function of genes that they identified as being involved in blood–brain barrier dysfunction, the researchers plan to create genetically modified mice with brain endothelial cells that either overexpress or lack a given gene. “If we can develop methods to stop these genes from being turned on, we may be able to limit the blood–brain barrier dysfunction,” Dr. Daneman said.

Genetic Variability in the Platelet Linked to Increased Risk for Clotting
Coronary heart disease and stroke, two of the leading causes of death in the United States, are associated with heightened platelet reactivity. An underlying reason for the variability in the risk of clotting may result from a genetic variation in a receptor on the surface of the platelet, according to researchers. In addition, people with this genetic variant may be less protected from clotting and thrombosis when taking current antiplatelet therapies such as aspirin and other blood-thinning medications.

Antiplatelet therapy has helped to reduce mortality associated with heart attacks and strokes significantly. Some individuals taking antiplatelet drugs are not fully protected from platelet clot formation, however. For example, black individuals are disproportionately affected by these diseases, compared with white individuals, even after adjusting for clinical and demographic factors.

Benjamin Tourdot, PhD, a postdoctoral fellow on a research team led by Michael Holinstat, PhD, Associate Professor of Pharmacology at the University of Michigan in Ann Arbor, recently discovered a genetic variant in a key platelet receptor, PAR4, that enhances platelet reactivity and is more frequently expressed in blacks than whites.

Although the genetic variation is more common in blacks than in whites, it is relatively common in both races. Approximately 76% of blacks and 36% of whites express at least one copy of the gene responsible for the hyper-responsiveness.

To determine whether individuals with the hyper-responsive form of PAR4 may be less protected following a myocardial infarction or stroke even after receiving recommended antiplatelet therapy, the investigators compared healthy individuals and cardiac patients with and without the mutation for their responsiveness to PAR4. Participants were taking standard-of-care antiplatelet therapy (ie, aspirin and Plavix). The preliminary data demonstrated that, independent of race, individuals with a copy of the hyperactive variant of PAR4 have an increase in PAR4-mediated platelet reactivity, compared with individuals without the variant, even in the presence of antiplatelet therapy.

This research could identify the PAR4 T120A variant as a potential risk factor for thrombosis and would require a new approach to treating patients with this genetic variant, including the development of PAR4 antagonists. A greater understanding of which patients benefit the most from current therapeutic strategies and which patients remain at elevated risk for a thrombotic event will aid in the development of new therapeutic targets for at-risk populations.

This study illustrates potential benefits of the personalized medicine approach to therapeutic intervention and challenges the one-size-fits-all approach, which often leaves at-risk populations without adequate protection from thrombotic events and stroke.

More Reasons Why Getting a Good Night’s Sleep Is Important
Not getting enough sleep not only makes our minds less alert, but our bodies, too. Studies have suggested that losing several hours of sleep can slow the body’s metabolism. A team of researchers from the University of South Carolina and Arizona State University found that metabolic effects are seen even when sleep is shortened by two hours.

In this study, 15 healthy nonobese young adult volunteers completed two oral glucose tolerance tests. One was after three days of sleep restricted by two hours each day, and the other was after three days of ad libitum sleep. Plasma samples were collected before and 30, 60, 90, and 120 minutes after consumption of a glucose drink to determine glucose and insulin concentrations. Fasting C-peptide concentration was also determined.

The researchers observed that glucose concentrations before and 30, 60, 90, and 120 minutes following consumption of glucose were not different during the two glucose tolerance tests. Glucose area under the curve was also similar. Insulin concentrations before and 60, 90, and 120 minutes following consumption of glucose were not different, but insulin concentration 30 minutes following consumption of glucose was higher after restricted sleep (31.4 uIU/mL) than ad libitum sleep (23.7 uIU/mL). Insulin area under the curve and fasting C-peptide concentration were also greater following restricted sleep than ad libitum sleep. Sleeping two hours less thus increased insulin concentration, suggesting that cutting sleep even a little can alter metabolism.

“Our study was conducted in a group of young healthy adults after only three days of shortened sleep by two hours,” said Xuewen Wang, PhD, Assistant Professor of Exercise Science at the University of South Carolina in Columbia. “The study findings are important because this amount of shortened sleep is often seen in real life. Our next step is to find out whether the sleep pattern of shortened sleep during the week and catching-up sleep during the weekend affects glucose metabolism in the longer term. We are also interested in finding out the responses in individuals who already have impaired glucose metabolism.”

Antioxidant Therapy May Have Promising Potential in Concussion Treatment
A study conducted by investigators at West Virginia University suggests that antioxidants may play a key role in reducing the long-term effects of concussions and could potentially offer a unique new approach for treatment.

It is estimated that 3.4 million concussions occur each year in the United States, and concussions are common among athletes and soldiers. The development of a readily available oral supplement would have the potential to improve brain function in a percentage of individuals with concussion.

