Inosine and neural growth

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Inosine and neural growth

Postby CaliReader » Wed Feb 06, 2013 7:31 am

Hi,

I'm surprised to report that there may be more to Inosine than just being the precursor to Uric acid.
I learned from this board that uric acid is an antioxidant, usually low in people with MS and helpful to protect against bladder infections etc.

I started taking Inosine as a way to jump start my uric acid.
Then I took the word Inosine as a search term to pub med central and discovered that the stroke doctors think this stuff is good for the regrowth of axons.

Here is a sample of what I found.

I'm off to enjoy a 12 hour work day, so I'll check in later. Hopefully this is helpful.

Promoting axonal rewiring to improve outcome after stroke
Neurobiol Dis. 2010 February; 37(2): 259.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2818530/


One molecule that enhances axon growth and improves outcome in a rat stroke model is inosine. Inosine is a naturally occurring purine nucleoside that gets transported across the cell membrane and activates Mst3b, a protein kinase that regulates the cell-signaling pathway through which trophic factors induce axon growth (Irwin et al., 2006; Lorber et al., 2009). Additional benefits of inosine after brain injury include its anti-inflammatory effects (Hasko et al., 2004), its ability to suppress glutamate-induced neural excitation (Shen et al., 2005), and the ability of its metabolite, uric acid, to protect proteins from peroxynitrite-induced damage (Scott et al., 2005, 2002). Following unilateral cortical damage, inosine enhances the ability of undamaged neurons to extend axon collaterals into areas that have lost their normal innervation; this growth is accompanied by improved performance with the limb contralateral to the stroke (Chen et al., 2002; Zai et al., 2009). As illustrated in Fig. 2, sustained delivery of inosine after injury to the caudal forelimb area in one hemisphere increases the ability of pyramidal cells on the undamaged side of the brain to extend axon collaterals and form synapses on the denervated side of the spinal cord (Fig. 2a-c). After 4 weeks, animals treated with inosine are far superior to saline-treated animals in their ability to use the paw contralateral to the damaged hemisphere in a test requiring fine motor control (Fig. 2d: Zai et al., 2009). Similar results have been obtained in studies using a closed-head injury model (Smith et al., 2007). At the molecular level, stroke on one side of the brain causes layer 5 pyramidal cells in the opposite hemisphere to undergo many changes in gene expression, presumably related to denervation and stress. Inosine reverses many of these changes, while at the same time inducing the expression of genes related to axon growth and the complement cascade (Zai et al., 2009). The latter changes may be of particular significance in view of recent studies linking the complement cascade to synaptic reorganization (Stevens et al., 2007).


Figure 2
Inosine enhances axonal rewiring and augments functional recovery in an animal model of stroke
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Re: Inosine and neural growth

Postby jimmylegs » Wed Feb 06, 2013 7:52 pm

i used zinc to boost my uric acid. i think the low uric acid seen in ms is just a marker of suboptimal zinc. for sure that was true in my case. not sure replacing inosine takes care of ALL the jobs zinc does. interesting re other functions of inosine, other than the uric acid thing :)
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Re: Inosine and neural growth

Postby CaliReader » Wed Feb 06, 2013 10:47 pm

Hi Jimmy,

I'm also taking zinc, thanks to you. Like I said, I was using inosine as a short cut, intending to cut back later. But now, I'm not sure about cutting back. I'm looking for non-toxic allies to slow down this thing. Axon regrowth sounds good to me. So does improved fine motor coordination. Kidney stones don't sound so good, so I'll stay alert for that.

I love the research that is being done re antioxidants and neuroprotection in brain and spine injury generally. I think the MS researchers get too worried about cause and prevention. That's fine, but I'm past the point that a vaccine will help.

