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.

 

 

Brain cells that control appetite identified for first time

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Dieting could be revolutionized, thanks to the ground-breaking discovery by the University of Warwick on the key brain cells which control our appetite. Professor Nicholas Dale in the School of Life Sciences has identified for the first time that tanycytes, cells found in part of the brain that controls energy levels, detect nutrients in food and tell the brain directly about the food we have eaten. According to the new research, tanycytes in the brain respond to amino acids found in foods, via the same receptors that sense the flavor of amino acids (“umami” taste), which are found in the taste buds of the tongue. Two amino acids that react most with tanycytes, and therefore are likely to make you feel more full, are arginine and lysine.

These amino acids are found in high concentrations in foods such as pork shoulder, beef sirloin steak, chicken, mackerel, plums, apricots, avocadoes, lentils and almonds. Therefore, eating those foods will activate the tanycytes, based on the research, and make you feel less hungry more quickly. The researchers made their discovery by adding concentrated amounts of arginine and lysine into brain cells, which were made fluorescent so that any microscopic reactions would be visible. They observed that within thirty seconds, the tanycytes detected and responded to the amino acids, releasing information to the part of the brain that controls appetite and body weight. They found that signals from amino acids are directly detected by the umami taste receptors by removing or blocking these receptors and observing that the amino acids no longer reacted with tanycytes.

Nicholas Dale, who is Ted Pridgeon Professor of Neuroscience at the University of Warwick, commented: “Amino acid levels in blood and brain following a meal are a very important signal that imparts the sensation of feeling full. Finding that tanycytes, located at the centre of the brain region that controls body weight directly sensing amino acids, has very significant implications for coming up with new ways to help people control their body weight within healthy bounds.” This major discovery opens up new possibilities for creating more effective diets, and even future treatments to suppress one’s appetite by directly activating the brain’s tanycytes, bypassing food and the digestive system. Nearly two thirds of the UK population is overweight or obese and one third of the U.S. population is obese. This excess weight elevates the risk of premature death and a range of illnesses, such as cancer, diabetes, cardiovascular disease and stroke, which greatly reduce quality of life. A new understanding of how appetite functions could curb the growing obesity crisis.

The research, ‘Amino Acid Sensing in Hypothalamic Tanycytes via Umami Taste Receptors’, will be published in Molecular Metabolism and is funded by the Biotechnology and Biological Sciences Research Council.

Adapted from: University of Warwick. (2017, September 27). Brain cells that control appetite identified for first time: Dieting could be revolutionized, thanks to the groundbreaking discovery by the University of Warwick of the key brain cells which control our appetite. ScienceDaily. Retrieved December 21, 2017 from http://www.sciencedaily.com/releases/2017/09/170927093254.htm

Nutrition Tip of the Day

Make snacks count! Be sure your snack consists of protein, whole grains and healthy fat for the trifecta that will keep you feeling fuller longer.

Daily Inspiration 

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