Neuroprotective drugs might seemÂ impractical or improbable right now, after twoÂ big clinical trials testing progesterone in traumatic brain injury didn’t work out. But oneÂ close observer of drug discovery isÂ predicting a “coming boom in brain medicines.” Maybe this research, which Emory scientists have been pursuing for a long time, will be part of it.
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.
Now researchers have found a potential path around this obstacle. The results were published in Neuron.
â€œWe 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,â€ says senior author Stephen Traynelis, PhD, professor of pharmacology at Emory University School of Medicine.
â€œThese 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.â€ Read more
The importance of the SorLA or LR11 receptor in braking Alzheimer’s was originally defined here at Emory by Jim Lah and Allan Levey’s labs. Japanese researchers recently determined the structure of SorLA and published the results in Nature Structural and Molecular Biology. Their findings point toward a direct role for SorLA in binding toxic circulating beta-amyloid and transporting it to the lysosome for degradation. Hat tip to Alzforum.
Gary Miller’s lab at Emory was the launching pad for this studyÂ from Rutgers, published last week in the FASEB Journal, showing a potentialÂ connection between a common type of insecticideÂ used at home and in agriculture, pyrethroids, and attention deficit hyperactivity disorder (ADHD).Â Read more
A new paper in PNAS from geneticist Steve Warren and colleagues illustratesÂ the complexity of the protein disrupted in fragile X syndrome. It touches on how proposed drug therapies that address one aspect of fragile X syndrome may not be able to compensate for all of them. [For a human side of this story, read/listen to this recent NPR piece from Jon Hamilton.]
Fragile X syndrome is the most common single-gene disorder responsible for intellectual disability. Most patients with fragile X syndrome inherit it because a repetitive stretch of DNA, which is outside the protein-coding portion of the fragile X gene, is larger than usual. The expanded number of CGG repeats silences the entire gene.
However, simple point mutations affecting the fragile X protein are possible in humans as well. In the PNAS paper, Warren’s team describes what happens with a particularly revealing mutation, which allowed researchers to dissect fragile X protein’s multifaceted functions. Read more
Much of neuroscientist Shannon Gourleyâ€™s work focuses on the idea that adolescence is a vulnerable time for the developing brain. She and graduate student Lauren DePoy recently published a paper in Frontiers in Pharmacology showing that in adolescent rodents, cocaine exposure can cause the loss of dendritic arbors in part of the brain important for decision-making.
The researchers examined neurons in the orbitofrontal cortex, a region of the brain thought to be important for â€œlinking reward to hedonic experience.â€ It was known that stimulants such as cocaine can cause the loss of dendritic spines: small protrusions that are critical for communication and interaction between neurons.
â€œTo make an analogy, itâ€™s like a tree losing some of its leaves,â€ Gourley writes. â€œLaurenâ€™s work shows for the first time that if cocaine is given in adolescence, it can cause the loss of dendrite arbors â€“ as if entire branches are being cut from the tree.â€
The mice are exposed to cocaine over the course of five days in early adolescence, and then their behavior is studied in adulthood. This level of cocaine exposure leads to impairments in instrumental task reversal, a test where mice need to change their habits (which chamber they poke their noses into) to continue receiving food pellets.
The findings suggestÂ a partial explanation for the increased risk of dependence in people who start using cocaine during adolescence.
Chorioamnionitis is a complication of pregnancy: inflammation of the membranes surrounding the fetus, caused by a bacterial infection. It has the potential to inflict damage to the brain of the fetus, especially when combined with fetal hypoxia, and is a known risk factor for developing cerebral palsy.
Chia-Yi (Alex) Kuan and his team, who study fetal brain injury in the Department of Pediatrics, have a new paper in Journal of Neuroscience on a strategy for inhibiting fetal brain inflammation. Postdoctoral fellows Dianer Yang, Yu-Yo Sun and Siddhartha Kumar Bhaumik are co-first authors.
The researchers show that a typeÂ of immune cells called Th17 cells seems to be driving inflammation because the rest of the fetal immune system is still immature. A marker of Th17 cells is elevated in blood samples from human infants with chorioamnionitis, the researchers found. Th17 cells are thought to be important for both autoimmunity and anti-microbial responses.
A drug called fingolimod, which stops immune cells from circulating out of the lymph nodes, was effective in reducing inflammation-induced fetal brain injury in animal models. Fingolimod has been approved by the FDA for use with multiple sclerosis and has been studied in clinical trials of kidney transplantation. The authors write that it may be a potential add-on to hypothermia as a treatment for infants in danger of hypoxia + infection-induced brain damage.
Pathologist Keqiang Ye and his colleagues have been studying the functions of an enzyme called AEP, or asparagine endopeptidase, in the brain. AEP is activated by acidic conditions, such as those induced by stroke or seizure.
AEP is a protease. That means it acts as a pair of scissors, snipping pieces off other proteins. In 2008, his laboratory published a paper in Molecular Cell describing how AEPâ€™s acid-activated snipping can unleash other enzymes that break down brain cellsâ€™ DNA.
Following a hunch that AEP might be involved in neurodegenerative diseases, Yeâ€™s team has discovered that AEP also acts on tau, which forms neurofibrillary tangles in Alzheimerâ€™s disease.
â€œWe were looking for additional substrates for AEP,â€ Ye says. â€œWe knew it was activated by acidosis. And we had readÂ in the literature that the aging brain tends to be more acidic, especially in Alzheimerâ€™s.â€
The findings, published in Nature Medicine in October, point to AEP as a potential target for drugs that could slow the advance of Alzheimerâ€™s, and may also lead to improved diagnostic tools. Read more
The locus coeruleus is a part of the brain that has been getting a lot of attention recently from Emory neuroscienceÂ researchers.
The locus coeruleus is the biggest source of the neurotransmitter norepinephrine in the brain. Located deep in the brainstem, it has connections all over the brain, and is thought to be involved in arousal and attention, stress, memory, the sleep-wake cycle and balance.
Researchers interested in neurodegenerative disease want to look at the locus coeruleus because it may be one of the first structures to degenerate in diseases such as Alzheimerâ€™s and Parkinsonâ€™s. In particular, the influential studies of German neuro-anatomist Heiko Braak highlight the locus coeruleus as a key â€œcanary in the coal mineâ€ indicator of neurodegeneration.
Thatâ€™s why neurologist Dan Huddleston, working with biomedical imaging specialists Xiangchuan Chen and Xiaoping Hu and colleagues at Emory, hasÂ been developing a method for estimating the volume of the locus coeruleus by magnetic resonance imaging (MRI). Their procedure uses MRI tuned in such a way to detect the pigment neuromelanin (see panel), whichÂ accumulate in both theÂ locus coeruleus and in the substantia nigra. Read more
Emory researchers led by neurologist Manuel Yepes, MD have identified a protein released by neurons while the brain is recovering from a stroke.Â The results were published online today inÂ Journal of Neuroscience.
The protein, called urokinase-type plasminogen activator or uPA, has been approved by the FDA to dissolve blood clots in the lungs. It has been tested in clinical trialsÂ in some countriesÂ as a treatment for acute stroke.
The Emory teamâ€™s findings suggest that in stroke, uPAâ€™s benefits may extend beyond the time when doctorsâ€™ principal goal is dissolving the blood clot that is depriving the brain of blood.
Instead, uPA appears to help brain cells recover from the injuries induced by loss of blood flow. Treating mice with uPA after an experimental stroke can improve their recovery of motor function, the researchers found.