The study adds to recent findings that concussions can lead to chronic traumatic encephalopathy. Head injuries often result in chronic traumatic encephalopathy, a disease associated with long-term brain damage and behavioral symptoms including memory loss, impulsive behavior, depression, and aggression. The number of retired athletes and veterans diagnosed with chronic traumatic encephalopathy has climbed in recent years.

“Concussions can contribute to long-term changes within the brain, and these changes are the result of cell death, which may be caused by oxidative stress,” said Brandon Lucke-Wold, an MD and PhD student at West Virginia University’s Medical School in Morgantown. “This study shows that antioxidants such as lipoic acid can reduce the long-term deficits when given after a concussion.”

In Mr. Lucke-Wold’s research, rats were separated into three groups: a nonconcussed control group, a group that experienced concussive injury, and another concussed group that received lipoic acid supplementation. Seven days after the concussion, the rats were tested for seemingly impulsive behavior through an elevated maze. The rats exposed to concussion without lipoic acid had increased impulsive behavior and spent more time exploring open spaces, which indicates risk-taking behavior.

“This increase in impulsive behavior was an indication of underlying brain damage,” said Mr. Lucke-Wold. Analysis of the brains of the group receiving supplementation showed markedly decreased impulsive behavior. “These findings make sense because lipoic acid works to help reduce toxic free radicals that can damage cells.

“By understanding the mechanisms behind brain injury following concussion, we can more effectively target treatment interventions to reduce these damaging effects,” Mr. Lucke-Wold concluded.

New Compounds Could Offer Therapy for Various Diseases
Newly developed compounds safely prevented harmful protein aggregation in preliminary tests using animals, according to an international team of more than 18 research groups. The research findings suggest that a new class of drugs may be on the horizon for the more than 30 diseases and conditions that involve protein aggregation, including spinal cord injury, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, diabetes, and cancer.

“Diseases caused by protein aggregation affect millions of people around the world,” said Gal Bitan, PhD, Associate Professor of Neurology at the David Geffen School of Medicine at the University of California, Los Angeles. “We hope that the new compounds will provide therapy for diseases caused by protein aggregation, many of which have no treatment at all.”

The researchers call the compounds that they developed molecular tweezers because of the way they wrap around the lysine amino acid chains that make up most proteins. The compounds are unique in their ability to attack only aggregated proteins, leaving healthy proteins alone.

To develop a new drug, researchers typically screen large libraries of compounds to find ones that affect a protein involved in a disease. Dr. Bitan’s team used a fundamentally different approach to develop the molecular tweezers.

“We looked at the molecular and atomic interactions of proteins to understand what leads to their abnormal clumping,” Dr. Bitan said. “Then we developed a tailored solution. So, unlike many other drugs, we understand how and why our drug works.”

The team is in the process of testing multiple versions of the tweezers, each with a slightly different molecular makeup. For CLR01, one of the most promising versions, the researchers have demonstrated therapeutic benefits in two rodent models of Alzheimer’s disease, two fish and one mouse model of Parkinson’s disease, a fish model of spinal cord injury, and a mouse model of familial amyloidotic polyneuropathy, a rare disease in which protein aggregation affects the nervous system, heart, and kidneys.

“Our data suggest that CLR01 or a derivative thereof may become a drug for a number of diseases that involve protein aggregation,” Dr. Bitan said. “We also found a high safety window for CLR01.”

In one of the safety tests, mice receiving a daily dose of CLR01 that was 250 times higher than the therapeutic dose for one month showed no behavioral or physiologic signs of distress or damage. In fact, blood cholesterol in the mice decreased by 40%, a possible positive side effect of CLR01.

The researchers are continuing to study CLR01 in animal models of various diseases and are working to secure funding for more animal studies. The investigators are also making improvements that would allow CLR01 to be administered in a pill or capsule rather than requiring an injection.

Neurologic Diseases Share Common Blood–Brain Barrier Defects
Although stroke, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis (ALS), and traumatic brain injury each affect the CNS differently, they share common defects in the blood–brain barrier that can be traced to a single set of genes, according to a new study. The findings could yield new approaches for treating brain diseases.

To protect the brain from harm, endothelial cells lining the blood vessels around the brain form a barrier that lets only specific molecules move from the blood to the brain. In people with certain diseases or brain injuries, the barrier doesn’t work properly and can allow dangerous molecules or pathogens into the brain.

“Our goal is to identify the mechanisms that lead to this disruption of the blood–brain barrier in stroke, multiple sclerosis, epilepsy, ALS, and traumatic brain injury,” said Richard Daneman, PhD, fellow at the University of California, San Diego, and leader of the research team. “For these diseases, the blood–brain barrier dysfunction is a significant contributor to symptoms and disease progression, so if we can stop the endothelial cells from going down this path, we could possibly limit the progression and the severity of these diseases.”

