Heard back from an MS researcher

[Guest guest]

Don't ya love it when you write to these guys and they reply? I'm

not sharing his name, he didn't give me permission and what he had

to say is not so compelling that you need to have the background.

But it IS interesting. He had written about how a type of glutamate

receptor in the brain called " AMPA " contributes to the destruction

of myelin, which is a key finding in MS, a finding in my very own

brain MRI, and possibly a key cause of certain types of neurological

distress.

I wrote him to ask if there were any drugs that blocked these

receptors effectively without accompanying toxicity. He wrote me

back to say that there are none on the market but are some in trials

for Parkinson's disease - if they're approved, they will probably be

prescribed for MS as well.

It's pretty fascinating stuff. the AMPA receptor, triggered by

glutamate, apparently contributes to the death of oligodendrocytes,

which are the cells that myelin grows out of. This is one reason why

glutamate build up in the brain is bad, and glutamate transport is

is so important.

Rich, if you're reading please let me know if I've mangled something.

Cheers all,

[Guest guest]

Hi, .

Glutathione protects against excitotoxicity mediated by the AMPA

receptors:

" J Neurochem. 2002 Jul;82(2):398-409. Related Articles, Links

AMPA receptor-mediated toxicity in oligodendrocyte progenitors

involves free radical generation and activation of JNK, calpain and

caspase 3.

Liu HN, Giasson BI, Mushynski WE, Almazan G.

Department of Pharmacology and Therapeutics, McGill University,

Montreal, Quebec, Canada.

The molecular mechanisms underlying AMPA (alpha-amino-3-hydroxy-5-

methylisoxazole-4-propionate) receptor-mediated excitotoxicity were

characterized in rat oligodendrocyte progenitor cultures. Activation

of AMPA receptors, in the presence of cyclothiazide to selectively

block desensitization, produced a massive Ca(2+) influx and

cytotoxicity which were blocked by the antagonists CNQX and GYKI

52466. A role for free radical generation in oligodendrocyte

progenitor cell death was deduced from three observations: (i)

treatment with AMPA agonists decreased intracellular glutathione;

(ii) depletion of intracellular glutathione with buthionine

sulfoximine potentiated cell death; and (iii) the antioxidant N -

acetylcysteine replenished intracellular glutathione and protected

cultures from AMPA receptor-mediated toxicity. Cell death displayed

some characteristics of apoptosis, including DNA fragmentation,

chromatin condensation and activation of caspase-3 and c-Jun N-

terminal kinase (JNK). A substrate of calpain and caspase-3, alpha-

spectrin, was cleaved into characteristic products following

treatment with AMPA agonists. In contrast, inhibition of either

caspase-3 by DEVD-CHO or calpain by PD 150606 protected cells from

excitotoxicity. Our results indicate that overactivation of AMPA

receptors causes apoptosis in oligodendrocyte progenitors through

mechanisms involving Ca(2+) influx, depletion of glutathione, and

activation of JNK, calpain, and caspase-3.

PMID: 12124441 [PubMed - indexed for MEDLINE] "

Rich

> Don't ya love it when you write to these guys and they reply? I'm

> not sharing his name, he didn't give me permission and what he had

> to say is not so compelling that you need to have the background.

>

> But it IS interesting. He had written about how a type of

glutamate

> receptor in the brain called " AMPA " contributes to the destruction

> of myelin, which is a key finding in MS, a finding in my very own

> brain MRI, and possibly a key cause of certain types of

neurological

> distress.

>

> I wrote him to ask if there were any drugs that blocked these

> receptors effectively without accompanying toxicity. He wrote me

> back to say that there are none on the market but are some in

trials

> for Parkinson's disease - if they're approved, they will probably

be

> prescribed for MS as well.

>

> It's pretty fascinating stuff. the AMPA receptor, triggered by

> glutamate, apparently contributes to the death of

oligodendrocytes,

> which are the cells that myelin grows out of. This is one reason

why

> glutamate build up in the brain is bad, and glutamate transport is

> is so important.

>

> Rich, if you're reading please let me know if I've mangled

something.

>

> Cheers all,

>

>