A dietary supplement dampens the brain hyperexcitability seen in seizures or epilepsy

Researchers have found that inducing a biochemical alteration in brain proteins via the dietary supplement glucosamine was able to rapidly dampen that pathological hyperexcitability in rat and mouse models. These results represent a potentially novel therapeutic target for the treatment of seizure disorders, and they show the need to better understand the physiology underlying these neural and brain circuit changes.

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Seizure disorders, including epilepsy, are associated with pathological hyperexcitability in brain neurons. Unfortunately, there are limited available treatments that can prevent this hyperexcitability. However, the *University of Alabama at Birmingham researchers have found that inducing a biochemical alteration in brain proteins via the dietary supplement glucosamine was able to rapidly dampen that pathological hyperexcitability in rat and mouse models.


These results represent a potentially novel therapeutic target for the treatment of seizure disorders, and they show the need to better understand the physiology underlying these neural and brain circuit changes. Proteins are the workhorses of living cells, and their activities are tightly and rapidly regulated in responses to changing conditions. Adding or removing a phosphoryl group of proteins is a well-known regulator of many proteins, and it is estimated that human proteins may have as many as 230,000 sites for phosphorylation. A lesser-known regulation comes from the addition or removal of N-acetylglucosamine to proteins, which is usually controlled by glucose, the primary fuel for neurons. Several years ago, neuroscientist Lori McMahon, Ph.D., professor of cell, developmental and integrative biology at UAB, found out from her colleague John Chatham, D.Phil., a UAB professor of pathology and a cardiac physiologist, that brain cells had the second-highest amounts of proteins with N-acetylglucosamine, or O-GlcNAcylation, in the body.

At the time, very little was known about how O-GlcNAcylation might affect brain function, so McMahon and Chatham started working together. In 2014, McMahon and Chatham, in a study led by graduate student Erica Taylor and colleagues, reported that acute increases in protein O-GlcNAcylation caused long-term synaptic depression, a reduction in neuronal synaptic strength, in the hippocampus of the brain. This was the first time acute changes in O-GlcNAcylation of neuronal proteins were shown to directly change synaptic function. Since neural excitability in the hippocampus is a crucial feature of seizures and epilepsy, they hypothesized that acutely increasing protein O-GlcNAcylation might dampen the pathological hyperexcitability associated with these brain disorders.

That turned out to be the case, as reported in the Journal of Neuroscience study, “Acute increases in protein O-GlcNAcylation dampen epileptiform activity in the hippocampus.” The study was led by corresponding author McMahon and first author Luke Stewart, a doctoral student in the Neuroscience Theme of the Graduate Biomedical Sciences Program. Stewart is co-mentored by McMahon and Chatham. “Our findings support the conclusion that protein O-GlcNAcylation is a regulator of neuronal excitability, and it represents a promising target for further research on seizure disorder therapeutics,” they wrote in their research significance statement. The researchers caution that the mechanism underlying the dampening is likely to be complicated.

Research details

Glucose, the primary fuel for neurons, also controls the levels of protein O-GlcNAcylation on proteins. However, high levels of the dietary supplement glucosamine, or an inhibitor of the enzyme that removes O-GlcNAcylation, leads to rapid increases in O-GlcNAc levels. In experiments with hippocampal brain slices treated to induce stable and ongoing hyperexcitability, UAB researchers found that an acute rise in protein O-GlcNAcylation significantly decreased the sudden bursts of electrical activity known as epileptiform activity in area CA1 of the hippocampus. An increased protein O-GlcNAcylation in normal cells also protected against a later induction of drug-induced hyperexcitability.

The effects were seen in slices treated with both glucosamine and an inhibitor of the enzyme that removes O-GlcNAc groups. They also found that treatment with glucosamine alone for as short a time as 10 minutes was able to dampen ongoing drug-induced hyperexcitability. In common with the long-term synaptic depression provoked by increased O-GlcNAcylation, the dampening of hyperexcitability required the GluA2 subunit of the AMPA receptor, which is a glutamate-gated ion channel responsible for fast synaptic transmission in the brain. This finding suggested a conserved mechanism for the two changes provoked by increased O-GlcNAcylation — synaptic depression and dampening of hyperexcitability.

The researchers also found that the spontaneous firing of pyramidal neurons in another region of hippocampus, area CA3, was reduced by increased O-GlcNAcylation in normal brain slices and in slices with drug-induced hyperexcitability. This reduction in spontaneous firing of CA3 pyramidal neurons likely contributes to decreased hyperexcitability in area CA1 since the CA3 neurons directly excite those in CA1. Similar to the findings for brain slices, mice that were treated to increase O-GlcNAcylation before getting drug-induced hyperexcitability had fewer of the brain activity spikes associated with epilepsy that are called interictal spikes. Several drug-induced hyperexcitable mice had convulsive seizures during the experiments, this occurred in both the increased O-GlcNAcylation mice and the control mice. Brain activity during the seizures differed between these two groups: The peak power of the brain activity for the mice with increased O-GlcNAcylation occurred at a lower frequency, as compared with the control mice.

