Combinational Approach of Genetic SHP-1 Suppression and Voluntary Exercise Promotes Corticospinal Tract Sprouting and Motor Recovery Following Brain Injury

Now we need to know EXACTLY HOW MUCH EXERCISE TO DO. Ask your doctor and stroke hospital what they are doing to get human research done to create protocols for this.  No research then the whole leadership team including the board of directors needs to be fired.  You don't leave incompetent people in place when 100% recovery is on the line.

Combinational Approach of Genetic SHP-1 Suppression and Voluntary Exercise Promotes Corticospinal Tract Sprouting and Motor Recovery Following Brain Injury

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Takashi Tanaka, PhD, Tetsufumi Ito, PhD, Megumi Sumizono, PhD, ...

First Published May 22, 2020 Research Article Find in PubMed

https://doi.org/10.1177/1545968320921827

Article information

Abstract

Background.
Brain injury often causes severe motor dysfunction, leading to difficulties with living a self-reliant social life. Injured neural circuits must be reconstructed to restore functions, but the adult brain is limited in its ability to restore neuronal connections. The combination of molecular targeting, which enhances neural plasticity, and rehabilitative motor exercise is an important therapeutic approach to promote neuronal rewiring in the spared circuits and motor recovery.  
Objective.
We tested whether genetic reduction of Src homology 2-containing phosphatase-1 (SHP-1), an inhibitor of brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling, has synergistic effects with rehabilitative training to promote reorganization of motor circuits and functional recovery in a mouse model of brain injury.
Methods.
Rewiring of the corticospinal circuit was examined using neuronal tracers following unilateral cortical injury in control mice and in Shp-1 mutant mice subjected to voluntary exercise. Recovery of motor functions was assessed using motor behavior tests.  
Results.
We found that rehabilitative exercise decreased SHP-1 and increased BDNF and TrkB expression in the contralesional motor cortex after the injury. Genetic reduction of SHP-1 and voluntary exercise significantly increased sprouting of corticospinal tract axons and enhanced motor recovery in the impaired forelimb.  
Conclusions.
Our data demonstrate that combining voluntary exercise and SHP-1 suppression promotes motor recovery and neural circuit reorganization after brain injury.

Keywords brain injury, corticospinal tract, functional recovery, SHP-1, voluntary exercise

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Systems Biology of Immunomodulation for Post-Stroke Neuroplasticity: Multimodal Implications of Pharmacotherapy and Neurorehabilitation

Whatever the fuck this means. Written to make sure survivors can't understand. Research like this isn't for survivors anyway, it is for our stroke doctors to implement even though they never read and analyze research for their patients. Someday 1 out of 100,00 doctors will quibble with that gross generalization.
http://journal.frontiersin.org/article/10.3389/fneur.2016.00094/full?utm_source=newsletter&

Mohammed Aftab Alam^†, V. P. Subramanyam Rallabandi^† and Prasun K. Roy*

• National Brain Research Centre, Gurgaon, India

Aims: Recent studies indicate that anti-inflammatory drugs, act as a double-edged sword, not only exacerbating secondary brain injury but also contributing to neurological recovery after stroke. Our aim is to explore whether there is a beneficial role for neuroprotection and functional recovery using anti-inflammatory drug along with neurorehabilitation therapy using transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS), so as to improve functional recovery after ischemic stroke.

Methods: We develop a computational systems biology approach from preclinical data, using ordinary differential equations, to study the behavior of both phenotypes of microglia, such as M1 type (pro-inflammatory) vis-à-vis M2 type (anti-inflammatory) under anti-inflammatory drug action (minocycline). We explore whether pharmacological treatment along with cerebral stimulation using tDCS and rTMS is beneficial or not. We utilize the systems pathway analysis of minocycline in nuclear factor kappa beta (NF-κB) signaling and neurorehabilitation therapy using tDCS and rTMS that act through brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) signaling pathways.