My neurologist told me that I wasn't disabled enough for physical therapy. He also said that therapy was about learning to live with permanent losses that are worse than my floppy feet. He obviously hasn't heard about the Terry Wahls approach to therapy. I think we get written off, because MS is degenerative. I don't like it. So if they won't give me what helps stroke patients and spinal injury patients, I'll go find some of it myself.
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Re: Inosine and neural growth

Postby CureOrBust » Thu Feb 07, 2013 5:23 am

...sustained delivery of inosine after injury to the caudal forelimb area in one hemisphere...
I am a big user of oral inosine, but I think I have seen this paper before, and it involved injecting it directly, not oral administration.
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Re: Inosine and neural growth

Postby jimmylegs » Thu Feb 07, 2013 2:14 pm

yeah we're on our own a lot, i find!
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Re: Inosine and neural growth

Postby CaliReader » Thu Feb 07, 2013 10:31 pm

Thanks for the heads up Cure. You're right that the rats were injected. It would be good to know whether inosine can cross the blood brain barrier without being injected into the brain. Although if I were having a relapse and my lesions were enhancing, than inosine in my blood would get into the brain along with everything else, right? It might be worth taking regularly just to have it in my system to regrow some axons during or just after new lesions form or old ones enhance. Partly kidding, partly not. I'm going to keep taking it as one of my nutriceuticals to hopefully slow this thing down.

If I understood what I read last Fall about neuroplasticity, then fifteen years ago, they were still teaching neurologists and psychologists that the adult brain could not effectively change. That neurons could not be repaired or replaced. That functional parts of the brain could not be repurposed to replace damaged parts. All of that is wrong. But we are living with a brain disease where the current treatment paradigms were developed more than twenty years ago. That says to me that possibilities for improving our brain and spine function are being ignored or overlooked by our doctors. That's why I'm so intrigued by the neuro muscular stimulation Dr Wahls uses along with her diet among other things.

Lots of people here have already been down this road, but it's new to me. Maybe I'll stumble on something useful.
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Re: Inosine and neural growth

Postby mrbarlow » Fri Feb 08, 2013 9:26 pm

I keep a stock of Inosine in 500mg capsules and take typically 50mmg every other day. If I feel symptoms flaring up I increase this to 1000mg a day on the basis of enhancing neuron protection.

Anyone else taking Inosine - if so what doses etc?
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Re: Inosine and neural growth

Postby CureOrBust » Sun Feb 10, 2013 2:43 am

mrbarlow wrote:Anyone else taking Inosine - if so what doses etc?
ummm.. me.

I take it twice a day, 4 capsules at 500mg (ie daily dose of 4g), and will continue until I get Gout, which after more than 4 years, still has not happened. Although my blood-work usually shows high uric acid, its not "off the charts". It was really low before I started.
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Re: Inosine and neural growth

Postby Liberation » Sun Feb 10, 2013 6:14 am

What are your experiences with Inosine? Any efect on the progression of the disease? Side effects?
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Re: Inosine and neural growth

Postby Liberation » Sun Feb 10, 2013 6:53 am

I have just realized that inosine an amino acid that can be bought as a food suplement. I have just found:

"Inosine is an amino acid that is precursor to adenosine, an important energy molecule, and plays many supportive roles in the body. Inosine is a small molecule that helps restore nerve function and is one of the few supplements shown to help regrow nerve connections in laboratory animals. It is being used in research and by some physicians for patients with MS, stroke injury , brain injury and autism. It is most effective when administered at the time of injury. It is used in France and Russia to improve energy production in the heart.

In 2002, researchers at Harvard's Children's Hospital, lead by Dr. Larry Benowitz, began using Inosine to switch damaged nerve cells in the cerebral cortex into a growth state. In 2002, they reported that inosine helped stroke-impaired rats to regrow nerve connections between brain and spinal cord and partially recover motor function. Benowitz's team reported that inosine could cause nerve cells in rats to sprout new axons -- the tendrils that nerve cells reach out to one another with.

Inosine acts as a kind of master switch to turn on a number of genes involved in the growth of nerve cells, the team at Boston's Children's Hospital and Harvard University reports. "Inosine switches on a whole constellation of genes," Dr. Larry Benowitz said.

