Nerve Regeneration

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Nerve Regeneration

Postby OddDuck » Sat Jan 08, 2005 10:21 am

Hi, folks!

Just when I thought I had "read it all"! Here's something I ran across that I found interesting. Don't ask me who this gentleman is exactly [EDIT: Oops, it's a woman!], but s/he's from the Brain Research Institute at the University of Zurich (that's Switzerland, right? :wink: )

Anyway, it's pretty easy reading. For some reason, I found "something" in it interesting, and maybe with some other comments from you all, we can pull it out and see where it leads. I think I'm sort of focusing on the specific "areas" of the brain he mentions. hmmmmmmmmm........... What ARE the correlations of MS to specific areas of the brain, etc. etc.?

Deb

Here 'tis:

Research Interests

Dr. Michaela Thallmair

I am interested in the cellular and molecular mechanisms underlying fate decisions of adult spinal cord progenitor cells and structural plasticity/nerve regeneration in the adult central nervous system (CNS).

During the last decade compelling evidence emerged that challenged the longstanding belief that regeneration in the CNS ceases with the end of development. Recent studies have shown that new neurons are continuously born throughout life in two areas of the brain: The subventricular zone of the forebrain and the dentate gyrus of the hippocampus.

Other adult CNS regions, such as the striatum, substantia nigra and the spinal cord, also contain proliferating cells. In vivo these cells give rise exclusively to glial cells. However, when proliferating cells from these so-called gliogenic/non-neurogenic regions are isolated and cultured, however, they are able to self-renew and to differentiate into the three major lineages of the CNS: astrocytes, oligodendrocytes and neurons. These findings suggest that adult progenitor cells are present not only in the neurogenic regions, the subventricular zone and the dentate gyrus, but along the entire neuroaxis.

A fundamental question in stem cell biology is how fate choices of stem cells are regulated.

Grafting experiments of cultured progenitor cells isolated from a gliogenic/non-neurogenic region into a neurogenic area demonstrated that heterotopically transplanted precursors migrate and differentiate according to their transplantation site. These observations suggest that the fate choice is due to extrinsic/environmental cues rather than to an intrinsic inability to respond to mitogenic and differentiation factors, and open the possibility to manipulate the fate choice of adult precursor cells.

The recruitment of endogenous progenitor cells for repair processes after a CNS injury or CNS disease might help to improve recovery. For example, modification of the local environment to manipulate the behavior of the endogenous precursors may be a possibility to control the differentiation of proliferating cells in neurogenic and gliogenic regions. The feasibility and limitations of remyelination and/or neuronal replacement through endogenous progenitor cells, however, remains to be investigated.

Spinal cord injury interrupts not only the communication between the brain and spinal cord, but triggers a cascade of events that eventually lead to neuronal degeneration, cell death, and scar formation. After an injury and in demyelinating diseases (e.g. multiple sclerosis, MS), axons that were not (initially) injured lose their myelin sheath. Although oligodendrocyte precursor cells proliferate after a CNS lesion and in MS, remaining intact fibers are only partially re-myelinated, one of the reasons for incomplete/missing recovery. The latter finding suggests that factors in the injured CNS inhibit or retard oligodendrocyte maturation and/or myelination or, alternatively, that factors that induce oligodendrocyte differentiation and myelination are absent.

Currently it is not known which factors instruct gliogenesis and/or suppress neurogenesis, the formation of new neurons, in the adult spinal cord. Understanding the regulation of gliogenesis in the intact spinal cord would help us finding means to influence the formation of astrocytes and oligodendrocytes. Manipulation of glial cells and ultimately regulating scar formation and myelination is especially important with respect to incomplete spinal cord injuries and diseases like multiple sclerosis, and may eventually improve recovery.

There remains a lot to be learned about the regulation of progenitor cells and gliogenesis in the intact and injured/diseased spinal cord. Which are the mechanisms that stimulate adult neural progenitor cells to proliferate in vivo in the intact or injured cord? Why do progenitor cells that proliferate after a CNS injury usually not replace the lost cell types? What are the factors that regulate the fate decision of adult spinal cord precursor in the intact and injured cord?

Understanding the basic mechanisms that regulate adult neural progenitor cell behavior are not only of great basic neurobiological interest, but are fundamental for developing strategies that aim to treat CNS injuries or diseases using neural stem cells.