Results: We demarcate the role of neuroinflammation and immunomodulation in post-stroke recovery, under minocycline activated-microglia and neuroprotection together with improved neurogenesis, synaptogenesis, and functional recovery under the action of rTMS or tDCS. We elucidate the feasibility of utilizing rTMS/tDCS to increase neuroprotection across the reperfusion stage during minocycline administration. We delineate that the signaling pathways of minocycline by modulation of inflammatory genes in NF-κB and proteins activated by tDCS and rTMS through BDNF, TrkB, and calmodulin kinase (CaMK) signaling. Utilizing systems biology approach, we show that the activation pathways for pharmacotherapy (minocycline) and neurorehabilitation (rTMS applied to ipsilesional cortex and tDCS) results into increased neuronal and synaptic activity that commonly occur through activation of N-methyl-d-aspartate receptors. We construe that considerable additive neuroprotection effect would be obtained and delayed reperfusion injury can be remedied, if one uses multimodal intervention of minocycline together with tDCS and rTMS.

Conclusion: Additive beneficial effect is, thus, noticed for pharmacotherapy along with neurorehabilitation therapy, by maneuvering the dynamics of immunomodulation using anti-inflammatory drug and cerebral stimulation for augmenting the functional recovery after stroke, which may engender clinical applicability for enhancing plasticity, rehabilitation, and neurorestoration.

Introduction

Recent investigations have reported that immune responses to inflammation are non-specific systemic infections associated with progression of neurodegenerative diseases via activation of macrophages (1). Minocycline is a tetracycline antibiotic having several properties, such as anti-inflammatory, anti-apoptosis, free radical scavenger, and protein misfolding (2). The therapeutic effects of minocycline in preclinical models of neurodegenerative diseases showed direct neuroprotection and reduction of microglial inflammatory responses (3). It has been reported in in vivo studies that minocycline blocks the adhesion of leukocytes to cerebrovascular endothelial cells induced by lipopolysaccharides, as well as tumor necrosis factor-α (TNF-α) production in the brain (4). In vitro studies have reported the anti-inflammatory effects of minocycline for neuroprotection (5) and in macrophages (6). Neuroprotective effects of minocycline include reduction of macrophage activation, prevention of the potentiation of ischemia-like injury to astrocytes and endothelial cells consolidating the brain tissue parenchyma (7). Although, the anti-inflammatory effects of minocycline are known to some extent, the direct effects of neuroprotection have not been well investigated in neurodegenerative diseases.

Several studies have shown that the physiological neuroprotection mechanisms that occur after stroke are targeted through various signaling pathways. Several studies suggest that the mechanisms associated with either reducing the size of infarct or enabling neurorestoration, involve the following entities: (i) anti-high mobility group box-1 activity (8); (ii) NF-κB (9); (iii) mammalian target of rapamycin (mTOR) inhibitor (10, 11); (iv) stimulation of toll-like receptors (TLR2 and TLR4) prior to brain ischemia (12, 13), (v) c-Jun N-terminal kinase (JNK) inhibitor (14); (vi) p38 mitogen-activated protein kinase (p38 MAPK) inhibitor (15); (vii) MEK1 pathway (16); (viii) MAPP/MEK/ERK inhibitor (17); and (ix) Minocycline-induced reduction of LPS-stimulated p38 MAPK activation, and stimulation of the phosphoinositide 3-kinase (PI3K)/Akt pathway (18).

Currently, little is known about endogenous counter regulatory immune mechanisms that can induce neurorestoration. The glycogen synthase kinase-3β (AKT/GSK-3β) pathway has been recognized as a protective pathway against cerebral ischemic injury. In cerebral ischemia models, it has been shown that remote limb conditioning does indeed activate and upregulate the pro-survival AKT pathway (19) and long-term protection against cerebral ischemia is afforded by limb post-conditioning that is associated with AKT, MAPK, phosphatidylinositol 3-kinase (PI3K), and protein kinase C (PKC) signaling pathways (20). NF-κB transcription factor family members, such as p50, p65/RelA in the hippocampus, are regulated by metabotropic glutamate receptor signaling and c-Rel transcription factor is responsible for the formation and maintenance of long-term memory (21). Minocycline directly inhibits matrix metalloproteinase (MMP)-9 activation through NF-κB pathway (22). In silico modeling of anti-inflammatory response has been reported for endotoxins (LPS) and corticosteroids by activating TLRs in NF-κB (23).

