Changing stroke rehab and research worldwide now.Time is Brain! trillions and trillions of neurons that DIE each day because there are NO effective hyperacute therapies besides tPA(only 12% effective). I have 523 posts on hyperacute therapy, enough for researchers to spend decades proving them out. These are my personal ideas and blog on stroke rehabilitation and stroke research. Do not attempt any of these without checking with your medical provider. Unless you join me in agitating, when you need these therapies they won't be there.

What this blog is for:

My blog is not to help survivors recover, it is to have the 10 million yearly stroke survivors light fires underneath their doctors, stroke hospitals and stroke researchers to get stroke solved. 100% recovery. The stroke medical world is completely failing at that goal, they don't even have it as a goal. Shortly after getting out of the hospital and getting NO information on the process or protocols of stroke rehabilitation and recovery I started searching on the internet and found that no other survivor received useful information. This is an attempt to cover all stroke rehabilitation information that should be readily available to survivors so they can talk with informed knowledge to their medical staff. It lays out what needs to be done to get stroke survivors closer to 100% recovery. It's quite disgusting that this information is not available from every stroke association and doctors group.

Sunday, July 15, 2018

NT-3 promotes proprioceptive axon regeneration when combined with activation of the mTor intrinsic growth pathway but not with reduction of myelin extrinsic inhibitors

Now if we just had a stroke leader to go to to ask for followup of this in humans. But we have NONE, basically just our fucking failures of stroke associations hiding and doing nothing for stroke survivors. Why the fuck is stroke in their names anyway? I want proprioception back again.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5090983/
About Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Exp Neurol. Author manuscript; available in PMC 2017 Sep 1.
Published in final edited form as:
PMCID: PMC5090983
NIHMSID: NIHMS795414
PMID: 27264357

Abstract

Although previous studies have identified several strategies to stimulate regeneration of CNS axons, extensive regeneration and functional recovery have remained a major challenge, particularly for large diameter myelinated axons. Within the CNS, myelin is thought to inhibit axon regeneration, while modulating activity of the mTOR pathway promotes regeneration of injured axons. In this study, we examined NT-3 mediated regeneration of sensory axons through the dorsal root entry zone in a triple knockout of myelin inhibitory proteins or after activation of mTOR using a constitutively active (ca) Rheb in DRG neurons to determine the influence of environmental inhibitory or activation of intrinsic growth pathways could enhance NT-3-mediate regeneration. Loss of myelin inhibitory proteins showed modest enhancement of sensory axon regeneration. In mTOR studies, we found a dramatic age related decrease in the mTOR activation as determined by phosphorylation of the downstream marker S6 ribosomal subunit. Expression of caRheb within adult DRG neurons in vitro increased S6 phosphorylation and doubled the overall length of neurite outgrowth, which was reversed in the presence of rapamycin. In adult female rats, combined expression of caRheb in DRG neurons and NT-3 within the spinal cord increased regeneration of sensory axons almost 3 fold when compared to NT-3 alone. Proprioceptive assessment using a grid runway indicates functionally significant regeneration of large-diameter myelinated sensory afferents. Our results indicate that caRheb-induced increase in mTOR activation enhances neurotrophin-3 induced regeneration of large-diameter myelinated axons.
Keywords: Rheb, mTOR signaling pathway, neurotrophin-3 (NT-3), axonal regeneration, dorsal root ganglion (DRG)

Introduction

Of the sensory axon populations examined large diameter myelinated axons show the poorest regeneration through the dorsal root entry zone (DREZ) and into the spinal cord. Proprioceptive axons are some of the largest diameter sensory axons in the body and express the NT3 receptor trkC. Numerous studies indicate that regenerative failure is most likely due to both reduced intrinsic growth ability by adult neurons and the inhibitory environment within the spinal cord. Spinal cord application of neurotrophin-3 (NT-3) is thought to enhance the intrinsic growth state of adult DRG neurons, as well as modify the extrinsic environment (Hanna-Mitchell et al., 2008) and promote some but limited amount of sensory afferent regeneration across the dorsal root entry zone after dorsal root rhizotomies (Ramer et al., 2001; 2002). Previous studies indicated that NT-3-induced regeneration is sufficient to bypass the gliotic region at the DREZ, but regeneration fails when axons encounter degenerative domain containing myelin debris (Ramer et al., 2001). Other studies have also shown that soluble Nogo receptor can promote regeneration of sensory afferents across the DREZ (Harvey et al., 2009); however, this regeneration was limited primarily within the dorsal columns.
On the other hand, intrinsic activation of mTOR by deletion of an upstream negative regulator PTEN increased axonal regeneration of retinal ganglion neurons and cortical neurons. Likewise, inhibition of mTOR with rapamycin blocked regeneration, suggesting that modulation of mTOR activity affects intrinsic axonal growth capacity within the CNS (Park et al., 2008). mTOR is a critical regulator of protein synthesis and plays an important role in cell growth, proliferation, and survival during development (Martin and Hall, 2005; Sarbassov et al., 2005). Previous studies have suggested that mTOR expression level is correlated with increased growth capacity (Abe et al., 2010; Park et al., 2008). mTOR activity is upregulated in DRG neurons after sciatic nerve lesion (Belin et al., 2015) and downregulated in retinal and cortical neurons after lesion (Park et al., 2008, Liu et al., 2010). In cultured DRG neurons, following PTEN inhibition and neurite growth induction, rapamycin did not completely block increased neurite outgrowth, suggesting other mechanisms by which PTEN knockdown might affect regenerative growth beyond mTOR activation alone (Christie et al., 2010). Ras homolog enriched in brain (Rheb) is a direct activator of mTOR and was shown to activate the mTOR pathway in many studies (Bai et al., 2007; Inoki et al., 2003; Long et al., 2005). To date, it is not reported whether direct and specific activation of mTOR pathway can affect axonal growth capacity after central branch injury in DRG neurons.
In this study we attempted to augment NT-3 mediated regeneration of large diameter myelinated axons using two approaches. The first was to overexpress NT-3 in the spinal cord of Nogo/MAG/OMgp triple knockout mice to determine if the elimination of extrinsic, myelin-associated inhibitors would augment NT-3 mediated primary afferent regeneration. In the second part we expressed a constitutively active form of Rheb to activate mTOR to determine if further enhancement of intrinsic growth would enhance NT-3-mediated proprioceptive sensory axon regeneration through the DREZ and into the spinal cord. Here, we observed the loss of myelin-associated inhibitors to have only a modest effect on enhancing regeneration in the presence of NT-3. However, expression of ca-Rheb in DRG neurons induced greater than a 2 fold increase in NT-3 mediated regeneration.
Much more at link. 

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