P.S. Oh! Here is where I found this at: http://www.hifo.unizh.ch/research/neuro ... st.en.html I am now flipping through their whole website. It looks like they are looking into some pretty interesting stuff!!! Regeneration. Cool!
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Postby OddDuck » Sat Jan 08, 2005 10:39 am

In reading this website (above), I just had the most BIZZARRE thought!

What if MS was really some strange form of epilepsy?????

That has come to my mind before, but I've dismissed it. It came AGAIN just now when I was reading: http://www.hifo.unizh.ch/research/neuro ... st.en.html

Now THERE is an interesting avenue of thought!!!

Deb
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nerve repair

Postby bromley » Sat Jan 08, 2005 10:52 am

Dear all,

An article on the same subject from the UK MS Society website:

Can the immune system repair brain damage in multiple sclerosis?
September 2004, we take a look at Dr. Alasdair Coles study of the immune system and its role in MS repair.

We have treated a small group of people with aggressive relapsing-remitting multiple sclerosis using an experimental drug called Campath-1H. This drug deliberately damages the immune system and is good at stopping further relapses. A large clinical trial is currently comparing the effectiveness and side-effects of Campath-1H and interferon-beta.

We imagined that Campath-1H treatment of multiple sclerosis would prevent further deterioration but would do nothing for damage already acquired. Quite unexpectedly however, most patients treated using a single dose of Campath-1H show a steady improvement in their disability over the next 12-24 months. This was encouraging but difficult to understand. The brain was being encouraged to repair itself; but why?

This project tests one possible explanation: that cells of the immune system are altered after Campath-1H treatment and they travel to the brain to release factors that encourage repair of nerve fibres. This touches on a fundamental question in multiple sclerosis research: does the process of inflammation, which is generally regarded as damaging, also actually encourage survival of nerve fibres?

Our approach is to look at the immune cells in the blood of people before and after Campath-1H. We put them in cultures in the laboratory and see if they release substances known to promote brain repair. So far we have had mixed results from these experiments. Secondly we take the soup released by these immune cells and pour it onto nerve cells growing in culture and watch what happens. Interestingly, after Campath-1H the immune cells do seem to encourage nerve cells to grow. Now we have to find out how!

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Postby OddDuck » Sat Jan 08, 2005 10:53 am

Ok..........here I go again.

Where's Wesley? WESLEY!?

Hey...........there's a common denominator here! Between epilepsy, multiple sclerosis, and diabetes. PPAR: "peroxisome proliferator-activated receptor-alpha (PPAR), a transcription factor that regulates the use of fatty acids within cells."

Remember my previous posting regarding TZDs and their probable effectiveness for SPMS at: http://www.thisisms.com/modules.php?nam ... hlight=tzd

Where and/or how might PPAR fit in?

Deb
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Postby OddDuck » Sat Jan 08, 2005 11:26 am

Ok...I'm jumping around a little, but it all is coming back to one area of the brain (i.e. regeneration). I take this one statement from my first post above:

Recent studies have shown that new neurons are continuously born throughout life in two areas of the brain: The subventricular zone of the forebrain and the dentate gyrus of the hippocampus.


"Dentate gyrus"............hmmmmmmmmm............it looks like a lot of "regeneration" takes place there. Ok........several things are running through my mind at once.

Epilepsy affects (does damage) to the dentate gyrus (where regeneration for the CNS takes place). That's one thing. Ok......second thing......PPAR.......that's connected to the dentate gyrus.

Ok.....third thing.....and I'm in SHOCK again! The drug I'm on.........desipramine..........one of the major areas where it does its "work" is in the dentate gyrus!!! AND I'm taking that drug WITH levetiracetam! An anti-epileptic drug that is different from most other AEDs........it targets itself to the CNS, also.

Ok.........desipramine.......what does it do in the dentate gyrus? I've posted this many times, but it goes back to GAP43 again. "...After comparing hybridized signals between control and desipramine treated groups, we found that chronic treatment with desipramine increased the expression of six genes and decreased the expression of two genes. One of the upregulated genes is growth associated protein GAP-43. In situ hybridization revealed that desipramine increased GAP-43 gene expression in dentate gyrus but not other brain regions. Northern and immunoblotting analysis revealed that desipramine increased GAP-43 mRNA and protein levels..."

