5 replies to this topic

[Pereise1]

Hello all, so after researching like a law student these last couple months, I think I have an idea on how it might be possible to repair a CNS glial scar. There's many variables naturally, but I'm curious if this approach seems right to everyone here. If so, it'd be exciting to see what help it could be for someone with TBI or MS. I posted the following to the Narcolepsy Network forums:

 

 

Now, it's known that after a traumatic brain injury (TBI) or a stroke, reactive gliosis by glial cells in the brain cause a glial scar to form. Evidence of this happening is detailed in the following studies:

 

https://www.ncbi.nlm...les/PMC2717206/ (Localized Loss of Hypocretin (Orexin) Cells in Narcolepsy Without Cataplexy)

 

https://www.uptodate...lts/abstract/57 (Pattern of hypocretin (orexin) soma and axon loss, and gliosis, in human narcolepsy)

 

 

 

Herein lies the hard part and the reason Narcolepsy is so hard to treat and solve. When a glial scar is formed in the Central Nervous System (CNS) or spinal cord, it forms a lining that resists axon growth. Therefore, without intervention, the scar would be permanent, and no amount of neurogenesis inducing substances would be able to penetrate the glial scar. However, research in this field has accelerated highly in recent years, and there is hope. 

 

The brain uses different growth factors such as BDNF, NGF, GDNF, NT3, and CNTF to extend dendritic branching and axons. The goal is to use these to grow new orexin neurons over the scar tissue in the hypothalamus, and/or convert the glial cells into functioning neurons. The glial scar has a number of ways that it inhibits growth. It's a little too complicated to go into too much detail, but I'll include a few main ones as well as links to a number of studies at the bottom.

 

1. Modification of sulphated proteoglycans

 

What are these you may ask? I'm going to quote extensively from the study "Regeneration Beyond The Glial Scar" (http://www.nature.co...ll/nrn1326.html). To start:

 

  Quote

 

 

In addition to growth-promoting molecules46, 47, astrocytes produce a class of molecules known as proteoglycans48, 49. These ECM molecules consist of a protein core linked by four sugar moieties to a sulphated GLYCOSAMINOGLYCAN (GAG) chain that contains repeating disaccharide units. Astrocytes produce four classes of proteoglycan; heparan sulphate proteoglycan (HSPG), dermatan sulphate proteoglycan (DSPG), keratan sulphate proteoglycan (KSPG) and chondroitin sulphate proteoglycan (CSPG)50. The CSPGs form a relatively large family, which includes aggrecan, brevican, neurocan, NG2, phosphacan (sometimes classed as a KSPG) and versican, all of which have chondroitin sulphate side chains. They differ in the protein core, as well as the number, length and pattern of sulphation of the side chains51, 52, 53. Expression of these CSPGs increases in the glial scar in the brain and spinal cord of mature animals54, 55, 56.

 

Proteoglycans have been implicated as barriers to CNS axon extension in the developing roof plate of the spinal cord57, 58, in the midline of the rhombencephalon and mesencephalon59, 60, at the dorsal root entry zone (DREZ)61, in retinal pattern development62, 63, and at the optic chiasm and distal optic tract64, 65. Extensive work has demonstrated that CSPGs are extremely inhibitory to axon outgrowth in culture. Neurites growing on alternating stripes of laminin and laminin/aggrecan had robust outgrowth on laminin, but at the sharp interface between the two surfaces, growth cones rapidly turned away (unlike their stalled behaviour in a gradient, see above). The inhibitory nature of the proteoglycan-containing lanes can repel embryonic as well as adult axons, and the effect can last for more than a week in vitro. The turning behaviour is not usually mediated by collapse of the entire growth cone, but rather by selective retraction of FILOPODIA in contact with CSPG and enhanced motility of those on laminin66, 67. CSPGs are potent inhibitors of a wide variety of other growth-promoting molecules, including fibronectin and L1 (Refs 68,69).

 

 

 

This is one of the most important steps to overcome. In the same study, it has been shown that, and I quote, "chondroitinase — an enzyme extracted from the bacterium Proteus vulgaris that selectively removes a large portion of the CSPG GAG side chain and renders CSPGs less inhibitory". Now, unfortunately I don't know where to get chondroitinase, if it passes the BBB, or how to guide it to the hypothalamus. However, after scouring pubmed for hours to find a replacement, I found good ol' Turmeric helps here:

 

  Quote

 

 

Curcumin improves neural function after spinal cord injury by the joint inhibition of the intracellular and extracellular components of glial scar

 

http://doi.org/10.10...jss.2014.12.055

 

Results

 

We found that cur inhibited the expression of proinflammatory cytokines, such as TNF-α, IL-1β, and NF-κb; reduced the expression of the intracellular components glial fibrillary acidic protein through anti-inflammation; and suppressed the reactive gliosis. Also, cur inhibited the generation of TGF-β1, TGF-β2, and SOX-9; decreased the deposition of chondroitin sulfate proteoglycan by inhibiting the transforming growth factors and transcription factor; and improved the microenvironment for nerve growth. Through the joint inhibition of the intracellular and extracellular components of glial scar, cur significantly reduced glial scar volume and improved the Basso, Beattie, and Bresnahan locomotor rating and axon growth.

 

 

 

Turmeric also has HDAC inhibiting properties, making the brain more malleable to change and encouraging it to return to homeostasis. I won't go too deep into HDAC but it seems to help.

