Agrin Involvement in Synaptogenesis Induced by Exercise in a Rat Model of Experimental Stroke

Sounds useful, Now we just need a stroke leader to write up a provisional protocol on this. Exercise is already recommended for all stroke patients so I can see no downside on this.  But nothing will occur, all stroke patients are screwed until we finally get rehab protocols, NOT GUIDELINES.

Agrin Involvement in Synaptogenesis Induced by Exercise in a Rat Model of Experimental Stroke

 

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Pengyue Zhang, MD, Liqiang Yang, MS, Guangxiang Li, MS, ...

First Published November 2, 2020 Research Article 

https://doi.org/10.1177/1545968320969939

Article information

 

Abstract

Background

Agrin is a proteoglycan that aggregates nicotinic acetylcholine receptors (AChRs) on neuromuscular junctions and takes part in synaptogenesis in the development of the central nervous system. However, its effects on neural repair and synaptogenesis after stroke are still unclear.

Objective

This study aimed to investigate the effects of agrin on neural repair and synaptogenesis after stroke and the effects of exercise on this process in vivo and in vitro.

Methods

Exercise with gradually increased intensity was initiated at 1 day after middle cerebral artery occlusion (MCAO) for a maximum of 14 days. Neurological deficit scores and foot fault tests were used to assess the behavioral recovery. Western blotting, immunofluorescence, and electron microscopic images were used to detect the expression of agrin, synaptogenesis-related proteins, and synaptic density in vivo. In vitro, the ischemic neuron model was established via oxygen-glucose deprivation (OGD). The lentivirus overexpressed agrin and CREB inhibitor were used to investigate the mechanism by which agrin promoted synaptogenesis.

Results

Exercise promoted behavioral recovery and this beneficial role was linked to the upregulated expression of agrin and increased synaptic density. Overexpressed agrin promoted synaptogenesis in OGD neuron, CREB inhibitor downregulated the expression of agrin and hampered synaptogenesis in cultured neurons.

Conclusions

These results indicated that exercise post stroke improved the recovery of behavioral function after stroke. Synaptogenesis was an important and beneficial factor, and agrin played a critical role in this process and could be a potential therapeutic target for the treatment of stroke and other nervous system diseases.

Keywords agrin, stroke, synaptogenesis, exercise, molecular mechanism

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Targeting Chondroitin Sulfate Proteoglycans: An Emerging Therapeutic Strategy to Treat CNS Injury

It is only two pages so your doctor can see if this needs to be added as an immediate intervention post stroke.

Did your doctor do ONE DAMN THING with this earlier research on chondroitin sulfate proteoglycans? So over 5 years of incompetency.

Traffic lights for axon growth: proteoglycans and their neuronal receptors

March 2014

Investigation of Sox9 ablation on neuroplasticity and recovery after ishcemic stroke

September 2014

 

Targeting Chondroitin Sulfate Proteoglycans: An Emerging Therapeutic Strategy to Treat CNS Injury

Corresponding Author Surajit Ghosh − Indian Institute of Technology Jodhpur, Karwar, India; orcid.org/0000-0002-8203-8613; Phone: +91-291-280-1212; Email: sghosh@iitj.ac.in Other Authors Nabanita Mukherjee − Indian Institute of Technology Jodhpur, Karwar, India Subhadra Nandi − Indian Institute of Technology Jodhpur, Karwar, India Shubham Garg − Indian Institute of Technology Jodhpur, Karwar, India Satyajit Ghosh − Indian Institute of Technology Jodhpur, Karwar, India Surojit Ghosh − Indian Institute of Technology Jodhpur, Karwar, India Ramkamal Samat − Indian Institute of Technology Jodhpur, Karwar, India Complete contact information is available at: https://pubs.acs.org/10.1021/acschemneuro.0c00004

Cite This: https://dx.doi.org/10.1021/acschemneuro.0c00004

ABSTRACT: 

Chondroitin sulfate proteoglycans (CSPGs) are the most abundant components of glial scar formed after severe traumatic brain injury as well as spinal cord injury and play a crucial inhibitory role in axonal regeneration by selective contraction of filopodia of the growth cone of sprouting neurites. Healing of central nervous system (CNS) injury requires degradation of the glycosamine glycan backbone of CSPGs in order to reduce the inhibitory effect of the CSPG layer. The key focus of this Viewpoint is to address a few important regenerative approaches useful for overcoming the inhibitory barrier caused by chondroitin sulfate proteoglycans. KEYWORDS: Central nervous system injury, axonal regeneration, glial scar, chondroitin sulfate proteoglycan, heparan sulfate proteoglycan, chondroitinase ABC enzyme

Enzyme Treatment Restores Breathing, Limb Function in Rats with Injured Spinal Cords

We need axon growth especially in our white matter. WHOM is going to be following up on this to see if this could help post stroke? Do our doctors even know if proteoglycan is present in our brain post stroke?