GAP43, as I've posted before, regenerates neurons AND axonal growth!

And that takes us back to what the guys from Auckland found recently, also (that was posted as a headline here on this website).

Ok.............so............back to epilepsy. IS there a connection then to the development of MS?

Deb
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Postby BioDocFL » Sat Jan 08, 2005 12:28 pm

What a coincidence.

I was at a seminar yesterday about RNA given by a Japanese researcher (Tokyo University). They take ribozymes (small hairpin forming RNA structures that can cut messenger RNAs, thus stopping the creation of proteins from the specific gene) and they add random sequences of RNA to the ribozyme sequence. A magnesium ion is critical to the catalytic activity.

With this, they have a library of ribozymes that can bind most if not all messenger RNAs from genes in the cell. They then dillute this way out so only one or two of their ribozymes get into any one cell when they transfect the ribozymes into tissue cultures.

One of the professor's previous students had transferred to a lab in the US and had tried this with glia cells. I believe they are about to publish the technique. What they were trying to do was interrupt one of the pathways of choice so that they could block the pathway to neuron development and only allow astrocyte or oligodendrocyte development.

Then, I guess through a process of elimination, they are starting to identify the genes they interrupted and are determining which ones are critical in the choice to neuron from glia cell. I didn't get all of the details of the protocol since that wasn't the main focus of the talk, but it sounded like a good approach to figuring out which genes are important in glia differentiation, or other precursor cell types.

Ribozyme libraries, I think this could be a big new technique like proteomics, micro arrays, and high-throughput screening.

OT: We got past the preliminary screening on the ovarian cancer grant I am applying for so now I am doing a full blown application. It will relate to the hypothesis I presented before.

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Postby OddDuck » Sat Jan 08, 2005 12:38 pm

Hi, Wesley!

Wow! That's great! Congrats!!

I'm reading up on PPARs now, and you'll see I started another thread on that, too.

I wish I could find more information on the EXACT genes desipramine affects! I have found a LOT of information that it does prevent DNA fragmentation and it regulates some genes, but I'm not sure which ones exactly. Well, except for GAP43. That's the only one, so far, that I can trace in connection to desipramine and how it probably applies to something like MS. That might prove interesting, if I could locate the others.

Deb

EDIT: Duh, Deb! I just realized, the caspase-3 gene is also one of them that desipramine affects. And again, over and over, caspase-3 is also integral in MS. I just gotta put on my thinking cap again. :lol:

SECOND EDIT: Yea, ok.........I'm getting there. Here's something else, although I'm not geneticist by any means, and I'm not sure how these even pertain to MS at all (yet), but here's a couple more items: ..."The stimulation of immediate early gene expression in brain and neuronal cell culture systems has been reported after various experimental paradigms such as chemiconvulsant-provoked seizures or specific drug applications. In particular, the induction of immediate early genes by adrenergic model substances has been demonstrated by several investigators. This report demonstrates that a single dose of desipramine (10 or 25 mg/kg), a classical tricyclic antidepressant drug acting on the adrenergic system, induced c-fos and zif268 expression in rat hippocampus without affecting c-jun. ...."
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Postby OddDuck » Sat Jan 08, 2005 12:50 pm

Well, I said in my original narrative (and in subsequent posts) that desipramine could be considered a mild gene therapy, similar to a TZD.

hmmmmmmmmmmm..................

Is there anything that doggoned drug DOESN'T do? (Just kidding.)

Deb
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Postby OddDuck » Sat Jan 08, 2005 1:05 pm

Oh, for crying out loud! Get this! I won't post it all, though. Suffice it to say, I ask that folks just believe me that I'm grabbing this stuff off the web right now as I research.

Ok..... "The transcription factors c-Fos and Zif268 have been used as markers of neuronal activity, and they also have been implicated in neuronal plasticity."

Also, apparently, those "genes" directly affect the eyes, too. (Beneficially, if they are upregulated. Good heavens, I just looked back at my original narrative. I must have found "something" before, too. I have a sentence in that narrative that says: "There is some fringe evidence that desipramine may promote retinal improvement." Well, yep, here's that substantiation.)

Ok.....also, here's another description of what Zif268 correlates to:

Prog Neurobiol. 2004 Nov;74(4):183-211. Related Articles, Links


A gene for neuronal plasticity in the mammalian brain: Zif268/Egr-1/NGFI-A/Krox-24/TIS8/ZENK?