 

2. Blocking the effects of myelin

 

Again, what's this and what would it do? Here's another citation from the same article:

 

  Quote

In addition to enhancing regeneration by removing the inhibitory effects of CSPGs, extensive work has shown that blocking Nogo, a myelin-associated inhibitor of regeneration, improves regeneration105. Antibodies directed against the Nogo receptor administered into spinal cord lesion sites106 or even systemically107 seem to enhance regeneration, although recent work108 has disputed whether this is truly enhanced regeneration or merely local sprouting. Indeed, it is now being suggested that most of the functional recovery that is seen when inhibitors of myelin are used occurs as a result of remodelling of local circuits, such that functional recovery is mediated along uninjured long axons108. This proposal, in conjunction with work from our laboratory demonstrating rapid axon regrowth from adult neurons in the presence of degenerating white matter83, 84, as well as the differences between growth cone collapse and dystrophy, indicates that myelin might not be acting fundamentally to inhibit long-distance regeneration. In fact, it has even been suggested that myelin might facilitate axon growth under certain conditions109.

 

So how do we get around this issue? Here, we turn to Longecity and the amazing research of some of users there (http://www.longecity...th/#entry737252). To cite only 2 studies, Ginseng and Horny Goat Weed (Icariin) are potent in this regard:

 

  Quote

RESULTS:

 

We determined 1) GTS (Ginsenoides) (5-80 mg/kg) treatment after a TBI improved the recovery of neurological functions, including learning and memory, and reduced cell loss in the hippocampal area. The effects of GTS at 20, 40, 60, and 80 mg/kg were better than the effects of GTS at 5 and 10 mg/kg. 2) GTS treatment (20 mg/kg) after a TBI increased the expression of NGF, GDNF and NCAM, inhibited the expression of Nogo-A, Nogo-B, TN-C, and increased the number of BrdU/nestin positive NSCs in the hippocampal formation.

 

 

  Quote

Icariin, the major active component of Chinese medicinal herb epimedium brevicornum maxim, is used widely in traditional Chinese medicine for the treatment of neurological diseases. However, the effects of icariin on myelin inhibitory factors are as yet unclear. In the present study, administration of icariin at 20 mg/kg showed a marked reduction in neurological deficit of middle cerebral artery occlusion rats. Icariin exhibited better inhibitory effects on myelin inhibitory factors: Nogo-A, myelin-associated glycoprotein and oligodendrocyte myelin glycoprotein in ischemia regions of middle cerebral artery occlusion rats compared with monosialotetrahexosylganglioside. These results indicate that icariin exhibits potent inhibitory effects on expression of myelin inhibitors after middle cerebral artery occlusion-induced focal cerebral ischemia in vivo. This effect may be mediated, at least in part, by the inhibition of both Nogo-A, myelin-associated glycoprotein and oligodendrocyte myelin glycoprotein activation, followed by the enhancement of axonal sprouting and regeneration, resulting in neurological functional...

 

Seems Nogo is among the easier things to inhibit, thankfully.

 

3. Enhancing the intrinsic growth machinery.

 

This is pretty straightforward, we want the best environment for these new axons to differentiate and turn into full neurons:

 

  Quote

Removal of extrinsic inhibitory cues from the glial scar with treatments such as chondroitinase might aid regeneration, but this might not be sufficient for long-range re-growth. Neurotrophin 3 (NT3) or nerve growth factor (NGF), when delivered directly to transected neurons in the dorsal columns of animals treated with peripheral nerve graft transplants, enhances growth into the graft, out the opposite end and beyond the glial scar into host tissue110, 111. Exogenous NGF administration also induces sprouting into the lesion of crushed dorsal columns112. Intrathecal or adenoviral application of NT3 or NGF to the injured DREZ induces DRG neurons to cross the peripheral nervous system/CNS barrier and penetrate some distance into the spinal cord113, 114, 115, 116, 117, where the regenerating fibres restore nocioceptive function. So, evidence from the injured spinal cord and DREZ indicates that regenerating axons can overcome proteoglycan barriers after neurotrophin stimulation, perhaps through induction of growth enhancing genes, offering an additional therapeutic strategy.

 

As for Nerve Growth Factor, there's myriad things that stimulate this, so whatever you decide to take, make sure you enhance it with Acetyl L-Carnitine, which is supposed to enhance NGF by x100 according to a study I've recently misplaced. As for Neurotrophin 3, again, we have some amazing phytoconstituents to help. Another Longecity thread (http://www.longecity...s-into-neurons/) helped me find studies for 2 substances in particular, Chinese Skullcap and Ziziphus Jujube:

 

  Quote

Baicalin promotes neuronal differentiation of neural stem/progenitor cells through modulating p-stat3 and bHLH family protein expression.

Signal transducer and activator of transcription 3 (stat3) and basic helix-loop-helix (bHLH) gene family are important cellular signal molecules for the regulation of cell fate decision and neuronal differentiation of neural stem/progenitor cells (NPCs). In the present study, we investigated the effects of baicalin, a flavonoid compound isolated from Scutellaria baicalensis G, on regulating phosphorylation of stat3 and expression of bHLH family proteins and promoting neuronal differentiation of NPCs. Embryonic NPCs from the cortex of E15-16 rats were treated with baicalin (2, 20 μM) for 2h and 7 days. Neuronal and glial differentiations were identified with mature neuronal marker microtubule associated protein (MAP-2) and glial marker Glial fibrillary acidic protein (GFAP) immunostaining fluorescent microscopy respectively. Phosphorylation of stat3 (p-stat3) and expressions of bHLH family genes including Mash1, Hes1 and NeuroD1 were detected with immunofluorescent microscopy and Western blot analysis. The results revealed that baicalin treatment increased the percentages of MAP-2 positive staining cells and decreased GFAP staining cells. Meanwhile, baicalin treatment down-regulated the expression of p-stat3 and Hes1, but up-regulated the expressions of NeuroD1 and Mash1. Those results indicate that baicalin can promote the neural differentiation but inhibit glial formation and its neurogenesis-promoting effects are associated with the modulations of stat3 and bHLH genes in neural stem/progenitor cells.

