tPA mouse research could help pwCCSVI

A forum to discuss Chronic Cerebrospinal Venous Insufficiency and its relationship to Multiple Sclerosis.

tPA mouse research could help pwCCSVI

Postby Cece » Sat Jul 21, 2012 8:31 am

http://www.medpagetoday.com/LabNotes/La ... id=5517461
Defanged tPA May Still Protect the Brain

Tissue plasminogen activator (tPA) may protect against the ravages of stroke through mechanisms separate from its clot-dissolving abilities, a study in the Journal of Neuroscience showed.

Manuel Yepes, MD, of Emory University in Atlanta, and colleagues explored the other functions of the drug in cultured neurons from the cerebral cortex. They showed that even when the drug was modified so it no longer converted plasminogen to plasmin, it protected cultured neurons from the stroke-related loss of oxygen and glucose by activating a pathway that helps cells withstand the insult.

When the researchers gave a form of tPA that did not have clot-busting abilities to mice with an induced stroke, they found that the drug still reduced the infarct size.

The experiments also showed that the protective effect could be achieved at lower doses than given in cases of acute stroke, which could have implications for designing a new therapy that does not carry an increased risk of bleeding.

"The risk of bleeding creates a lot of anxiety, and it has resulted in the regrettable fact that only a small number of stroke patients currently benefit from treatment with tPA," Yepes said in a statement.

I have been on the lookout for drugs that could help us post-CCSVI treatment for long-term MS care with the new perspective of MS as the neurological end-stage of a vascular disease.

In CCSVI, any drug that activates a pathway that helps cells withstand the insult of diminished oxygenation and diminished glucose is of interest. I am not familiar with this form of tPA that does not have clot-busting abilities, since all I know about tPA is that it's used to bust clots, so no idea of the risk profile or possible long-term use of it, but it's at least a new unexplored option that fits the new theory.
“tPA is more than a clot-busting drug, it functions naturally as a neuroprotectant."
Exposing cultured neurons from the cerebral cortex to tPA protects the neurons from dying after being deprived of oxygen and glucose, the researchers found. tPA appears to induce a set of proteins that helps cells deal with the lack of oxygen and glucose that come from an interruption of blood flow.
http://news.emory.edu/stories/2012/07/s ... index.html
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Re: tPA mouse research could help pwCCSVI

Postby 1eye » Sun Jul 22, 2012 7:13 am

Isn't anybody interested in this? It doesn't sound like any magic bullet, as no drugs are, but hey, we knew it was neuroprotective in cases where the neural damage is due to low or no oxygen and, possibly in cases where there is old, stagnant blood around, so why could it not help CCSVI victims? The thing that springs to my mind, is: do we know exactly why there is a time-limit on use of this drug in stroke? Is it useful long after that time, in neuroprotection of neurons that are at risk of future low-oxygen situations?

The risk and side-effect information should be well known by now. This is definitely an off-label use of the drug. The problem, if it were useful, would be getting the world to recognize the condition that it is used off-label for!
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Re: tPA mouse research could help pwCCSVI

Postby Cece » Sun Jul 22, 2012 2:42 pm

The time limit of the drug after stroke has to do with the risk of bleeding, from what I understand. But in the modified tPA discussed in the article, the tPA was modified to not have a clot-busting effect which should do away with the bleeding risk.

I think this is potentially a bullseye of a drug for pwCCSVI. Decreased oxygen and glucose to our neurons is present chronically in us. Even after CCSVI treatment, there may not be complete correction, and we may still have blood flow issues. But tPA is not currently in production in the modified form and the modified form has not been tested on people. tPA itself is well understood and in use, so this is not a drug from nowhere that might have opposite effects in humans. It's been shown in stroke studies to have a neuroprotectant effect that shows up three months afterwards, which because of the length of time would seem to be separate from its clot-busting effect.

When we go in for steroids during a relapse, maybe steroids plus modified tPA would work better than steroids alone. Maybe modified tPA could help in progressive MS. Maybe modified tPA could be taken before activites that may put us at risk such as travel to high altitudes. I don't know if the dosage could be low enough yet still effective that could be taken on a long-term basis or if it could only be taken occasionally, which would limit to events such as a relapse.

There's research needed to make any of that a reality but this would seem to be an excellent direction to go.
Is it useful long after that time, in neuroprotection of neurons that are at risk of future low-oxygen situations?

Good question. I need to look up more on the studies that showed a neuroprotective effect for patients who'd had tPA, three months later.
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Re: tPA mouse research could help pwCCSVI

Postby MarkW » Mon Jul 23, 2012 6:14 am

Cece wrote:.........There's research needed to make any of that a reality but this would seem to be an excellent direction to go.
Is it useful long after that time, in neuroprotection of neurons that are at risk of future low-oxygen situations?

Cece wrote:Good question. I need to look up more on the studies that showed a neuroprotective effect for patients who'd had tPA, three months later.

Interesting lateral thinking Cece but other drugs eg Prozac have neuroprotective effects if you are looking at studies. I would look at marketed drugs before ones in trials. They can be prescribed even if off label.
Happy researching,
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Mark Walker - Oxfordshire, England. Registered Pharmacist (UK). 11 years of study around MS.
Mark's CCSVI Report 7-Mar-11:
http://www.telegraph.co.uk/health/8359854/MS-experts-in-Britain-have-to-open-their-minds.html
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Re: tPA mouse research could help pwCCSVI

Postby 1eye » Mon Jul 23, 2012 8:44 am

The time limit of the drug after stroke has to do with the risk of bleeding, from what I understand. But in the modified tPA discussed in the article, the tPA was modified to not have a clot-busting effect which should do away with the bleeding risk.


I must be thinking of a different drug. I thought it was in the range of hours after the stroke symptoms appear, after which it is too late. I had not heard about bleeding risk. Sounds like with this drug you are between a clot and a hard place.
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Re: tPA mouse research could help pwCCSVI

Postby Cece » Mon Jul 23, 2012 8:57 am

Do you know the reason for the neuroprotective effect of Prozac? With this one, the specific mechanism of action of "activating a pathway that helps cells withstand the insult" of stroke-related oxygen and glucose was a good fit theoretically with CCSVI, so I would be looking for other drugs that are similar. I'm not planning to experiment pharmacologically on myself! I figured I already did that with my few years on Copaxone. But I would like pharmacological options for people including myself if it were proven to be effective. And you can't prove effective what's not being researched. So frustrating.

1eye, that is the exact drug we are talking about: tPA. It needs to be given within 3 hours or so of a stroke to be helpful in busting the clot that caused the stroke. After three hours, the risks outweigh the benefit. But, in this research, they've modified tPA to remove the main effect of tPA which is the clot-busting effect! So it is possible that the risk of the drug is removed and the neuroprotective aspect remains, and it may be neuroprotective in the exact way we need as CCSVI patients.
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