Taken together, the modulation of cell survival and death signaling by hypoxic/ischemic preconditioning appears to be capable of targeting multiple levels of signaling cascades. Several inhibitors targeted the point of convergence through distinct and interacting signaling pathways (crosstalk mechanism) for inflammation by activating macrophages that lead to neuroprotection. Also, cerebral stimulation-based transcranial magnetic stimulation and direct current stimulation enhances brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) signaling (24, 25). In this study, we harness the convergent signaling pathways of pharmacotherapy (anti-inflammatory, immunomodulatory) and neurorehabilitation therapy (functional recovery) for efficient post-stroke neurorestoration by experimental and systems-level approach. We modeled using the systems biology approach of minocycline modulation of MMPs through NF-κB signaling pathway, a master regulator of inflammatory responses along with neurorehabilitation-based activation in BDNF and TrkB signaling.

More at link.

Systems Biology of Immunomodulation for Post-stroke Neuroplasticity: Multimodal Implications of Pharmacotherapy and Neurorehabilitation

It would seem that this should have been broken into multiple trials. Putting anti-inflammation drugs, tDCS, and rTMS into the same trial  is a recipe for not knowing which intervention did what.  A good mentor would have known that and changed the trial appropriately. 

Systems Biology of Immunomodulation for Post-stroke Neuroplasticity: Multimodal Implications of Pharmacotherapy and Neurorehabilitation

Mohammed A. Alam¹, V.P. S. Rallabandi¹ and Prasun K. Roy^1*

• ¹National Brain Research Centre, India

AIMS: Recent studies indicate that anti-inflammatory drugs, act as a double-edged sword, not only exacerbating secondary brain injury but also contributing to neurological recovery after stroke. Our aim is to explore whether there is a beneficial role for neuroprotection and functional recovery using antiinflammatory drug along with neurorehabilitation therapy using transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS), so as to improve functional recovery after ischemic stroke.
METHODS: We develop a computational systems biology approach from preclinical data using ordinary differential equations, to study the behavior of both phenotypes of microglia such as M1 type (pro-inflammatory) vis-à-vis M2 type (anti-inflammatory) under anti-inflammatory drug action (minocycline). We explore whether pharmacological treatment along with cerebral stimulation using tDCS and rTMS is beneficial or not. We utilize the systems pathway analysis of minocycline in NF-κB (nuclear factor kappa beta) signaling and neurorehabilitation therapy using tDCS and rTMS which act through brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) signaling pathways.
RESULTS: We demarcate the role of neuroinflammation and immunomodulation in post-stroke recovery, under minocycline activated microglia and neuroprotection together with improved neurogenesis, synaptogenesis and functional recovery under the action of rTMS or tDCS. We elucidate the feasibility of utilizing rTMS/tDCS to increase neuroprotection across the reperfusion stage during minocycline administration. We delineate that the signaling pathways of minocycline by modulation of inflammatory genes in NF-κB and proteins activated by tDCS and rTMS through BDNF, Trk-B and Calmodulin kinase (CaMK) signaling. Utilizing systems biology approach, we show the activation pathways for pharmacotherapy (minocycline) and neurorehabilitation (rTMS applied to ipsilesional cortex and tDCS) results into increased neuronal and synaptic activity that commonly occur through activation of N-methyl-D-aspartate (NMDA) receptors. We construe that considerable additive neuroprotection effect would be obtained and delayed reperfusion injury can be remedied, if one uses multimodal intervention of minocycline together with tDCS and rTMS.
CONCLUSION: Additive beneficial effect is thus noticed for pharmacotherapy along with neurorehabilitation therapy, by maneuvering the dynamics of immunomodulation using anti-inflammatory drug and cerebral stimulation for augmenting the functional recovery after stroke, which may engender clinical applicability for enhancing plasticity, rehabilitation and neurorestoration.

Keywords: Stroke, Neuroprotection, Rehabilitation, Minocycline, direct current stimulation, Transcranial magnetic stimulation.
Citation: Alam MA, Rallabandi VS and Roy PK (2016). Systems Biology of Immunomodulation for Post-stroke Neuroplasticity: Multimodal Implications of Pharmacotherapy and Neurorehabilitation. Front. Neurol. 7:94. doi: 10.3389/fneur.2016.00094

Received: 22 Jan 2016; Accepted: 07 Jun 2016.