 

  Quote

The treatment with jujube water extract stimulated the expressions of neurotrophic factors in a dose-dependent manner, with the highest induction of ~100% for NGF, 100% for brain-derived neurotrophic factor (BDNF), 100% for glial cell line-derived neurotrophic factor (GDNF) and 50% for neurotrophin 3 (NT3). These results supported the neurotrophic role of jujube on the brain.

 

 

 

Now, I have no idea how long it would take, under ideal circumstances, for the brain to regrow orexin neurons after disinhibiting growth and inducing axon growth in this manner. Any help understanding the process behind regrowing the hypothalamus and guiding growth to this section of the brain would be much appreciated. In the meantime, I leave everyone with some studies:

 

https://www.ncbi.nlm...les/PMC2693386/ (Glial inhibition of CNS axon regeneration)

 

https://www.ncbi.nlm...les/PMC3140701/ (Enhancing Central Nervous System Repair-The Challenges)

 

http://www.nature.co...ll/nrn1326.html (Regeneration Beyond The Glial Scar)

 

Also, these longecity threads helped me find a few relevant studies as well as substances to help neurogenesis:

 

http://www.longecity...ich-heal-axons/

 

http://www.longecity...brain-regrowth/

 

http://www.longecity...le/#entry735916

[monowav]

Since you've mentioned it a lot, here's all my info on nogo-A.

https://www.livinghe...city-switch-ltp

 

Reticulon 4 Is More Than A Growth Inhibitor

Nogo-A is one of the most potent growth inhibitors in the central nervous system. It is involved in creating new blood cells, developing new stem cells, protecting growth of cancer, and modulating the immune system. It is highly expressed after adolescent development, traumatic brain injuries, and many myelin-related diseases. 

 

 

 

Contents

1. Basics
2. Benefits Of Inhibiting Nogo-A
3. Downsides Of Inhibiting Nogo-A
4. Mechanism Of Action
5. How To Inhibit Nogo-A
6. More Research
7. Video

 

Basics

 

 

 

 

 

Schwab and Caroni discovered that myelin (the fatty white substance that surrounds the axon of some nerve cells) from the central nervous system (CNS) inhibits neurite outgrowth. R

Myelin from the peripheral nervous system (PNS) does the opposite. R

In the human brain, the growth of myelin is regulated by multiple systems: 

• oligodendrocyte-myelin glycoprotein (OMgp) R
• the reticulon RTN4 (Nogo) R
• semaphorins R
• ephrins R
• chondroitin sulphate proteoglycans R

When Nogo-A is active, it acts as a myelin-derived neurite and axon growth inhibitor. R

It suppresses growth and sprouting of neurons, thus stabilizing the wiring of the adult CNS. R

It does this by regulating axonal and neural stem cells and progenitor cells. R R

Nogo-A can also inhibit the neuronal benefits of brain derived neurotrophic factor (BDNF). R

Nogo-A And Cell Functioning

Nogo-A is involved with normal cell-functioning, along with neuropsychiatric functions. R R

It helps regulate cell death and/or growth mechanisms. R

Nogo-A can protect against hydrogen peroxide-induced cell death. R

It does this by interacting with the enzyme peroxiredoxin 2, which scavenges reactive oxygen species (ROS). R

Nogo-A is upregulated in many cells as an inhibitory factor on the growth of tumor cells, helping prevent the spread of cancer. R

Nogo-A And Injury

After injury NgR (Nogo receptors) increase. R

Nogo-A increases in the cell body of injured neurons. R

It restricts axonal regeneration after injury. R

Nogo-A In The Brain

Nogo-A is expressed in neurons throughout the brain and spinal cord (and also oligodendrocytes). R

In humans, Nogo-A has been detected in the spinal cord, in the hippocampus, in the cerebral cortex, in the cerebellum and in the brain stem. R

Neuronal Nogo-A is highly expressed during ages of development and down-regulated when we are adults (from birth to adolescence, it is expressed in different areas of the brain and in adulthood it is expressed more in the cerebral cortex). R R

Nogo-A expression helps the development of immature neurons before myelination. R

After myelination, Nogo-A expression is stays high in plastic CNS regions such as the hippocampus, olfactory bulb, deep cerebellar nuclei, spinal motor neurons, and dorsal root ganglia. R R

Nogo-A and Immunity

Several lymphocytes including B cells and T cells express NgR1 (Nogo-A's receptor) and further up-regulate it upon activation of the immune response. R

In the lymph nodes, T cells are activated by dendritic cellls (DCs), which express NgR1 and NgR2 during development, but are downregulated during matruation (which is inversely correlated with myelin). R

Nogo-A And Disease

Nogo-A is up-regulated in:

• After Stroke R
• After Spinal Cord Injury R
• During Epilepsy R
• During Multiple Sclerosis R
• During ALS R
• During Parkinson's Disease R

 

Benefits Of Inhibiting Nogo-A

 