Benowitz indicated his team found that inosine can cause severed nerves to regenerate axons in rats. "It juices them up nicely," he said, but adding that the experiment will have to be repeated before he can be sure it really works the way he thinks it does.

Benowitz said his team found in the latest experiment, published in the Journal of Neuroscience, that inosine passes through the nerve cell's membrane and activates an enzyme that in turn controls the cell's molecular program for axon growth.

"We think it is directly targeting and activating a protein kinase, an enzyme, inside the cell, that is the linchpin of the signaling pathway that activates growth," Benowitz said. Inosine promotes the production of a substance known as 2,3-DPG that is necessary for the transport of oxygen molecules from the red blood cells to body tissues for energy.

In 2004, Dr. Craig Hooper and colleagues at Thomas Jefferson University, Philadelphia, administered inosine to 11 people with MS in a study. Among 11 people taking inosine for 10 or 15 months, neurological exams showed some clinical improvement in three patients, and stability in 8 patients. Some areas of myelin damage seen on MRI in two patients could not be detected after treatment (Multiple Sclerosis, October 2001). Based on these findings, a larger study is underway at the University of Pennsylvania, comparing inosine to placebo in 30 people with relapsing-remitting MS.

Caution: Although it has few or no side effects, inosine is broken down to the purine end-product, uric acid. Because of this, inosine supplements should not be used in people with a history of gouty arthritis, hyperuricemia or purine autism unless being monitored by a physician. Pregnant women and nursing mothers should also avoid its use."

http://www.autismcoach.com/product_p/ef-005.htm

Can you recommend any efficient brand?
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Re: Inosine and neural growth

Postby mrbarlow » Mon Feb 11, 2013 1:30 am

Thanks for the link.


I buy my inosine from bodybuild. com. The brand is Mega Pro. Its about $8 for 60 capsules (500mg) so pretty cheap. I know it works because I had before and after uric acid tests. I was about 4.8 before and 7.4 after.

Whether it works is anyones guess but 2.5 years after symptoms first started Id say Im slightly better and haven't declined in any noticeable way. My aim is to stay working (with limited career aspirations) and live as normal a life as possible. So far so good.
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Re: Inosine and neural growth

Postby CureOrBust » Mon Feb 11, 2013 5:12 am

CureOrBust wrote:I take it twice a day, 4 capsules at 500mg (ie daily dose of 4g), and will continue until I get Gout, which after more than 4 years, still has not happened. Although my blood-work usually shows high uric acid, its not "off the charts". It was really low before I started.
After posting the above, I thought it sounded a little high... I checked the pack, and its 500mg and the recommended dose is 1-3 tablets before a workout. No mention to be cautious of Gout.

Its hard to say exactly how much it has helped, but I think it has; if I miss a few doses, I *think* I notice it. Generally, I do not miss doses of inosine so its only so useful (see the study at the end, more than one persons results)

I have a fair bit of data on my disk about inosine, and when I tried looking for it on line, I came across the following:
The Master Switch

A whole set of genes is synchronically activated to produce proteins when neural cells engage in regenerative activity. What has eluded scientists for a long time is the answer to this question: Were these genes controlled by many distinct pathways activated by a plethora of growth factors? Or was there some 'master switch' to which many different signals converge to control the molecular program for growth?

Recently, a master switch has been discovered (3). Furthermore, a small, naturally occurring molecule, Inosine, has been shown to promote this molecular program and induce axon growth in the CNS. It seems that Inosine activates this program and activates genes important in neural regeneration. In the normal human brain this system is silent. It only needs to be targeted and turned on, and it appears Inosine serves this function quite well. Isolating the gene that encodes for the enzyme that Inosine works on is the next very important step in using gene therapy to activate this master switch for benefit in regenerating the central nervous system.
http://biomed.brown.edu/Courses/BI108/BI108_2001_Groups/Nerve_Regeneration/Gene_Therapy/Gene_Therapy_Page_2.htm

"Inosine, the Company's lead compound for nerve regeneration, easily appears to be the most effective compound ever identified (as documented in the scientific literature) in regenerating nerve connections in the CNS. Based on our previous results in stimulating nerve regeneration in the long motor tracts of the spinal cord (as published in the November 9, 1999 issue of the Proceedings of the National Academy of Sciences), we are very excited at the prospect that Inosine may eventually prove to be an effective regenerative therapy for stroke," added Dr. Lanser.