Edited by:
Anirban Dutta, Leibniz-Institut für Arbeitsforschung an der TU Dortmund, Germany

Reviewed by:
Raju S. Bapi, University of Hyderabad, India
Mamta Naidu, GRI/ CCSB-Tufts Sch Med, USA  

Copyright: © 2016 Alam, Rallabandi and Roy. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Prof. Prasun K. Roy, National Brain Research Centre, NH-8, Nainwal Road, Manesar, Grgaon, 122051, Haryana, India, pkroy@nbrc.ac.in

Running exercise delays neurodegeneration in amygdala and hippocampus of Alzheimer’s disease (APP/PS1) transgenic mice

Is your doctor going to figure out a way for you to get some kind of running exercise to counteract your 33% chance of getting dementia post-stroke?
Even though this is just in mice what is the downside of doing this for stroke survivors? Keep demanding answers from your doctors, they are supposed to be helping you recover.
http://www.sciencedirect.com/science/article/pii/S1074742714002196 

• Tzu-Wei Lin^a,
• Yao-Hsiang Shih^a,
• Shean-Jen Chen^{b, c, d},
• Chi-Hsiang Lien^b,
• Chia-Yuan Chang^b,
• Tung-Yi Huang^e,
• Shun-Hua Chen^{a, f},
• Chauying J. Jen^{a, e},
• Yu-Min Kuo^{a, g, ,}

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doi:10.1016/j.nlm.2014.12.005

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Highlights

•

Neurodegeneration occurs in the hippocampus and amygdala of young transgenic mice.

•

Neurodegeneration in the amygdala is more severe than that in the hippocampus.

•

Exercise counteracts the transgene-induced neurodegeneration.

•

Exercise enhances the BDNF signaling pathways and Aβ clearance.

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Abstract

Alzheimer’s disease (AD) is an age-related neurodegenerative disease. Post-mortem examination and brain imaging studies indicate that neurodegeneration is evident in the hippocampus and amygdala of very early stage AD patients. Exercise training is known to enhance hippocampus- and amygdala-associated neuronal function. Here, we investigated the effects of exercise (running) on the neuronal structure and function of the hippocampus and amygdala in APP/PS1 transgenic (Tg) mice. At 4-months-old, an age before amyloid deposition, the amygdala-associated, but not the hippocampus-associated, long-term memory was impaired in the Tg mice. The dendritic complexities of the amygdalar basolateral neurons, but not those in the hippocampal CA1 and CA3 neurons, were reduced. Furthermore, the levels of BDNF-TrkB signaling molecules (i.e. p-TrkB, p-Akt and p-PKC) were reduced in the amygdala, but not in the hippocampus of the 4-month-old Tg mice. The concentrations of Aβ₄₀ and Aβ₄₂ in the amygdala were higher than those in the hippocampus. Ten weeks of treadmill training (from 1.5- to 4-month-old) increased the hippocampus-associated memory and dendritic arbor of the CA1 and CA3 neurons, and also restored the amygdala-associated memory and the dendritic arbor of amygdalar basolateral neurons in the Tg mice. Similarly, exercise training also increased the levels of p-TrkB, p-Akt and p-PKC in the hippocampus and amygdala. Furthermore, exercise training reduced the levels of soluble Aβ in the amygdala and hippocampus. Exercise training did not change the levels of APP or RAGE, but significantly increased the levels of LRP-1 in both brain regions of the Tg mice. In conclusion, our results suggest that tests of amygdala function should be incorporated into subject selection for early prevention trials. Long-term exercise protects neurons in the amygdala and hippocampus against AD-related degeneration, probably via enhancements of BDNF signaling pathways and Aβ clearance. Physical exercise may serve as a means to delay the onset of AD.

Brain Reserve Regulators in Alzheimer’s Disease

I need this, it's only 14 pages for your doctor to explain to you for resisting the effects of dementia. 