1. May Improve Recovery After Tramautic Brain Injury

 

 

 

 

Nogo-A expression in the brain is significantly increased after stroke. R

Animals treated with anti-Nogo-A antibodies after injury have enhanced neuroplasticity and functional recovery. R R

Although, the ability of hippocampal recovery after stroke using anti-Nogo-A antibodies has been disputed. R

Anyway, inhibiting Nogo-A enhances axonal sprouting and increases dendritic complexity of neurons in the sensorimotor forelimb cortex (this area is important for skilled reaching and motor movements). R

Some studies show that treatment with Nogo-A antibodies after stroke is most effective if it is used by up to one week after injury. R R

It should be noted that inhibiting Nogo-A during stroke worsened the outcome in rodent studies (by increasing apoptosis via p53). R

In contrast, Nogo-A deficient mice that were subjected to traumatic brain injury (TBI) showed significantly worse outcomes than regular mice after TBI. R

2. May Improve Outcome of Spinal Cord Injury

Spinal cord injury (SCI) is associated with axonal disconnection. R

This leads to significant disabilities, even though there can be minimal neuronal death. R

To myelin growth regulators (MAG and OMgp) synergize with Nogo-A to restrict axonal growth after SCI. R

In mice with SCI, a Nogo-A receptor antagonist is able to increase axon regeneration. R

It also increased neuronal reorganization and behavioural improvements. R

In monkeys, Nogo-A antibodies helped improve fine motor movement recovery. R

ATI355, an anti-human Nogo-A antibody, has been shown to be safe for SCI in human clinical trials. R

3. May Improve Parkinson's Disease

 

 

 

Parkinson’s disease (PD) is a neurodegenerative disorder that is mainly characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) with additional loss of dopamine innervation in the striatum. R

Nogo-A expression is high in the SNc in patients with PD. R

One useful strategy to replete the dopaminergic neurons in the brain is with a graft of fetal human ventral mesencepahlic dopaminergic neurons. R

For example, rats with PD were given graft transplants of dopaminergic neurons into their brain and Nogo-A inhibition made this procedure more effective (by two-fold). R

Also, antagonizing Nogo receptors significantly increased dopaminergic cell numbers. R

Tumor necrosis factor alpha (TNFa) and interleukin 6 (IL-6) are two biomarkers for inflammation during PD. R

In a model of PD, Nogo-A inhibition was able to inhibit the increase of TNFa and IL-6 (two proinflammatory cytokines) by lipopolysaccharide (LPS). R

4. Improves Multiple Sclerosis

Nogo-A activation can help identify multiple sclerosis (MS). R

Both Nogo-A and NgR1 are expressed in multiple sclerosis (MS) lesions. R

 In animal models, deactivating Nogo-A expression can help ameliorate MS and promote axonal repair. R R

Using a Nogo-A antibody was able to prevent damage to the spinal cord in MS. R

5. Increases New Memory Formation

 

 

 

In the hippocampus, nogo-a stabilizes the architecture of the hippocampus. R

Nogo-A (along with PirB), also negatively influences long-term potentiation (LTP) in the hippocampus (via modulation of AMPA). R R R

Nogo-A influences spatial learning and memory retention by regulating the use of more efficient hippocampus-dependent strategies. R

So, inhibiting Nogo-A would theoretically allow new memories to form and overwrite old ones. R

This may be helpful for Post-Tramautic Stress Disorder, since Nogo-A expression prevents the erasure of fear memories. R

6. Protects The Eyes During Injury

Nogo-A is highly expressed in Müller glia (a type of retinal glial cell). R

It regulates inflammation and axonal growth of the optic nerve.

For example, overexpression of Nogo-A was able to help promote regeneration of retinal ganglion cells (RGCs) after optic nerve injury. R

In contrast, in multiple studies mice unable to express Nogo-A had significantly better abilities to heal their optic nerve after injury. R R R R R

For example. spatial frequency and contrast sensitivity was increased in Nogo-A deficient mice than regular mice after eye damage. R

Even inhibiting Nogo-A activity had similar results in multiple studies. R R

Also if RGCs were in an active growth state, inhibition of Nogo enhanced optic nerve regeneration even more. R

7. Promotes Angiogenesis

 

 

 

Nogo-A is a negative regulator of angiogensis (the growth of new blood cells). R

In mice, inhibiting Nogo-A increased blood cell formation in the brain. R

In humans, besides Nogo-A, Nogo-B regulates vascular remodeling. R

8. May Increase Healing After Peripheral Nerve Injury

Injured peripheral nerves often regenerate well, but inhibition of Nogo-A promotes their healing, especially of Schwann cells. R

9. May Prevent Hearing Loss

 

 

 

Nogo-A is found in sensory organs such as the inner ear. R

Nogo-A is involved in maintaining a non-regenerative state of hair cells. R

In mice, no hearing loss was observed in 10 month old Nogo-A knock-out mice as compared to wild type. R

10. May Help Amyotrophic Lateral Sclerosis 

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron loss and muscle wasting. R

Nogo can influence the progression of ALS. R

Nogo-A expression is correlated with the severity of symptoms in ALS patients. R R R

Expression may significantly contribute to functional motor impairment. R

A Nogo-A test is able to identify ALS early in the course of the disease when diagnosis is difficult. R

In a human clinical trial, intravenous ozanezumab (anti-Nogo-A antibody) inhibited demylination of the muscle nerve fibers. R

It was also well tolerated shown to be safe. R

There are more human clinical trials showing its efficacy. R

In contrast, in an animal model, inhibiting Nogo-A promoted and worsened ALS. R

 

