Stroke, here's how the brain's healthy hemisphere influences recovery: the revolutionary research

 Where is the EXACT PROTOCOL THAT DELIVERS RECOVERY? Oh NO, you fucking failed at your only job; creating stroke recovery protocols! You're fired! Your incompetent? doctor and hospital need to ensure human testing occurs.

Do you prefer your doctor, hospital and board of director's incompetence NOT KNOWING? OR NOT DOING? Your choice; let them be incompetent or demand action!

Stroke, here's how the brain's healthy hemisphere influences recovery: the revolutionary research

Rome, March 6. (Adnkronos Health) - After a stroke, attention focuses on the portion of the brain directly affected by the lesion, where neurons have been damaged. However, the functioning of the nervous system does not depend on isolated individual areas, but on networks of connections distributed between the two cerebral hemispheres. When one of the two is damaged, the other can also modify its activity, contributing decisively to recovery or hindering it. A study conducted by the Neuropharmacology Laboratory of Irccs Neuromed in Pozzilli (Isernia), in collaboration with Lund University in Sweden (Tadeusz Wieloch) and Washington University, St. Louis, USA (Adam Bouer), published in 'Stroke', focuses on this balance between the two cerebral hemispheres.

　The research - Neuromed informs - has identified a crucial node for the recovery of motor function precisely in the contralateral hemisphere, i.e., the one opposite to the lesion. In other words, after a stroke, the configuration of brain networks changes profoundly: the unaffected hemisphere can become excessively active, leading to a functional imbalance that hinders recovery.

　To identify possible pharmacological strategies capable of restoring the balance between the two hemispheres - a note explains - researchers focused on type 5 metabotropic glutamate receptors, or mGlu5, proteins that regulate communication between neurons and synaptic plasticity processes, i.e., the brain's ability to modify its connections. To precisely understand how mGlu5 receptors act in promoting or hindering post-stroke recovery, scientists used light-sensitive molecules, capable of being selectively activated or deactivated in specific brain regions. This approach, called photopharmacology, allows modulating the drug's effect in very circumscribed areas without genetically intervening on neurons.

　"Our research - explains Federica Mastroiacovo, from Neuromed's Neuropharmacology Laboratory, the study's first author - has shown that motor recovery after a stroke can be decisively influenced by the cerebral hemisphere not affected by the lesion. By selectively blocking mGlu5 receptors in the homotopic cerebral area contralateral to the lesion, we observed a significant improvement in function, while the same intervention in the lesioned area did not produce comparable effects." For the researchers, this is therefore an intervention aimed at functional recovery, regardless of the extent of ischemic damage and any previous vascular therapeutic strategies.

　"This study - comments Ferdinando Nicoletti, full professor of Pharmacology at Sapienza University of Rome and head of Neuromed's Neuropharmacology Laboratory - precisely identifies the cerebral site necessary for the blockade of mGlu5 receptors to promote recovery. The results indicate that the contralateral hemisphere is not merely a spectator of the damage, but an active participant in network reorganization processes. Understanding these mechanisms is essential for developing increasingly targeted interventions in the post-ischemic phase of stroke".

　The research - the note specifies - was conducted in animal models of stroke and represents an advancement in understanding the neurobiological mechanisms that regulate brain plasticity after ischemic damage. Further studies will be needed to verify if and to what extent these results can be translated into therapeutic applications in humans.

(2026/03/07-06:46)

Adnkronos International: info@adnkronos.com

Insilico Binding Studies of Resveratrol for Protective Effects in Neurodegeneration Using Glutamate Receptor 3B as Target Model

How fucking long before this is tested in humans?  Don't try this on your own, you have no clue how to translate resveratrol and then convert that to bottles of red wine. Our fucking failures of stroke associations will do nothing with this, just like they always do nothing with promising research.

Insilico Binding Studies of Resveratrol for Protective Effects in Neurodegeneration Using Glutamate Receptor 3B as Target Model

• Authors
• Authors and affiliations

• C. S. Reddy Nallagouni
• K. Pratap ReddyEmail author

• C. S. Reddy Nallagouni
  • 1
• K. Pratap Reddy
  • 2
  Email author

1. 1.Department of ZoologyUniversity College of Science, Osmania UniversityHyderabadIndia
2. 2.Neuroscience Lab, Department of ZoologyOsmania UniversityHyderabadIndia

Chapter

First Online: 27 December 2017

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Part of the SpringerBriefs in Applied Sciences and Technology book series (BRIEFSAPPLSCIENCES)