Enzyme Treatment Restores Breathing, Limb Function in Rats with Injured Spinal Cords

Tue, 11/27/2018 - 3:46pm

by Kenny Walter - Digital Reporter -

@RandDMagazine

Using an enzyme approach, Case Western Reserve University researchers have found a way to reverse the long-term impact of spinal cord trauma on breathing and limb functions in rodent models.
The researchers found a new treatment regimen that reawakens certain special types of nerve cells that can regenerate extensions called axons within damaged spinal cord areas.
The treatment focuses on the body’s natural ability to slowly sprout new axon branches from a sub-population of nerve cells that remain intact below the injured site that is completely stifled by a family of potentially inhibitory molecules called proteoglycans.

Deeper Insights

Emerging HPC Trends

“The strategy was to use a simple, one-time injection of an enzyme, chondroitinase, that breaks down the inhibitory proteoglycan molecules,” senior author Jerry Silver, PhD, professor of neurosciences at Case Western Reserve University School of Medicine, said in a statement. “The enzyme was administered, not within the lesion itself, but lower down within the spinal cord where motor nerve cells reside that send axons out to the diaphragm and forearm.”
The researchers found that rats with spinal cords half severed at the second cervical vertebrae regained complete diaphragm and partial forelimb function on the severed side after treatment and the recuperative effects were fully maintained six months after treatment.
“For the first time we have permanently restored both breathing and some arm function in a form of high cervical, chronic spinal cord injury-induced paralysis,” Silver said. “The complete recovery, especially of breathing, occurs rapidly after a near lifetime of paralysis in a rodent model.”
The enzyme only marginally helped restore nerve growth with minimal functional recovery in animals treated immediately following the injury. However, when treated long after a spinal cord injury, the animals saw better therapeutic effects.
For example, one week after treatment, chronically injured rats saw new nerve extensions begin to restore diaphragm function that had been silent for several months. About 70 percent of the rats treated also started to use their forelimbs to move about and explore their environments, while only 30 percent of the control group restored those functions.
“Surprisingly, the technique worked far better at chronic stages than at acute stages after injury,” Silver said.
In fact, the longer the animals had been paralyzed, the greater the restorative effects. Even 18 months following injury, the rats who received the treatment recovered full diaphragm activity.
The researchers also found that exposing the rats to brief periods of low oxygen levels helped strengthen growing nerve extensions, but when the rats were treated with the enzyme combined with excessive amounts of respiratory therapy, they developed chaotic activity in their once paralyzed diaphragms.
The team now hopes to optimize both therapy options to maximize recovery, specifically in the forearm and paw.
“Our data illustrate the relative ease with which an essential motor system can regain functionality months to years after severe spinal cord injury,” Silver said. “The treatment regimen in our study is relevant to multiple types of chronic incomplete spinal traumas, and we are hopeful it may also help restore motor function following spinal cord injury in humans.”
According to research, there are between 250,000 and 500,000 new cases of chronic spinal cord injuries annually, with more than half of injuries impairing the person’s ability to breathe and the most severe injuries completely paralyzing the victim.
The study was published in Nature Communications.

A Drug Might Heal Spinal Injuries By Sparking Nerve Growth

Of course this is in rats and other research possibilities never seem to have made it into clinical practice, so don't get your hopes up on this. Nothing will occur. Nobody will think about possibly using this for stroke survivors because there aren't two functioning neurons in all of stroke medical leadership. 

• proteoglycans (9 posts to September 2012)

A Drug Might Heal Spinal Injuries By Sparking Nerve Growth

A scientist who chose to ignore the mainstream nearly 30 years ago has found a new way to regenerate nerves in the spinal cord, at least in animals. A drug that Jerry Silver, a professor of neuroscience at Case Western Reserve University, helped design a drug that has allowed paralyzed rats to regain bladder function and even walk.
The drug works by releasing nerve fibers that have become trapped in scar tissue after a spinal cord injury, Silver says. "Now we've got something that might work in people," though it hasn't been tested in humans yet, he says.
The study was published Wednesday in Nature.