Downsides Of Inhibiting Nogo-A

 

1. May Sprout Irregular Growth

Inhibiting Nogo-A may not only favor sprouting of lesioned axons, but may also induce unspecific growth of axons, causing undesired pathologies. R

Mice that couldn't express Nogo-A had decreased spine density. R

2. May Induce Schizophrenia

 

 

 

in mice that had the Nogo-A gene deleted, they experienced behaviorail abnormalities resembling schizophrenia-related endophenotypes: R

• deficient sensorimotor gating
• disrupted latent inhibition
• perseverative behavior
• increased sensitivity to the locomotor stimulating effects of amphetamine

They also had altered monoaminergic transmitter levels in specific striatal and limbic structures, as well as changes in dopamine D2 receptor expression in the same brain regions. R

3. May Disrupt Circadian Rhythm

Mice lacking Nogo-A had problems with  motor co-ordination and balance (via modulation of dopaminergic and motor systems). R

This was accompanied with spontaneous locomotor activity. R

Activity was increased in during the night. R

4. May Promote Cancer

Nogo-A acts as a downregulator for tumor growth. R

It is highly expressed in tumors, helping prevent their growth. R

Inhibition can theoretically allow excessive tumor growth, but I would like to see more research on this topic.  

5. May Promote Alzheimer's Disease

 

 

 

Nogo-A/Nogo-A receptors (NgR) modulate the production of amyloid β-protein (Aβ), which is thought to be a major cause of Alzheimer's Disease (AD). R

One way it does this is through mediating neuroinflammation via modulating microglia adhesion and migration. R

The Nogo-A/NgR and the downstream Rho-ROCK pathway inhibits axon outgrowth and synapse remodeling. R

This is an obstacle to neuronal regeneration and blocking the recovery of damaged neural networks in AD. R

PirB is a novel receptor for Nogo-A that interacts with Aβ and mediates its neurotoxicity. R

S1PR2 is also a receptor for Nogo-A that activates ROCK and mediates neuronal plasticity. R

NgR also influences the metabolism of amyloid precursor protein (APP). R

NgR can bind to APP and Aβ. R

In mice, there is an increased Aβ accumulation in the hippocampal dentate gyrus and cerebral cortex of mice lacking NgR. R

Applying NgR(310)ecto-Fc (an Anti-NgR blocking protein) reduced Aβ plaque deposition in those mice. R

Also in cultures, overexpression of NgR decreases Aβ production. R

As mice aging, their ability to bing Nogo-A to Aβ decreases. R

In contrast, blocking reticulon 3 (different than reticulon 4) is beneficial for reducing Aβ. R

Also, in humans Nogo-A is over-expressed in hippocampal neurons in AD and also associated with high levels of Aβ in the hippocampus. R

Nogo is able to bind and inhibit the β-amyloid-converting enzyme 1 (BACE1), which transforms the amyloid precursor protein (APP) into aggregating β-amyloid. R

 

Mechanism Of Action

 

 

 

 

 

 

 

 

 

Nogo-A (aka reticulon 4) belongs to the reticulon family that consists of four genes named RTN1, RTN2, RTN3 and RTN4. R

RTNs infleunce the curvature of the endoplasmic reticulum (ER) and are structural regulators for the ER. R

RTNs also interact with anti-apoptotic intracellular proteins Bcl-2 or Bcl-XL in regulating cell death. R

RTN4 encodes for three major isoforms (Nogo-A, B and C). R

Nogo-A (Nogo-66 and Nogo-A-D20) naturally binds to its receptor NgR1. R R R

NgR1 has to form a complex with LINGO-1, TROY or p75. R

p75 interacts with GPI and activates the Rho/ROCK pathway. R

Nogo-66 binding with PirB can also activate the Rho/ROCK pathway. R

Neurite growth inhibition is regulated by RhoB, Rac1, and TSPAN3 (tetraspanin-3). R R R

Nogo-A turns on RhoA, but deactivates RhoB and Rac1. R

When Nogo-A binds to Sphingolipid Receptor S1PR2, synaptic plasticity is surpressed. R

Nogo-D20 works via S1PR2. R

 

 

Nogo-A:

• Activates RhoA R
• Antagonizes mTOR (for LTP) R
• Downregulates cAMP R
• Lowers ROS R

Nogo-A Inhibition:

• Decreases IGF-1 (in hippocampus) R
• Does not affect CGRP R
• Increases BDNF R
• Increases Dopaminergic neurons R
• Increases FGF2 R
• Increases GAP43 R
• Increases Glutamate AMPA and NMDA receptors (in hippocampus) R
• Increases NGF R
• Increases VEGF R
• Inhibits IL-6 R
• Inhibits TNFalpha R

 

How To Inhibit Nogo-A

 

Natural:

• Catalpol/Rehmannia R
• Electroacupuncture R
• Green Tea (EGCG and GTPP) R
• High Dose of Vitamin E R
• Hyperbaric oxygen chamber therapy R
• Icariin R
• Increasing BDNF R
• Panax Ginseng R R
• Yougui R
• Zuogui R

Other:

• Anti-Nogo-A Antibodies (to such as LINGO-1, ROCK, and ATI355) R R R R
• Fasudil R
• Ganglioside (GM1 activation) R
• GPR50 Expression R
• LILRA3 R
• Nogo-66 antagonist peptides R
• Ozanezumab R
• TAT-M9 and TAT-NEP1-40 (but also increases expression of Tau GAP43 and MAP-2)

 

More Research

 

• Rewiring induced by the Nogo-A–specific antibody treatment did not generate chronic pain. R
• Nogo-A does not inhibit retinal axon regeneration in the lizard Gallotia galloti. R
• Easier deilvery of anti-nogo peptides can be made in alginate nanospheres. R
• More on Nogo-A signaling pathways R

 

It may look weird since i just copied and pasted all from the page https://www.livinghe...city-switch-ltp

[Pereise1]

 

 

Thanks for all that amazing information! This will definitely be a huge help.

