This Is MS Multiple Sclerosis Community: Knowledge & Support

Public release date: 16-Oct-2007
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Contact: Debra Kain
ddkain@ucsd.edu
619-543-6163
University of California - San Diego

UCSD findings could lead to new therapy for spinal cord injury-induced spasticity and rigidity
Research led by scientists at the University of California, San Diego (UCSD) School of Medicine has identified a target with potential as an effective new therapy for chronic spasticity and rigidity, a painful condition that often results from spinal cord injury.

In work with rats, Martin Marsala, M.D., a professor in the Department of Anesthesiology at the University of California, San Diego (UCSD) School of Medicine, demonstrated that an AMPA receptor antagonist called NGX424 (tezampanel), being developed by TorreyPines Therapeutics, Inc., of La Jolla, California, is highly potent in suppressing spasticity and rigidity. The study will be published in the October 17 issue of the Journal of Neuroscience.

Paraplegia from spinal cord ischemia is a serious complication that occurs in 20 to 40 percent of patients undergoing a surgical process called aortic cross-clamping. When the surgeon works on the aorta to correct a potentially lethal aneurysm, this large vessel carrying all of the blood flow from the heart must be temporarily blocked. If clamping occurs for more than 30 minutes, the procedure can result in the loss of specialized spinal cord neurons called spinal inhibitory neurons. Loss of these neurons can lead to irreversible spasticity and rigidity, or loss of muscle control, in the lower limbs.

“This exaggerated muscle tone, or uncontrolled spasms, is a serious complication of either ischemic or traumatic injury to the spinal cord -- such as injuries resulting from a diving or car accident,” said Marsala. Several other conditions can lead to spasticity/rigidity, including brain trauma, multiple sclerosis, cerebral palsy or Parkinson’s disease – all of which lead to increased peripheral muscle tone.

The most effective treatment for the spastic muscle condition – which results in pain and tremendous spasms, even in those patients who have partial motor recovery – has been a drug called Baclofen, a GABA-B receptor agonist that is delivered either systemically or spinally to patients. However, according to Marsala, patients taking this drug often develop tolerance and need increased dosage to achieve the same effect.

“A new therapy to control spasticity is very important,” said lead author Michael P. Hefferan, Ph.D., of UCSD’s Department of Anesthesiology. “This AMPA receptor blockade offers a novel means of reducing the spasticity and rigidity in muscles because it works through a totally different receptor system than current drugs being used.”

Spinal spasticity is the result of increased spinal neuronal excitability. The NGX424 compound – which is delivered via intrathecal catheters that inject the drug into the fluid surrounding the spinal cord – suppresses the AMPA-mediated neuronal excitation, relieving otherwise increased muscle tone.

The authors also demonstrated that intrathecal delivery of GluR1 antisense (a treatment that blocks expression of one of the subunits in the AMPA receptor complex) provides a similar antispasticity effect. This further demonstrates a role for AMPA receptors in spasticity and rigidity, and indicates that blockade of this subunit by NGX424 likely plays a key role in the observed antispasticity effect.

Marsala added that additional large animal safety testing will be required before the researchers can consider clinical trials in humans. However, the rat data from this study indicates no toxicity using infused NGX424. Subcutaneous delivery of the drug is currently being evaluated for treating migraines.


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Additional researchers include Karolina Kucharova, Kiyohiko Kinjo, Osamu Kakinohana, Tony L. Yaksh, UCSD Department of Anesthesiology; Gabriella Sekerkova, Feinberg School of Medicine, Northwestern University; Seiya Nakamura and Tatsuya Fuchigami, UCSD Department of Anesthesiology and University of the Ryukyus, Okinawa, Japan; Zoltan Tomori, Institute of Experimental Physics, Slovak Academy of Scineces; and Neil Kurtz, TorreyPines Therapeutics, Inc., La Jolla.

Funding for the research was provided by the National Institutes of Health, an American Heart Association post-doctoral fellowship and TorreyPines Therapeutics Inc.



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_________________
Dom

2 years later.

I found this article (one of many, no doubt ) from Feb. 09 updating us on this drug:
http://headacheandmigrainenews.com/the-latest-on-tezampanel-a-new-migraine-drug/

It says that along with NGX424 (injectible), is NGX426.
"Another related drug in an earlier stage of testing is NGX426. This is a "prodrug" of Tezampanel, which means that it causes Tezampanel to be formed in the body."
NGX426 is an oral medication.
As of Feb. '09 ngx426 completed its phase 1 trial. ngx424 is further long in testing. It's a TorreyPines Pharmeceuticals drug, as mentioned before.

Amputation could cure spasticity. I have doubts about what they mean by saying cure/improve. Will this drug have the miraculous effect of baclofen, that relaxes spastic muscles, as well as non spastic muscles, making walking impossible? I don't care if it improves the markers by a whole decimal point. Can it improve mobility?

sou

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Shortest joke: "We may not be able to cure MS but we can manage its symptoms."

sou please check out the ms and sodium thread:
http://www.thisisms.com/ftopict-8651.html
it relates to the dependence of proper nerve function on potassium sodium balance... noting baclofen as a sodium channel blocker.. great interactive video teaching tools...

I think that potassium might be irrelevant, because no matter how much you take, the kidneys will remove it. It is one of the fastest and most potent mechanisms of regulation in our body.

sou

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Shortest joke: "We may not be able to cure MS but we can manage its symptoms."

irrelevant, yet 4500mg is the recommended daily intake.... i'm not sure i agree with you sou

You have put me into internet searching. I still doubt that it would be any useful, but I am not sure at all. There is nothing to lose by just trying it, let's say for a month.

Do you still take it? Do you find it effective?

Thanks,

sou

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Shortest joke: "We may not be able to cure MS but we can manage its symptoms."

Sou, I found that capsaicin, a couple of grams a day on a FULL stomach aided bladder, spasticity and bowel.

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The effects were noticeable but I was quite ill at the time.

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3 years antibiotics, 06/09 bilateral jug stents at C1, 05/11 ballooning of both jug valves, 07/12 stenting of renal vein, azygos & jug valve ballooning,

hi sou, to keep things in perspective my spasticity and muscular problems have not been incapacitating - more like annoying sometimes painful.

the first thing i learned about to help was magnesium and the second was potassium.

i am noticing positive effects of both these things. i get bad cramps in my feet sometimes and the other evening a single 600mg potassium pill fixed it.

usually in stores i see potassium pills at 50mg or 99mg and those would obviously be useless when you need 4500mg per day.

please have a read through the MS and sodium thread (link above) - the two links to axon-messaging-interactive-animations really show you the importance of potassium.

HTH!
JL