Knapska E, Kaczmarek L.

Department of Neurophysiology, Nencki Institute, Pasteura 3, 02-093 Warsaw, Poland.

Zif268 is a transcription regulatory protein, the product of an immediate early gene. Zif268 was originally described as inducible in cell cultures; however, it was later shown to be activated by a variety of stimuli, including ongoing synaptic activity in the adult brain. Recently, mice with experimentally mutated zif268 gene have been obtained and employed in neurobiological research. In this review we present a critical overview of Zif268 expression patterns in the naive brain and following neuronal stimulation as well as functional data with Zif268 mutants. In conclusion, we suggest that Zif268 expression and function should be considered in a context of neuronal activity that is tightly linked to neuronal plasticity.

PMID: 15556287 [PubMed - in process]


EDIT: Ok, I'm stopping. These genes are also the ones that affect bladder functioning. AGAIN, referring back to my original narrative regarding desipramine's beneficial affects for bladder problems. Well, that's how - through those transcription factors or "genes".

I give up!

SECOND EDIT: Oh, yea....and how does this all fit with my first post above? Guess where ALL this takes place? In the "dentate gyrus" for one. 8O
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Postby OddDuck » Sat Jan 08, 2005 1:52 pm

Ok..........I thought I was done.

The first article I posted above mentioned the "striatum" as another location where oligodendrocytes, etc. regenerated.

That rang another bell. Since it wasn't associated with desipramine, I wonder if it rang a bell because it related to levetiracetam!

Sure enough!

Eur J Pharmacol. 2003 Sep 30;478(1):11-9. Related Articles, Links

Localization and photoaffinity labelling of the levetiracetam binding site in rat brain and certain cell lines.

Fuks B, Gillard M, Michel P, Lynch B, Vertongen P, Leprince P, Klitgaard H, Chatelain P.

UCB S.A, Pharma Sector, In vitro Pharmacology, Building R4, Chemin du Foriest, 1420, Braine-l'Alleud, Belgium. bruno.fuks@ucb-group.com

Levetiracetam (2S-(2-oxo-1-pyrrolidinyl)butanamide, KEPPRA, a novel antiepileptic drug, has been shown to bind to a specific binding site located in the brain (Eur. J. Pharmacol. 286 (1995) 137). To identify the protein constituent of the levetiracetam binding site in situ, we synthesized the photoaffinity label [3H]ucb 30889 ((2S)-2-[4-(3-azidophenyl)-2-oxopyrrolidin-1-yl]butanamide), a levetiracetam analog with higher affinity for the levetiracetam binding site. This radioligand was used to map the levetiracetam binding site within the brain and to study its cellular and subcellular distribution. Autoradiography experiments using [3H]ucb 30889 in rat brain revealed a unique distribution profile that did not match that of classical receptors known to be involved in the generation of epileptic seizures. There was a high level of binding in the dentate gyrus, the superior colliculus, several thalamic nuclei, the molecular layer of the cerebellum and to a lesser extent in the cerebral cortex, the striatum and the hypothalamus. The levetiracetam binding site was restricted to neuronal cell types, undifferentiated PC12 cells and was highly enriched in synaptic vesicles. [3H]ucb 30889 was also used in photoaffinity labelling studies and shown to bind covalently to a membrane protein with a molecular weight of approximately 90 kDa.

PMID: 14555179 [PubMed - indexed for MEDLINE]


I looked back AGAIN on what I had said originally in my narrative regarding levetiracetam. Yep, I said it was "neuroprotective" and speculated that it might be synergistic with desipramine.

Jeez Louise! If levetiracetam is neuroprotective in the striatum, then it might at least help protect the O's, right? Thereby allowing the O's to regenerate? Assuming, that is, that the very first article I posted here is fairly correct. (Again, this leads us back to epilepsy, too. But probably not in the "traditional" sense of the word.) hmmmmmmmmmmm.............
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Postby OddDuck » Sat Jan 08, 2005 2:20 pm

Bromley posted above something about Campath, also.