Abstract

Resveratrol, a phytoalexin phenolic compound found in different plants, like berries, grapes, and peanuts and studied on defensive mechanisms of neurodegeneration. Glutamate receptors are synaptic receptors, which are situated on the films of neuronal cells. Glutamate is utilized to gather proteins, however, it additionally works as a neurotransmitter and is especially copious in the sensory system. NMDA receptor 3B utilized clinically as a part of the treatment of AD and in this way it offers a fantastic apparatus to encourage translational extrapolation. In this work, we have demonstrated a three-dimensional structure for glutamate [NMDA] receptor 3B subunit utilizing MODELLER9V7 programming with 2RCA as layout. With the guide of molecular elements and molecular recreations, it was distinguished that the created structure was dependable. This structure was utilized to recognize better inhibitor utilizing docking with Resveratrol. The Resveratrol was docked to the glutamate receptor 3B structure into the dynamic site containing deposits, for example, ASP21, LEU30, TYR31, HIS59, and MET60. Our test studies can be further used to build up a superior medication for Alzheimer’s disease.

Scientists chart how brain signals connect to neurons

Good news. Now our stroke medical professionals can use this to devise a strategy to reconnect brain signals disrupted by your stroke. I would expect an updated strategy in weeks. ROFLMAO
https://medicalxpress.com/news/2017-12-scientists-brain-neurons.html
Scientists at Johns Hopkins have used supercomputers to create an atomic scale map that tracks how the signaling chemical glutamate binds to a neuron in the brain. The findings, say the scientists, shed light on the dynamic physics of the chemical's pathway, as well as the speed of nerve cell communications.

It's long been known that brain neurons use glutamate as a way to communicate with each other. As one neuron releases glutamate, an adjacent neuron latches onto the chemical through a structure on the neuron's surface called a receptor. The glutamate-receptor connection triggers a neuron to open chemical channels that let in charged particles called ions, creating an electric spark that activates the neuron.
"All of this happens within a millisecond, and what hasn't been known is the way receptors latch onto glutamate. Our new experiments suggest that glutamate molecules need to take very particular pathways on the surface of glutamate receptors in order to fit into a pocket within the receptor," says Albert Lau, Ph.D., assistant professor of biophysics and biophysical chemistry at the Johns Hopkins University School of Medicine.
For the research, the Johns Hopkins scientists used a supercomputer called Anton, which is run by the Pittsburgh Supercomputing Center. They also worked with researchers at Humboldt University in Berlin who specialize in recording how charged particles flow between biological membranes.
A report of the experiments will be published in the Jan. 3 issue of Neuron.
To develop their model of how glutamate might connect to brain cell receptors, Lau and Johns Hopkins research fellow Alvin Yu used a computing technique called molecular dynamic simulations, which was developed by Martin Karplus, Michael Levitt and Arieh Warshel and earned them a Nobel Prize in 2013. The simulations use Sir Isaac Newton's laws of motion and a set of mathematical rules, or algorithms to assign energy functions to atoms and the substances made from those atoms.
"It takes an enormous amount of computer processing power to do these types of simulations," says Lau.
In their experiment, Yu and Lau immersed glutamate molecules and a truncated version of the glutamate receptor in a water and sodium chloride solution. The supercomputer recorded dynamics and interactions among nearly 50,000 atoms in the solution.

"There are many ways glutamate can connect with a receptor," says Lau. But some pathways are more direct than others. "The difference is like taking the faster highway route versus local roads to get to a destination."
Yu and Lau counted how frequently they saw glutamate in every position on the receptor. It turns out that glutamate spends most of its time gliding into three distinct pathways.

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Simulation of how a glutamate molecule enters one of three main pathways into the pocket of a glutamate receptor. Red-tipped ends represent negative charges; blue-tipped ones are positive charges. Credit: Alvin Yu and Albert Lau