Brain Reserve Regulators in Alzheimer’s Disease

1. Introduction

Brain reserve refers to the ability of the brain to tolerate pathological changes such as those seen in AD before manifesting clinical signs and symptoms [1-3]. Neurotrophic factors (NTFs), most notably Brain Derived Neurotrophic Factor (BDNF) and its receptor Tyrosine kinase B

(TrkB), regulate synaptic plasticity and functional efficiency in adulthood [4-6] and thus may influence brain reserve. BDNF/TrkB signaling affects memory formation and retention [7,8],determines neurite length [9,1], and governs regeneration upon neuronal injury [11,12] by modifying neuronal cytoskeleton. Abnormalities in the neuronal cytoskeleton are well

documented in AD. However, how these abnormalities affect AD progression remains unclear.  In Drosophila, neurodegeneration stems directly from mutations in alpha and beta subunits of the actin capping protein (CP), demonstrating that a mutation in a gene encoding an actin

cytoskeleton regulator can lead to demise of neurons [13]. Further, a causative role for actin cytoskeleton abnormalities in neurotoxicity has been documented in a Drosophila tauopathy model [14]. Important evidence that cytoskeletal abnormalities are critically involved in the pathogenesis of neurodegeneration stems from the studies demonstrating the effect of apolipoprotein E isoform ε4 (ApoE ε4), the well-documented genetic risk factor for the most common form of AD, late-onset AD [15], on neuronal cytoskeleton. In the United States, the ApoEε4 allele occurs in 

60% of AD patients. ApoEε4 inhibits neurite outgrowth in cultured neuronal cells[16] and correlates with the simplification of dendritic branching patterns in the brains of AD patients [17]. ApoE ε4 dose inversely correlates with dendritic spine density in dentate gyrusneurons of both AD and aged normal controls [18]. Overexpression and neuron-specificproteolytic cleavage of ApoEε4 result in tau hyperphosphorylation in neurons of transgenic mice, suggesting a role of ApoEε4 in cytoskeletal destabilization and the development of AD-related neuronal deficits [19,20]. Humanized ApoE ε4 knock-in homozygous transgenic mice

Nerve Growth Factor, Brain-Derived Neurotrophic Factor, Neurotrophin-3 and Glial-Derived Neurotrophic Factor Enhance Angiogenesis in a Tissue-Engineered In Vitro Model

We need angiogenesis to support stem cells and migrating neurons to the damaged area. Ask your doctor to apply this to your recovery. Its going to take some intellect to transfer this knowledge from skin to the brain.
http://online.liebertpub.com/doi/abs/10.1089/ten.tea.2012.0745

ABSTRACT

Skin is a major source of secretion of the neurotrophic factors nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and glial-derived neurotrophic factor (GDNF) controlling cutaneous sensory innervation. Beside their neuronal contribution, we hypothesized that neurotrophic factors also modulate the cutaneous microvascular network. First, we showed that NGF, BDNF, NT-3, and GDNF were all expressed in the epidermis, while only NGF and NT-3 were expressed by cultured fibroblasts, and BDNF by human endothelial cells. We demonstrated that these peptides are highly potent angiogenic factors using a human tissue-engineered angiogenesis model. A 40% to 80% increase in the number of capillary-like tubes was observed after the addition of 10 ng/mL of NGF, 0.1 ng/mL of BDNF, 15 ng/mL of NT-3, and 50 ng/mL of GDNF. This is the first characterization of the direct angiogenic effect of NT-3 and GDNF. This angiogenic effect was mediated directly through binding with the neurotrophic factor receptors tropomyosin-receptor kinase A (TrkA), TrkB, GFRα-1 and c-ret that were all expressed by human endothelial cells, while this effect was blocked by addition of the Trk inhibitor K252a. Thus, if NGF, BDNF, NT-3, and GDNF may only moderately regulate the microvascular network in normal skin, they might have the potential to greatly increase angiogenesis in pathological situations.

Stroke Treatment Reveals Targets For Better Recovery

regenerating blood vessels in the brain.
http://www.webpronews.com/stroke-treatment-reveals-targets-for-better-recovery-2012-12

From 2003

The ACCESS Study

Evaluation of Acute Candesartan Cilexetil Therapy in Stroke Survivors

http://stroke.ahajournals.org/content/34/7/1699.short
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The angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST): a randomised, placebo-controlled, double-blind trial

http://www.sciencedirect.com/science/article/pii/S0140673611601049

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Candesartan but not ramipril pretreatment improves outcome after stroke and stimulates neurotrophin BDNF/TrkB system in rats

http://journals.lww.com/jhypertension/Abstract/2008/03000/Candesartan_but_not_ramipril_pretreatment_improves.25.aspx 