Everybody else in the world was asking why nerves grow where they do. And I thought I'd do something different and ask why they don't grow where they don't.

Jerry Silver

The research that led to this drug began in the 1980s. At the time, Silver and many other scientists were studying nerves. "Everybody else in the world was asking why nerves grow where they do," he says. "And I thought I'd do something different and ask why they don't grow where they don't."
Silver figured the body must produce a substance that acts like a sort of guardrail – preventing nerves from going where they are not supposed to. And after about five years of searching, he found a substance in cartilage called a proteoglycan that could redirect a growing nerve. Silver's team published their finding in the early 1990s. "Nobody believed it," he says.
It took another 10 years to convince the scientific world that the finding was real. And even then, the discovery didn't get much attention until Silver realized that the proteoglycan he had discovered played a big role in spinal injuries and paralysis.

Eventually, just a few years ago, Silver and Harvard biologist John Flanagan showed that the proteoglycan interacts with severed nerve fibers in a way that glues the fibers to scar tissue "like a fly on flypaper."
That got Silver thinking about people who are paralyzed because of damage to nerve fibers in the spinal cord. "You've got an untapped source of nerve fibers," he says. "Thousands upon thousands of them, you know, sitting around just waiting to be released."
Silver thought if he could release these trapped fibers, the nerves might be able to regenerate. So his team designed a drug that was able to free nerve fibers in a Petri dish. Then they tried the drug on rats with spinal injuries that left them unable to walk and without bladder control.
A graduate student gave the animals daily injections under the skin, Silver says. But after seven weeks of treatment, the rats weren't any better and the student asked if he could stop giving the injections. "I said fine, we'll quit," Silver says. "We put the rats aside and about two to three weeks later they started to improve."

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Even A Very Weak Signal From The Brain Might Help Paraplegics

The injections really had freed the trapped nerve fibers and they had begun growing. But that didn't fix the problem the way you might think. The severed nerve ends were not reconnecting. Instead they were sprouting all over the place, like kudzu. And all this new growth was flooding the spinal cord with the hormone serotonin.
It was this new supply of serotonin that was helping the rats function by amplifying the signals carried by nerves that were still intact. "If you have lots of extra serotonin in the spinal cord those few nerve connections that are just a whisper will become a roar," Silver says. "And you can get function back really nicely."
All of the paralyzed rats that got a high dose of the drug regained some bladder control and a third were able to walk again, Silver says.
The new drug represents an important step forward, says Lyn Jakeman, a program director at the National Institute of Neurological Disorders and Stroke, which helps fund Silver's research. One reason, she says, is that it can be injected under the skin.
Other promising treatments, such as stem cells, risk causing more damage because they can disturb the part of the spinal cord that is already injured, Jakeman says. "They're all very invasive."
The new drug also was remarkably effective at improving bladder function, Jakeman says, which is a major concern for many paralyzed people. "A small change in bladder function, the ability to restore a small amount of sexual function, these are big changes for people whether they can get out of their wheelchair and walk or not."

Mechanisms of axon regeneration: The significance of proteoglycans

You need this so you will have to hope that your doctor is the one in a million that correctly creates a stroke protocol out of this.  But nevermind, you are screwed. 

Mechanisms of axon regeneration: The significance of proteoglycans

• Kazuma Sakamoto,
• Kenji Kadomatsu^,

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https://doi.org/10.1016/j.bbagen.2017.06.005

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---

Highlights

•

Neuronal intrinsic pathways for axonal regeneration/sprouting after injury.

•

Intracellular/extracellular promoters/inhibitors for axonal regeneration

•

Proteoglycan and its neuronal cell surface receptors as major inhibitors

---

Abstract

Background

Therapeutics specific to neural injury have long been anticipated but remain unavailable. Axons in the central nervous system do not readily regenerate after injury, leading to dysfunction of the nervous system. This failure of regeneration is due to both the low intrinsic capacity of axons for regeneration and the various inhibitors emerging upon injury. After many years of concerted efforts, however, these hurdles to axon regeneration have been partially overcome.

Scope of review

This review summarizes the mechanisms regulating axon regeneration. We highlight proteoglycans, particularly because it has become increasingly clear that these proteins serve as critical regulators for axon regeneration.