I'm not familiar with Campath, so I went back and took a look. Here's a pretty good layman's description with links to other research abstracts. As Bromley's post also implies, there appear to be mixed results, but that doesn't mean it isn't worth watching!

http://www.mult-sclerosis.org/Campath1H.html

Deb

EDIT: Oops, I see there's a separate category here for Campath altogether, so I won't expound on Campath here any farther. And I'm not certain how much more on "nerve regeneration" that Campath has shown at this point in time. We'll just have to watch as more info comes out! :wink:
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Postby OddDuck » Sat Jan 08, 2005 7:48 pm

Wesley, and all:

Ok.......regarding axon "regeneration" in the ADULT CNS. I found a terrific LENGTHY article.

I'll post some of it here, but what it basically is saying is what Wesley alluded to earlier here, and what the original discussion I posted first in this thread is talking about. Axon regeneration in the adult CNS is somehow inhibited. This is what researchers are now working on. How to "trigger" or activate the regeneration process in the adult (i.e. postnatal) CNS.

These excerpts below are talking about how to activate "in vivo" (key words there) axonal regeneration in the CNS. The thought is it takes not only growth factors and neurotrophins, but ALSO an elevation in cAMP at the same time in order for CNS regeneration to result.

I propose to go one step farther (based on prior research of mine). If you can also block PKC activity, inhibit Nogo-A/NgR (which is a protein that has been found to impair regeneration in the CNS after injury), and also enhance GAP-43 at the same time as increasing neurotrophins and elevating cAMP, what have you got then? The possibility or even probability of activating axonal regeneration in the adult CNS in vivo?? I'd say YES!

Here are some interesting findings. I'll warn you, they are lengthy. The whole article can be found at http://www.genesdev.org/cgi/content/full/17/8/941

Control of neuronal responsiveness to trophic peptides

An interesting difference between the ability of trophic peptides to promote axon growth by CNS and PNS neurons has been identified. Peptide trophic factors, such as neurotrophins, are sufficient to induce axon growth by purified PNS neurons in culture. In contrast, to elicit axon growth from CNS neurons in culture, peptide trophic signals alone are insufficient. For instance, retinal ganglion cells (RGCs) fail to survive in the presence of such trophic signals as BDNF or CNTF unless their cAMP levels are elevated, either pharmacologically or by depolarization (Meyer-Franke et al. 1995 ). cAMP elevation and depolarization do not promote axon growth on their own. Similarly, RGCs kept alive with Bcl-2 overexpression extend axons only poorly in response to BDNF, but this axon growth is greatly potentiated by cAMP elevation or by physiological levels of electrical activity, either from endogenous retinal activity or from direct electrical stimulation when cultured on a silicon chip (Goldberg et al. 2002a )....

…. This trophic dependence contrasts with PNS neurons, which survive and regenerate their axons in response to trophic peptides in the absence of cAMP elevation or electrical activity, raising the hypothesis that the trophic signaling of axon growth may differ between CNS and PNS neurons. Could this difference contribute to their different abilities to regenerate in vivo? Previous studies have suggested that trophic factor delivery alone or electrical stimulation alone do not induce CNS axonal regeneration. If axon growth normally depends on activity in vivo, and if damaged cells are less active, or elevate cAMP less effectively in response to activity, a CNS neuron's ability to regenerate its axon could be impaired. Therefore it may be crucial to provide trophic peptides as well as signals such as cAMP elevation to ensure an optimal axon growth response (Shen et al. 1999 ; Goldberg and Barres 2000 ). Although cAMP elevation has been implicated in overcoming inhibitory signals at the growth cone (Ming et al. 2001 ), it is interesting to speculate whether some of the effect of cAMP in promoting regeneration in vivo is actually attributable to improving the neurons' response to trophic or other positive peptide signals (Neumann et al. 2002 ; Qiu et al. 2002 )....