[monowav]

 

 

 

Thanks for all that amazing information! This will definitely be a huge help.

 

[Pereise1]

So I've found a few more things that are helpful for repairing the brain:

 

 

Hyperbaric Oxygen Therapy:

 

 

Abstract

BACKGROUND:

Inflammation, angiogenesis, neurogenesis, and gliosis are involved in traumatic brain injury (TBI). Several studies provide evidence supporting the neuroprotective effect of hyperbaric oxygen (HBO2) therapy in TBI. The aim of this study was to ascertain whether inflammation, angiogenesis, neurogenesis, and gliosis during TBI are affected by HBO2 therapy.

METHODS:

Rats were randomly divided into three groups: TBI + NBA (normobaric air: 21% O2 at 1 absolute atmospheres), TBI + HBO2, and Sham operation + NBA. TBI + HBO2 rats received 100% O2 at 2.0 absolute atmospheres for 1 hr/d for three consecutive days. Behavioral tests and biochemical and histologic evaluations were done 4 days after TBI onset.

RESULTS:

TBI + NBA rats displayed: (1) motor and cognitive dysfunction; (2) cerebral infarction and apoptosis; (3) activated inflammation (evidenced by increased brain myeloperoxidase activity and higher serum levels of tumor necrosis factor-α); (4) neuronal loss (evidenced by fewer NeuN-positive cells); and (5) gliosis (evidenced by more glial fibrillary protein-positive cells). In TBI + HBO2 rats, HBO2 therapy significantly reduced TBI-induced motor and cognitive dysfunction, cerebral infarction and apoptosis, activated inflammation, neuronal loss, and gliosis. In addition, HBO2 therapy stimulated angiogenesis (evidenced by more bromodeoxyuridine-positive endothelial and vascular endothelial growth factor-positive cells), neurogenesis (evidenced by more bromodeoxyuridine-NeuN double-positive and glial cells-derived neurotrophic factor-positive cells), and overproduction of interleukin-10 (an anti-inflammatory cytokine).

CONCLUSIONS:

Collectively, these results suggest that HBO2 therapy may improve outcomes of TBI in rats by inhibiting activated inflammation and gliosis while stimulating both angiogenesis and neurogenesis in the early stage.

___________________________________________________________________________________________________________________________________________________________

 

Abstract

OBJECTIVE:

To investigate whether hyperbaric oxygenation (HBO) can improve the recovery of motor functions in rats after suction ablation of the right sensorimotor cortex.

METHODS:

The experimental paradigm implies the following groups: Control animals ©, Control + HBO (CHBO), Sham controls (S), Sham control + HBO (SHBO), Lesion group (L), right sensorimotor cortex was removed by suction, Lesion + HBO (LHBO). Hyperbaric protocol: pressure applied 2.5 atmospheres absolute, for 60 minutes, once a day for 10 days. A beam walking test and grip strength meter were used to evaluate the recovery of motor functions. Expression profiles of growth-associated protein 43 (GAP43) and synaptophysin (SYP) were detected using immunohistochemistry.

RESULTS:

The LHBO group achieved statistically superior scores in the beam walking test compared to the L group. Additionally, the recovery of muscle strength of the affected hindpaw was significantly enhanced after HBO treatment. Hyperbaric oxygenation induced over-expression of GAP43 and SYP in the neurons surrounding the lesion site.

CONCLUSIONS:

Data presented suggest that hyperbaric oxygen therapy can intensify neuroplastic responses by promoting axonal sprouting and synapse remodelling, which contributes to the recovery of locomotor performances in rats. This provides the perspective for implementation of HBO in clinical strategies for treating traumatic brain injuries.

 

 

 

 

Gastrodia Elata

 

 

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE:

Traumatic brain injury (TBI) has an incident rate of 200-300 people per 100,000 annually in the developed countries. TBI has relatively high incidence at an early age and may cause long-term physical disability. Patients suffered from severe TBI would have motor and neuropsychological malfunctions, affecting their daily activities. Traditionally, Gastrodia elata Blume is a Chinese Medicines which was used for the head diseases, while their efficiency on reducing brain damage was still largely unknown. In the present study, we aimed to examine the effect of water extract of G. elata Blume (GE) against TBI and elucidate its underlying mechanism.

MATERIALS AND METHODS:

Sprague-Dawley rats were treated with GE for 7 days, immediately after controlled cortical impact-induced TBI. Impaired neurobehavioral functioning was measured on day 3 and 6 after TBI. Histology of TBI was examined to assess the extent of inflammation, and the expressions of pro-inflammatory cytokines were examined by immunofluorescence study on day 7.

RESULTS:

GE treatment significantly improved the impaired locomotor functions induced by TBI. GE treatment reduced inflammation and gliosis in the penumbral area. The increase in brain levels of pro-inflammatory cytokines interleukin-6 and tumor necrosis factor-alpha observed in non-GE treated TBI rats were also reversed.