Major conclusions

Studies on proteoglycans have revealed that glycans not only assist in the modulation of protein functions but also act as main players—e.g., as functional ligands mediating intracellular signaling through specific receptors on the cell surface. By regulating clustering of the receptors, glycans in the proteoglycan moiety, i.e., glycosaminoglycans, promote or inhibit axon regeneration. In addition, proteoglycans are involved in various types of neural plasticity, ranging from synaptic plasticity to experience-dependent plasticity.

General significance

Although studies on proteins have progressively facilitated our understanding of the nervous system, glycans constitute a new frontier for further research and development in this field. This article is part of a Special Issue entitled Neuro-glycoscience, edited by Kenji Kadomatsu and Hiroshi Kitagawa.

Keywords

• Axon regeneration;
• Proteoglycans;
• Glycosaminoglycans;
• Neural plasticity

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This article is part of a Special Issue entitled Neuro-glycoscience, edited by Kenji Kadomatsu and Hiroshi Kitagawa.

Investigation of Sox9 ablation on neuroplasticity and recovery after ishcemic stroke

Another research project for our great stroke association to tackle. Unless you really think your neurologist is smart enough to figure out how to accomplish this by themselves. 

Investigation of Sox9 ablation on neuroplasticity and recovery after ishcemic stroke

Bethany Robin Lenore Bass, The University of Western OntarioFollow

Room 447 Medical Science Building

Degree

Master of Science

Program

Anatomy and Cell Biology

Supervisor

Dr. Arthur Brown

Delay of Publication

1

Abstract

Neuroplasticity is a key factor in post-stroke functional recovery. A chief inhibitor of post-stroke neuroplasticity is the expression of chondroitin sulfate proteoglycans (CSPGs). Recent research has shown that the transcription factor SOX9 is responsible for upregulating the expression of CSPGs in the injured central nervous system. Accordingly, CSPG levels are significantly lower in mice with the Sox9 gene conditionally knocked out. The purpose of this study was to determine how Sox9 ablation affects neuroplasticity and recovery after stroke. Behavioural test results revealed that Sox9 KO mice exhibited significantly improved functional recovery after stroke compared to controls. This correlated with increased contralesional corticofugal plasticity in the Sox9 KO animals, as highlighted by tract tracing studies. An increase in one type of glutamatergic input marker (VGLUT1) was observed at the deafferented red nucleus of the Sox9 KO mice, but not at the denervated the cervical spinal cord ventral horn. Further investigation into the effects of Sox9 ablation on post-stroke neuroplasticity would be beneficial to determine the potential of Sox9 as a therapeutic target.

Recommended Citation

Bass, Bethany Robin Lenore, "Investigation of Sox9 ablation on neuroplasticity and recovery after ishcemic stroke" (2014). University of Western Ontario - Electronic Thesis and Dissertation Repository. Paper 2338.
http://ir.lib.uwo.ca/etd/2338

Traffic lights for axon growth: proteoglycans and their neuronal receptors

You'll have to ask your neurologist which is more important; axon pathfinding or neurite outgrowth? And what the difference in stroke protocols is for each one. Your doctor had better know all this stuff.
You do expect 100% recovery using their knowledge, Don't you?

Traffic lights for axon growth: proteoglycans and their neuronal receptors

Yingjie Shen

Department of Neuroscience and Center for Brain and Spinal Cord Repair, Wexner Medical Center, The Ohio State University, 460 w 12th Ave,

Columbus, OH 43210, USA

Abstract

Axon growth is a central event in the development and post-injury plasticity of the nervous

system. Growing axons encounter a wide variety of environmental instructions. Much like traffic

lights in controlling the migrating axons, chondroitin sulfate proteoglycans (CSPGs) and heparan

sulfate proteoglycans (HSPGs) often lead to “stop” and “go” growth responses in the axons,

respectively. Recently, the LAR family and NgR family molecules were identified as neuronal

receptors for CSPGs and HSPGs. These discoveries provided molecular tools for further study of

mechanisms underlying axon growth regulation. More importantly, the identification of these

proteoglycan receptors offered potential therapeutic targets for promoting post-injury axon regeneration.