To identify molecular pathways and genes that are important for blood–brain barrier dysfunction, Dr. Daneman developed a way to isolate blood–brain barrier endothelial cells and compare gene expression in cells from healthy brain tissue to cells from the brains of mouse models of stroke, multiple sclerosis, epilepsy, traumatic brain injury, and ALS.

“Even though the diseases we looked at all have different triggers, we see very similar genes changing in all the different diseases within the brain endothelial cells,” said Dr. Daneman. “The fact that we found a common pathway means we could potentially find a single therapeutic target that could stop these different neurological diseases from occurring or progressing.”

To learn more about the exact function of genes that they identified as being involved in blood–brain barrier dysfunction, the researchers plan to create genetically modified mice with brain endothelial cells that either overexpress or lack a given gene. “If we can develop methods to stop these genes from being turned on, we may be able to limit the blood–brain barrier dysfunction,” Dr. Daneman said.

Genetic Variability in the Platelet Linked to Increased Risk for Clotting
Coronary heart disease and stroke, two of the leading causes of death in the United States, are associated with heightened platelet reactivity. An underlying reason for the variability in the risk of clotting may result from a genetic variation in a receptor on the surface of the platelet, according to researchers. In addition, people with this genetic variant may be less protected from clotting and thrombosis when taking current antiplatelet therapies such as aspirin and other blood-thinning medications.

Antiplatelet therapy has helped to reduce mortality associated with heart attacks and strokes significantly. Some individuals taking antiplatelet drugs are not fully protected from platelet clot formation, however. For example, black individuals are disproportionately affected by these diseases, compared with white individuals, even after adjusting for clinical and demographic factors.

Benjamin Tourdot, PhD, a postdoctoral fellow on a research team led by Michael Holinstat, PhD, Associate Professor of Pharmacology at the University of Michigan in Ann Arbor, recently discovered a genetic variant in a key platelet receptor, PAR4, that enhances platelet reactivity and is more frequently expressed in blacks than whites.

Although the genetic variation is more common in blacks than in whites, it is relatively common in both races. Approximately 76% of blacks and 36% of whites express at least one copy of the gene responsible for the hyper-responsiveness.

To determine whether individuals with the hyper-responsive form of PAR4 may be less protected following a myocardial infarction or stroke even after receiving recommended antiplatelet therapy, the investigators compared healthy individuals and cardiac patients with and without the mutation for their responsiveness to PAR4. Participants were taking standard-of-care antiplatelet therapy (ie, aspirin and Plavix). The preliminary data demonstrated that, independent of race, individuals with a copy of the hyperactive variant of PAR4 have an increase in PAR4-mediated platelet reactivity, compared with individuals without the variant, even in the presence of antiplatelet therapy.

This research could identify the PAR4 T120A variant as a potential risk factor for thrombosis and would require a new approach to treating patients with this genetic variant, including the development of PAR4 antagonists. A greater understanding of which patients benefit the most from current therapeutic strategies and which patients remain at elevated risk for a thrombotic event will aid in the development of new therapeutic targets for at-risk populations.

This study illustrates potential benefits of the personalized medicine approach to therapeutic intervention and challenges the one-size-fits-all approach, which often leaves at-risk populations without adequate protection from thrombotic events and stroke.

More Reasons Why Getting a Good Night’s Sleep Is Important
Not getting enough sleep not only makes our minds less alert, but our bodies, too. Studies have suggested that losing several hours of sleep can slow the body’s metabolism. A team of researchers from the University of South Carolina and Arizona State University found that metabolic effects are seen even when sleep is shortened by two hours.

In this study, 15 healthy nonobese young adult volunteers completed two oral glucose tolerance tests. One was after three days of sleep restricted by two hours each day, and the other was after three days of ad libitum sleep. Plasma samples were collected before and 30, 60, 90, and 120 minutes after consumption of a glucose drink to determine glucose and insulin concentrations. Fasting C-peptide concentration was also determined.

The researchers observed that glucose concentrations before and 30, 60, 90, and 120 minutes following consumption of glucose were not different during the two glucose tolerance tests. Glucose area under the curve was also similar. Insulin concentrations before and 60, 90, and 120 minutes following consumption of glucose were not different, but insulin concentration 30 minutes following consumption of glucose was higher after restricted sleep (31.4 uIU/mL) than ad libitum sleep (23.7 uIU/mL). Insulin area under the curve and fasting C-peptide concentration were also greater following restricted sleep than ad libitum sleep. Sleeping two hours less thus increased insulin concentration, suggesting that cutting sleep even a little can alter metabolism.

“Our study was conducted in a group of young healthy adults after only three days of shortened sleep by two hours,” said Xuewen Wang, PhD, Assistant Professor of Exercise Science at the University of South Carolina in Columbia. “The study findings are important because this amount of shortened sleep is often seen in real life. Our next step is to find out whether the sleep pattern of shortened sleep during the week and catching-up sleep during the weekend affects glucose metabolism in the longer term. We are also interested in finding out the responses in individuals who already have impaired glucose metabolism.”