CONCLUSIONS:

GE treatment attenuated the locomotor deficit caused by TBI. The anti-inflammatory activity might be mediated by inhibition of pro-inflammatory cytokines responses in the TBI-brain.

 

 

Agmatine

 

 

Abstract

BACKGROUND:

The mechanisms of agmatine-induced neuroprotective effects in traumatic brain injury (TBI) remain unclear. This study was to test whether inhibition of gliosis, angiogenesis, and neurogenesis attenuating TBI could be agmatine stimulated.

METHODS:

Anesthetized rats were randomly assigned to sham-operated group, TBI rats treated with saline (1 mL/kg, intraperitoneally), or TBI rats treated with agmatine (50 mg/kg, intraperitoneally). Saline or agmatine was injected 5 minutes after TBI and again once daily for the next 3 postoperative days.

RESULTS:

Agmatine therapy in rats significantly attenuated TBI-induced motor function deficits (62° vs. 52° maximal angle) and cerebral infarction (88 mm vs. 216 mm), significantly reduced TBI-induced neuronal (9 NeuN-TUNEL double positive cells vs. 60 NeuN-TUNEL double positive cells) and glial (2 GFAP-TUNEL double positive cells vs. 20 GFAP-TUNEL double positive cells) apoptosis (increased TUNEL-positive and caspase-3-positive cells), neuronal loss (82 NeuN-positive cells vs. 60 NeuN-positive cells), gliosis (35 GFAP-positive cells vs. 72 GFAP-positive cells; 60 Iba1-positive cells vs. 90 Iba1-positive cells), and neurotoxicity (30 n-NOS-positive cells vs. 90 n-NOS-positive cells; 35 3-NT-positive cells vs. 90 3-NT-positive cells), and significantly promoted angiogenesis (3 BrdU/endothelial cells vs. 0.5 BrdU/endothelial cells; 50 vascular endothelial growth factor positive cells vs. 20 vascular endothelial growth factor-positive cells) and neurogenesis (27 BrdU/NeuN positive cells vs. 15 BrdU/NeuN positive cells).

CONCLUSIONS:

Resultantly, agmatine therapy may attenuate TBI in rats via promoting angiogenesis, neurogenesis, and inhibition of gliosis.

 

 

 

 

Taurine

 

 

Abstract

We investigated the effect of taurine on inflammatory cytokine expression, on astrocyte activity and cerebral edema and functional outcomes, following traumatic brain injury (TBI) in rats. 72 rats were randomly divided into sham, TBI and Taurine groups. Rats subjected to moderate lateral fluid percussion injury were injected intravenously with taurine (200mg/kg) or saline immediately after injury or daily for 7days. Functional outcome was evaluated using Modified Neurological Severity Score (mNSS). Glial fibrillary acidic protein (GFAP) of the brain was measured using immunofluorescence. Concentration of 23 cytokines and chemokines in the injured cortex at 1 and 7days after TBI was assessed by Luminex xMAP technology. The results showed that taurine significantly improved functional recovery except 1day, reduced accumulation of GFAP and water content in the penumbral region at 7days after TBI. Compared with the TBI group, taurine significantly suppressed growth-related oncogene (GRO/KC) and interleukin (IL)-1β levels while elevating the levels of regulated on activation, normal T cell expressed and secreted (RANTES) at 1day. And taurine markedly decreased the level of 17 cytokine: eotaxin, Granulocyte colony-stimulating factor (G-CSF), Granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-gamma (IFN-γ), IL-1α, IL-1β, IL-4, IL-5, IL-6, IL-10, IL-12p70, IL-13, IL-17, leptin, monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), vascular endothelial growth factor (VEGF), and only increased the level of MIP-1α in a week. The results suggest that taurine effectively mitigates the severity of brain damage in TBI by attenuating the increase of astrocyte activity and edema as well as pro-inflammatory cytokines.

 

 

 

 

Progesterone

 

 

Abstract

Vascular remodeling plays a key role in neural regeneration in the injured brain. Circulating endothelial progenitor cells (EPCs) are a mediator of the vascular remodeling process. Previous studies have found that progesterone treatment of traumatic brain injury (TBI) decreases cerebral edema and cellular apoptosis and inhibits inflammation, which in concert promote neuroprotective effects in young adult rats. However, whether progesterone treatment regulates circulating EPC level and fosters vascular remodeling after TBI have not been investigated. In this study, we hypothesize that progesterone treatment following TBI increases circulating EPC levels and promotes vascular remodeling in the injured brain in aged rats. Male Wistar 20-month-old rats were subjected to a moderate unilateral parietal cortical contusion injury and were treated with or without progesterone (n=54/group). Progesterone was administered intraperitoneally at a dose of 16mg/kg at 1 h post-TBI and was subsequently injected subcutaneously daily for 14 days. Neurological functional tests and immnunostaining were performed. Circulating EPCs were measured by flow cytometry. Progesterone treatment significantly improved neurological outcome after TBI measured by the modified neurological severity score, Morris Water Maze and the long term potentiation in the hippocampus as well as increased the circulating EPC levels compared to TBI controls (p<0.05). Progesterone treatment also significantly increased CD34 and CD31 positive cell number and vessel density in the injured brain compared to TBI controls (p<0.05). These data indicate that progesterone treatment of TBI improves multiple neurological functional outcomes, increases the circulating EPC level, and facilitates vascular remodeling in the injured brain after TBI in aged rats.

 

 

 

Edited by Pereise1, 14 August 2018 - 10:11 PM.