Manipulating the extracellular matrix and its role in brain and spinal cord plasticity and repair

Sounds extremely important. What is your doctor going to do with this knowledge to help you? You need to demand an answer so you can pay it forward to future stroke survivors.
http://onlinelibrary.wiley.com/doi/10.1111/nan.12114/abstract

1. Emily R. Burnside,
2. Elizabeth J. Bradbury^*

DOI: 10.1111/nan.12114

This article is protected by copyright. All rights reserved.

Issue

Neuropathology and Applied Neurobiology

Accepted Article (Accepted, unedited articles published online and citable. The final edited and typeset version of record will appear in future.)

Additional Information(Show All)

Author InformationPublication History

1. This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/nan.12114

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Abstract

Brain and spinal cord injury can result in permanent cognitive, motor, sensory and autonomic deficits. The CNS has a poor intrinsic capacity for regeneration, although some functional recovery does occur. This is mainly in the form of sprouting, dendritic remodelling and changes in neuronal coding, firing and synaptic properties; elements collectively known as plasticity. An important approach to repair the injured CNS is therefore to harness, promote and refine plasticity. In the adult, this is partly limited by the extracellular matrix (ECM). While the ECM typically provides a supportive framework to CNS neurons, its role is not only structural; the ECM is homeostatic, actively regulatory and of great signalling importance, both directly via receptor or co-receptor-mediated action and via spatially and temporally relevant localisation of other signalling molecules. In an injury or disease state, the ECM represents a key environment to support a healing and/or regenerative response. However, there are aspects of its composition which prove suboptimal for recovery: some molecules present in the ECM restrict plasticity and limit repair. An important therapeutic concept is therefore to render the ECM environment more permissive by manipulating key components, such as inhibitory chondroitin sulphate proteoglycans. In this review we discuss the major components of the ECM and the role they play during development and following brain or spinal cord injury and we consider a number of experimental strategies which involve manipulations of the ECM, with the aim of promoting functional recovery to the injured brain and spinal cord.

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Myelin associated inhibitors; molecular mechanisms and therapeutic potential

A great thesis, why can't regular stroke researchers come up with novel ideas to research like this? Only 59 pages for your doctor to read and explain to you. 

Myelin associated inhibitors; molecular mechanisms and therapeutic potential

Summary
Whereas the peripheral nervous system can readily regenerate after injury, regeneration is very limited in the central nervous system of adult vertebrates. Over the past three decades, it has become clear that this lack of regeneration has a molecular basis. The myelin that provides electrical insulation of neuronal fibers has a different composition in the central nervous system, as compared to peripheral nervous system myelin. Several proteins expressed on myelin have been found to have inhibitory effects for neuronal regeneration and were dubbed myelin-associated inhibitors. The three classical myelin-associated inhibitors (Nogo, MAG and OMgp) were found to signal all three through two distinct receptor complexes, providing a puzzling redundancy for these interactions. This signaling is speculated to be important for stabilizing neuronal circuitry in healthy adult organisms. Other proteins known to be involved in axonal guidance, such as semaphorins, ephrins, netrins and Wnts, as well as extracellular matrix components such as the chondroitin sulfate proteoglycans, have also been shown to have regeneration inhibitory effects. Downstream signaling by neuronal effector proteins culminates in modulation of the cytoskeleton and transcription, explaining the morphological changes of the neurons that are observed upon signaling. The fact that the lack of regeneration has a molecular basis provides prospects for therapeutic intervention to stimulate regeneration for injuries of the central nervous system, like spinal cord injury or stroke. Indeed, a substantial body of different proteins, peptides and small molecules that intervene with the different steps involved in the inhibition of regeneration shows promising effects, both in vitro and in vivo.
This review will discuss the advances made on understanding the lack of regeneration in the central nervous system. After an introduction on the nervous system, injury and regeneration, the molecular mechanisms of inhibition will be discussed. A special focus will be on the three classical myelin associated inhibitors and their receptor complexes, but other molecules that are inhibitory for regeneration will be discussed as well. The current understanding of the downstream signaling cascades of the myelin associated inhibitors will be reviewed and finally, different strategies that demonstrate the therapeutic potential of interfering with these mechanisms will be discussed.

Table of content
Summary ................................................................................................... 2
Table of content .......................................................................................... 3
Introduction ............................................................................................... 4
Molecular Mechanisms ................................................................................. 9
Downstream Events ................................................................................... 32
Therapeutic Potential ................................................................................. 39
Conclusion and Perspectives ....................................................................... 46
List of Abbreviations .................................................................................. 47