 

N-Acetylserotonin Neuroprotection, Neurogenesis, and the Sleepy Brain

Get your doctor to translate this into a stroke protocol, that's what they are for.
 http://nro.sagepub.com/content/18/6/645.abstract?etoc

Abstract

N-Acetylserotonin (NAS) is a naturally occurring chemical intermediate in biosynthesis of melatonin. Previous studies have shown that NAS has different brain distribution patterns from those of serotonin and melatonin, suggesting that NAS might have functions other than as a precursor or metabolite of melatonin. Indeed, several studies have now shown that NAS may play an important role in mood regulation and may have antidepressant activity. Additional studies have shown that NAS stimulates proliferation of neuroprogenitor cells and prevents some of the negative effects of sleep deprivation. It is believed that the antidepressant and neurotrophic actions of NAS are due at least in part to the capability on this molecule to activate the TrkB receptor in a brain-derived neurotrophic factor–independent manner. Emerging evidence also indicates that NAS and its derivatives have neuroprotective properties and protect retinal photoreceptor cells from light-induced degeneration. In this review, the authors discuss the literature about this exciting and underappreciated molecule.

Lithium induces brain-derived neurotrophic factor and activates TrkB in rodent cortical neurons: an essential step for neuroprotection against glutamate excitotoxicity.

Only from 2002.
http://www.ncbi.nlm.nih.gov/pubmed/12504924

Abstract

Mechanisms underlying the therapeutic effects of lithium for bipolar mood disorder remain poorly understood. Recent studies demonstrate that lithium has neuroprotective actions against a variety of insults in vitro and in vivo. This study was undertaken to investigate the role of the brain-derived neurotrophic factor (BDNF)/TrkB signaling pathway in mediating neuroprotection of lithium against glutamate excitotoxicity in cortical neurons. Pretreatment with either lithium or BDNF protected rat cerebral cortical neurons from glutamate excitotoxicity. The duration of treatment required to elicit maximal neuroprotection by BDNF (1 day) was much shorter than that by lithium (6 days). K252a, an inhibitor of Trk tyrosine kinases, and a BDNF neutralizing antibody suppressed the neuroprotective effect of lithium. Treatment of cortical neurons with lithium increased the cellular BDNF content in 3 days and the phosphorylation of TrkB at Tyr490 in 5 days, suggesting that long-term lithium administration enhances BDNF expression/secretion, leading to the activation of TrkB receptor. Lithium failed to protect against glutamate excitotoxicity in cortical neurons derived from homozygous and heterozygous BDNF knockout mice, although lithium fully protected cortical neurons prepared from wild type mice littermates. Taken together, these data suggest that the BDNF/TrkB pathway plays an essential role in mediating the neuroprotective effect of lithium.

Experimental drug helps the brain recover from stroke -- in mice

You'll have to read the complete article at the link, copyrighted. Has your competent? doctor gotten human testing going? NO? So, you DON'T have a functioning stroke doctor, do you? FIRE THEM!

Experimental drug helps the brain recover from stroke -- in mice

Though stroke is a major cause of long-term disability, the only proven treatment for patients is to dissolve a clot or stop the bleeding in the brain while the stroke is happening. Once it’s over, doctors and therapists can only offer rehabilitation to minimize the damage. The experimental drug being developed by scientists from Stanford University School of Medicine, Weill Cornell Medical College and UC San Francisco aims to change that.
The drug is designed to mimic a protein called brain-derived neurotrophic factor, or BDNF, which is thought to help stimulate growth of new neurons and make the brain “plastic,” or able to adapt to changes. BDNF works in cooperation with a receptor in the brain called TrkB. So the scientists set out to find a way to activate TrkB in hopes that doing so would mimic the action of BDNF and promote actual healing in the brain.
The researchers turned to a small molecule called LM22A-4 that – like BDNF – is known to bind to TrkB. The compound was made by a company called Ricerca Biosciences.
From another source:
 The results are promising because the compound wasn’t administered to the animals until a full three days after they had suffered strokes, noted Buckwalter. As such, the treatment – if proven effective in humans – could be particularly useful for patients who suffer strokes while sleeping or don’t readily recognize the symptoms and don’t get to the hospital fast enough for existing therapeutic agents to be administered.