*I am very proud to say UA (though UA Tuscaloosa) is my graduate program home!

Adapted from: Luke T. Stewart, Anas U. Khan, Kai Wang, Diana Pizarro, Sandipan Pati, Susan C. Buckingham, Michelle L. Olsen, John C. Chatham, Lori L. McMahon. Acute Increases in Protein O-GlcNAcylation Dampen Epileptiform Activity in HippocampusThe Journal of Neuroscience, 2017; 37 (34): 8207 DOI: 10.1523/JNEUROSCI.0173-16.2017

Nutrition Daily Nugget…..and a bit of wine! 

Watch out for added sugars! They add extra calories but no helpful nutrients. Sugar-sweetened beverages and soft drinks are the number one source of added sugars for most of us.

AND….if you are looking for some excellent wine selections, check out Bright Cellars. The link is also on the right side of my blog for future reference.

Daily Inspiration Nugget

Never stop believing in hope. Miracles happen everyday.



Pass the salt: Mapping the neurons that drive salt cravings

D.+Sodium+intake+Just+as+thirst+stimulates+water+intake,+salt+craving+triggers+a+need+to+ingest+NaCl..jpgWhile the average American’s high-salt diet has been linked to high blood pressure and cardiovascular disease, the truth is we couldn’t live without this once scarce mineral. Salt helps the body balance its water content and plays a critical role in regulating blood pressure and cellular function throughout the body. As salt is lost through excretion and other metabolic processes, hormones are released in response to sodium deficiency. However, exactly how these hormones work on the brain to trigger salt-seeking and salt-consuming behavior has remained a mystery.

Now, a team of scientists in the Division of Endocrinology, Diabetes and Metabolism at Beth Israel Deaconess Medical Center (BIDMC), have shed new light on the process. In research published (September, 2017) in the journal Neuron, a team of scientists working in the lab of Bradford Lowell, MD, PhD, identified the sub-population of neurons that respond to the body’s sodium deficiency and mapped the brain circuitry underlying the drive to consume salt. “We identified a specific circuit in the brain that detects sodium deficiency and drives an appetite specific for sodium to correct the deficiency,” said co-first author Jon M. Resch, PhD, a post-doctoral fellow in Lowell’s lab. “In addition, this work establishes that sodium ingestion is tightly regulated by the brain, and dysfunction in these neurons could lead to over or under consumption of sodium, which could lead to stress on the cardiovascular system over time.”

The team focused on a subset of neurons, known as NTSHSD2, discovered a decade ago by co-corresponding author, Joel Geerling, MD, PhD, formerly of BIDMC and now assistant professor in the Department of Neurology at Carver College of Medicine at the University of Iowa. In a series of experiments in sodium-deficient mice, the researchers demonstrate that sodium deficiency activates these neurons. They also showed that the presence of the hormone aldosterone, which the body releases during sodium deficiency, increases the neurons’ response. “These neurons appear to be highly influenced by these hormones and less so by inputs from other neurons — though further study is warranted,” said Resch. “This is a unique and very unexpected feature of these NTSHSD2 neurons.”

The researchers also revealed that NTSHSD2 neurons, located in a part of the brain called the nucleus of the solitary tract, are not solely responsible for driving the sodium appetite. In experiments using mice not deficient in sodium, artificial activation of NTSHSD2 neurons triggered sodium consumption only when there was also concurrent signaling by angiotensin II, a hormone also released by the body during sodium deficiency. From this, Resch and colleagues concluded that another set of neurons sensitive to angiotensin II likely plays a role in driving sodium appetite. These neurons have yet to be identified.

The findings demonstrated that only a synergistic relationship between the two distinct sub-populations of neurons that respond to aldosterone and angiotensin II can cause the rapid and robust onset of the sodium appetite seen in the experimentally deficient mice. Resch notes the sodium-appetite circuity he and colleagues have revealed provides a physiological framework for a hypothesis put forth in the early 1980s. “Several questions remain with regard to how sodium appetite works, but a major one is where ATII is acting in the brain and how the signal works in concert with NTSHSD2 neurons that respond to aldosterone,” he said. “We have already begun work to help us close these gaps in our knowledge.”

Adapted from: Jon M. Resch, Henning Fenselau, Joseph C. Madara, Chen Wu, John N. Campbell, Anna Lyubetskaya, Brian A. Dawes, Linus T. Tsai, Monica M. Li, Yoav Livneh, Qingen Ke, Peter M. Kang, Géza Fejes-Tóth, Anikó Náray-Fejes-Tóth, Joel C. Geerling, Bradford B. Lowell. Aldosterone-Sensing Neurons in the NTS Exhibit State-Dependent Pacemaker Activity and Drive Sodium Appetite via Synergy with Angiotensin II Signaling. Neuron, 2017; 96 (1): 190 DOI: 10.1016/j.neuron.2017.09.014

Nutrition Tip of the Day

Make it fun for kids to try new fruits and vegetables! Let them pick out a new fruit or vegetable in the grocery store each week, and figure out together how to cook or prepare it in a healthy way.

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