[Pereise1]

Here's a few more things that can help regenerate CNS scar tissue:

 

 

Acetylcholinesterase Inhibitors:

 

 

Abstract

We previously reported that neuroinflammation contributes to the amnesia of AβPPswe/PSEN1dE9 Alzheimer's disease model mice fed a high-fat diet to induce type-2 diabetes (T2DM-AD mice), but the underlying mechanism for the memory decline remained unclear. Recent studies have suggested that cholinergic modulation is involved in neuroinflammatory cellular reactions including neurogenesis and gliosis, and in memory improvement. In this study, we administered a broad-spectrum cholinesterase inhibitor, rivastigmine (2 mg/kg/day, s.c.), into T2DM-AD mice for 6 weeks, and evaluated their memory performance, neurogenesis, and neuroinflammatory reactions. By two hippocampal-dependent memory tests, the Morris water maze and contextual fear conditioning, rivastigmine improved the memory deterioration of the T2DM-AD mice (n = 8, p < 0.01). The number of newborn neurons in the hippocampal dentate gyrus was 1138±324 (Ave±SEM) in wild-type littermates, 2573±442 in T2DM-AD-Vehicle, and 2165±300 in T2DM-AD-Rivastigmine mice, indicating that neurogenesis was accelerated in the two T2DM-AD groups (n = 5, p < 0.05). The dendritic maturation of new neurons in T2DM-AD-Vehicle mice was severely abrogated, and rivastigmine treatment reversed this retarded maturation. In addition, the hippocampus of T2DM-AD-Vehicle mice showed increased proinflammatory cytokines IL-1β and TNF-α and gliosis, and rivastigmine treatment blocked these inflammatory reactions. Rivastigmine did not change the insulin abnormality or amyloid pathology in these mice. Thus, cholinergic modulation by rivastigmine treatment led to enhanced neurogenesis and the suppression of gliosis, which together ameliorated the memory decline in T2DM-AD model mice.

 

 

 

 

Cannabidiol

 

CBD was already reported to exert a marked anti-inflammatory effect through the A2A and 5HT1A receptors [18], [19], as well as to improve brain function [20]. In addition, it has been already demonstrated that CBD markedly downregulate reactive gliosis by reducing pro-inflammatory molecules and cytokine release that strongly occurs in Aβ neurotoxicity. This activity was linked to its ability to act as a potent inhibitor of NFκB activation induced by Aβ challenge [21]. The present findings, confirming the formerly obtained results and extending our knowledge about CBD pharmacology, indicate that a selective PPARγ activation occurs upstream to CBD-mediated NFκB inhibition. Such activation appears to be responsible for a large plethora of CBD effects. Indeed, the interaction of CBD at the PPARγ site results in a profound inhibition of reactive gliosis as showed by the reduction of both GFAP and S100B protein expression together with a marked decline of pro-inflammatory molecules and cytokine release observed in Aβ challenged astrocytes.

 

 

 

Methylene Blue:

 

 

Abstract

Ischemic stroke in rodents stimulates neurogenesis in the adult brain and the proliferation of newborn neurons that migrate into the penumbra zone. The present study investigated the effect of methylene blue (MB) on neurogenesis and functional recovery in a photothrombotic (PT) model of ischemic stroke in rats. PT stroke model was induced by photo-activation of Rose Bengal dye in cerebral blood flow by cold fibre light. Rats received intraperitoneal injection of either MB (0.5 mg/kg/day) from day 1 to day 5 after stroke or an equal volume of saline solution as a control. Cell proliferative marker 5-bromodeoxyuridine (BrdU) was injected twice daily (50 mg/kg) from day 2 to day 8 and animals were sacrificed on day 12 after PT induction. We report that MB significantly enhanced cell proliferation and neurogenesis, as evidenced by the increased co-localizations of BrdU/NeuN, BrdU/DCX, BrdU/MAP2 and BrdU/Ki67 in the peri-infarct zone compared with vehicle controls. MB thus effectively limited infarct volume and improved neurological deficits compared to PT control animals. The effects of MB were accompanied with an attenuated level of reactive gliosis and release of pro-inflammatory cytokines, as well as elevated levels of cytochrome c oxidase activity and ATP production in peri-infarct regions. Our study provides important information that MB has the ability to promote neurogenesis and enhance the newborn-neurons’ survival in ischemic brain repair by inhibiting microenvironmental inflammation and increasing mitochondrial function.

 

 

 

Ashwagandha (Withaferin A):

 

Results: WFA significantly improved neurobehavioural function and alleviated histological alteration of spinal cord tissues in traumatized mice. Brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) significantly increased in WFA-treated mice. Meanwhile, the expression of Nogo-A and RhoA remarkably decreased in the presence of WFA. Furthermore, the apoptotic cell death was attenuated in mice treated with WFA (31.48 ± 2.50% vs. 50.08 ± 2.08%) accompanied by decreased bax and increased bcl-2. In addition, WFA decreased the expression of pro-inflammatory mediators such as IL-1β (11.20 ± 1.96 ng/mL vs. 17.59 ± 1.42 ng/mL) and TNF-α (57.38 ± 3.57 pg/mL vs. 95.06 ± 9.13 pg/mL). The anti-inflammatory cytokines including TGF-β1 (14.32 ± 1.04 pg/mL vs. 9.37 ± 1.17 pg/mL) and IL-10 (116.80 ± 6.91 pg/mL vs. 72.33 ± 9.35 pg/mL) were elevated after WFA administration.