Inosine can be conveniently administered directly into the Cerebral Spinal Fluid (CSF) which bathes the brain, thereby exposing the specifically injured brain tissue to therapeutic amounts of Inosine while minimizing the potential for systemic toxicity. Inosine can potentially be administered via a widely-used delivery system for several months if necessary, in order to promote the optimal amount of regeneration. The Company's Inosine Development Program will concentrate on the optimization of dosage and duration of treatment, pharmacokinetic and toxicity studies, and cGMP production of Inosine for human use. If the preclinical development program is successful, the Company hopes to initiate human trials in 2001.
http://www.mult-sclerosis.org/news/Jun2000/CNSNerveRegeneration.html

In the meantime, Boston Life Sciences Inc., a company developing novel diagnostics and therapeutics for various diseases and disorders, plans to begin Phase I clinical trials using inosine with stroke patients this fall. Phase I trials target safety levels and toxicity of drugs. Since inosine is a naturally occurring molecule, and no toxicity has been detected in animal models, Benowitz and Boston Life Sciences have high hopes for its potential clinical uses.
http://www.childrenshospital.org/dream/dream-fall01/circuits.html
This was back in 2001, I wonder how it went? even better, time enough for Phase II?

And the actual paper I was looking for: https://www.ncbi.nlm.nih.gov/pubmed/17121380
Therapeutic value of serum uric acid levels increasing in the treatment of multiple sclerosis.
Toncev G.
Source
Clinical Center Kragujevac, Center of Neurology, Kragujevac, Srbija.
Abstract
BACKGROUND/AIM:
Uric acid was successfully used in both, prevention and treatment of the animal model of multiple sclerosis (MS). Recently it has been shown that inosine, a ribosylated precursor of uric acid, might be used to elevate serum uric acid levels in MS patients. The aim of this study was to evaluate the safety and efficacy of oral inosine as a single drug treatment in patients with MS.
METHOD:
We administered inosine orally to 32 MS patients from 2001-2004 year at doses from 1-2 g daily (given twice) depending on the pretreatment serum uric acid levels. The mean follow-up interval was 37.69+/-6.55 months. The other 32 MS patients, without any treatment except for a relapse period (matched by age, sex, duration of disease and functional disability), were used as controls. The follow-up interval of these patients was 36.39 +/- 2.68 months. The neurological disability was evaluated by the Expanded Disability Status Scale score (EDSS).
RESULTS:
During the observed period the treated MS patients were found to have the lower relapses rate than the non-treated MS patients (Chi-square test, p = 0.001). None of the patients have showed any adverse effect of inosine treatment. The non-treated MS patients were found to have a higher increasing in the mean EDSS score than the treated ones (two-way ANOVA-repeated measures/factor times, p = 0.025).
CONCLUSION:
Our results suggested that the treatment approaches based on the elevation of serum uric acid levels might prove beneficial for some MS patients.

I actually have a faxed copy of the full paper. This was a human trial using oral Inosine. Not mice injected with Inosine.
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Re: Inosine and neural growth

Postby Liberation » Sat Mar 02, 2013 5:23 am

Any data on progressive patients (PPMS)? The Serbian study showed only slower increase in EDSS for inosine takers, but does not say anything about stopping the progression. Anyone could halt the progression of the disease with inosine?
Last edited by Liberation on Sat Mar 02, 2013 5:40 am, edited 1 time in total.
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Re: Inosine and neural growth

Postby Liberation » Sat Mar 02, 2013 5:25 am

How does uric acid level correlate with MS progression? My uric acid level has been in the lower part of the accepted area.
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Re: Inosine and neural growth

Postby Liberation » Sat Mar 02, 2013 5:38 am

...
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