Zooming in more closely at those pathways, the scientists found that the chemical's negatively charged atoms are guided by positively charged atoms on the neuron's glutamate receptors.
"What we see is an electrostatic connection, and the path glutamate follows is determined by where the charges are," says Lau. In the world of physics, when two objects near each other have opposing electrical charges, they attract each other.
Lau says that the positively charged residues on the glutamate receptor may have evolved to shorten the time that glutamate takes to find its binding pocket.
To test this idea, Lau teamed up with scientists at Humboldt University to introduce mutations into the gene that codes for the glutamate receptor to change positively charged residues into either negatively charged or uncharged ones.
Then, they measured the resulting electrical currents to determine if there was a change in the rate of the receptor's activation in the presence of glutamate.
The results of that experiment showed that mutated glutamate receptors activated at half the speed of the normal version of the receptor.
"If, as we think is the case, communication between neurons has to happen at a particular rate for effective brain activity, then slowing down that rate means that the brain won't work as well," says Lau. "We believe that these glutamate receptors have evolved a way to speed up the binding process."
The scientists add that, in some cases, glutamate seems to be able to bind to the receptor upside down. When this happens, the glutamate receptor's pocket can't close entirely, possibly making it unable to fully open its channels to allow ions into the neuron.
Lau says that further research is needed to determine if other compounds that target the glutamate receptor, such as quisqualic acid, which is found in the seeds of some flowering plants, tread the same three pathways that glutamate tends to follow.
So far, Lau's team has focused its computer simulations only on the main binding region of the glutamate receptor. The researchers plan to study other areas of glutamate receptors exposed to glutamate.

Explore further: Scientists capture first image of major brain receptor in action

More information: Neuron (2017). DOI: 10.1016/j.neuron.2017.11.024 , http://www.cell.com/neuron/fulltext/S0896-6273(17)31077-2

Journal reference: Neuron
Provided by: Johns Hopkins University School of Medicine

CUMC researchers capture first snapshot of key brain receptor in action

Our researchers should be able to use this to  see what is wrong with these glutamate receptors post-stroke  and some up with solutions to glutamate poisoning in the neuronal cascade of death
http://www.news-medical.net/news/20170724/CUMC-researchers-capture-first-snapshot-of-key-brain-receptor-in-action.aspx

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July 24, 2017

Columbia University Medical Center (CUMC) researchers have captured the first three-dimensional snapshots of the AMPA-subtype glutamate receptor in action. The receptor, which regulates most electrical signaling in the brain, is involved in several important brain activities, including memory and learning.
The findings were published today in Nature.
"With our new findings, we can now, for the first time, visualize how the neurotransmitter glutamate opens glutamate receptor ion channels," said Alexander Sobolevsky, PhD, associate professor of biochemistry and molecular biophysics at Columbia and senior author of the paper. "This is the fundamental process that directly affects learning and memory, and finding its structural determinants has been the primary goal of molecular neuroscience since the '90s."
Most signaling in the brain is triggered by glutamate, a neurotransmitter that activates proteins on the surface of neurons called glutamate receptors. Glutamate receptors underlie a variety of high cognitive functions, including learning and memory. AMPA receptors are glutamate receptors that open and close very quickly--in less than a millisecond--and are involved in fast processes in the brain, such as the rapid perception and reaction of an organism to its surrounding environment.
Previously, the Sobolevsky lab deciphered the structures of the AMPA receptor alone and in complex with other proteins that regulate the speed and strength of synaptic connections. In the current study, the researchers captured the AMPA receptor in action, as glutamate activates the receptor to allow ions to flow through its channel and initiate signaling in the brain. This provides the first precise insights into how receptors mediate brain function.
To freeze the AMPA receptor in an active state, the researchers fused it with stargazin, a regulatory protein that prompts the channel to open. The images they captured show that when signaling molecules such as glutamate are present, the entrance to the AMPA receptor, which consists of four units, opens up like a camera's iris, or aperture, to reveal its pore. To shepherd the ions through, the receptor widens the diameter of its channel, and a specialized channel pore lining ushers the ions into the cell.

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"These new fundamental discoveries have implications for our understanding of neurotransmission by glutamate, our brain's major neurotransmitter" says Edward C. Twomey, a PhD candidate at CUMC and first author of the paper. "Understanding these processes will impact future studies on glutamate receptor signaling in neurodegenerative diseases as well as drug design."
To study the receptor, Sobolevksy's team used cryo-electron microscopy, a technique that captures an array of two-dimensional images of a molecule and combines them into a three-dimensional structural image. The method was pioneered by co-author Joachim Frank, PhD, professor of biochemistry and molecular biophysics and of biological sciences at CUMC.
Defects in glutamate receptors, or the processes they mediate, are implicated in neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis and glaucoma; psychiatric disorders such as anxiety, depression, schizophrenia, and drug use disorders; as well as in acute disorders such as brain trauma and stroke. The new structure of an active AMPA receptor and understanding of the activating mechanism create a solid platform for developing therapeutics to treat neurological disorders that are associated with glutamate receptor dysfunction.

Source:

http://newsroom.cumc.columbia.edu/blog/2017/07/24/scientists-capture-first-image-major-brain-receptor-action/