…. Intrinsic growth ability of CNS neurons is developmentally regulated

Is the rate and extent of axon growth dependent purely on extracellular signals and substrates, or does it also depend on the intrinsic state of the neuron? This is a critical, though largely unanswered, question in research on axon growth and regeneration. Embryonic CNS neurons can regenerate their axons quite readily, but they lose their capacity to regenerate with age (Schwab and Bartholdi 1996 ; Fawcett 1997 ). For example, in the spinal cord, axons lose the ability to regenerate between P4 and P20 (Kalil and Reh 1982 ; Reh and Kalil 1982 ; Saunders et al. 1992 ). This developmental loss of regenerative ability has generally been attributed to the maturation of CNS glial cells, both astrocytes and oligodendrocytes, and to the production of CNS myelin, all of which strongly inhibit regenerating axons after injury (Schwab and Bartholdi 1996 ). Embryonic neurons also develop responsiveness to myelin-associated inhibitors through this period (Bandtlow and Loschinger 1997 ). In experiments in which a PNS nerve graft (David and Aguayo 1981 ; Bray et al. 1987 ) or anti-myelin neutralizing antibodies (Huang et al. 1999 ) or removal of proteoglycans associated with reactive astrocytes (Moon et al. 2001 ) allow axons to circumvent contact with these inhibitory CNS glia, however, only a few percent of axons regenerate, and functional recovery typically proceeds remarkably slowly. For example, RGCs take 2 mo to regenerate through a peripheral nerve graft (Aguayo et al. 1987 ; Bray et al. 1987 ). These experiments indicate that an inhibitory environment is likely only part of the explanation.
Are the neurons themselves partly responsible? Axons from P2 or older hamster retinas have lost the ability to reinnervate even embryonic tectal explants (Chen et al. 1995 ). Purkinje cells in cerebellar slices show a similar age-related inability to re-extend axons out of cultured slices (Dusart et al. 1997 ). This suggests that changes in a CNS neuron's intrinsic ability to grow could also explain this developmental loss of regenerative ability. The lack of postnatal neurons to re-extend their axons might also be explained by the development of glial cells, however, which are largely generated postnatally. Therefore the ability to separate neurons from CNS glia remains critical to determining whether CNS neurons actually change in their intrinsic axon growth ability during development.

By purifying neurons away from nearby glia at various developmental stages, we recently showed that neonatal RGCs undergo a profound, irreversible loss in their intrinsic ability to regenerate their axons (Goldberg et al. 2002b ). When cultured in strongly trophic environments in the complete absence of CNS glia and at clonal density, embryonic RGCs extend axons up to 10 times faster than postnatal RGCs. The evidence for this decreased growth ability being intrinsically maintained is twofold. First, we found that embryonic RGCs grew at a faster rate than postnatal RGCs in a variety of environments that should facilitate growth, including in media containing neurotrophic factors, in media conditioned by cells from the embryonic visual pathway, and after transplantation into developing pathways in vivo. In all cases, embryonic RGCs extended their axons at rates substantially higher than did the postnatal RGCs, suggesting that any extrinsic growth-promoting environment is dependent on an intrinsically set maximal growth rate. Second, we found that RGCs purified from either embryonic or postnatal ages, and cultured away from all of the other cell types with which they normally interact, retained their faster or slower growth phenotypes, respectively. Therefore the difference in the abilities of embryonic and postnatal RGCs to elongate axons is not dependent on continued signaling by neighboring cell types, but is intrinsically maintained. ....
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Postby Ptwo » Sun Jan 09, 2005 7:00 am

Deb, I found this yesterday and though it's a little OT it has to do with stopping brain cell degeneration.

Old drugs with new use
A family of existing antibiotics may help prevent nerve damage and death in neurological injury including amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), according to a report in the January 6, 2005, issue of Nature. The findings may be applicable to a wide variety of neurodegenerative diseases as well as to other neurological diseases including epilepsy, peripheral neuropathy, and disorders of learning and memory.
The authors demonstrated that ceftriaxone, a beta-lactam antibiotic, turns on a gene that encodes for the glutamate transporter GLT-1. As a result, more glutamate transporter protein is present and functioning in the brain; the authors showed this to be protective against brain cell degeneration.
The newfound ability of ceftriaxone, other beta-lactam antibiotics, and other classes of drugs to activate glutamate transporters and to protect nerves, and the drugs' potential therapeutic use in a wide range of neurological and psychiatric conditions, are covered by patent applications held by The Johns Hopkins University and licensed to Ruxton Pharmaceuticals, Inc. The work described in the Nature article is being extended in part under a sponsored research agreement by Ruxton Pharmaceuticals, Inc., with Johns Hopkins. Glutamate is the most abundant neurotransmitter in the brain. Glutamate transporters clear the neuronal synapses of excess glutamate similar to the way an air vent circulates and clears the air in a room. Too much glutamate resulting from too few glutamate transporters, as is observed in neurodegenerative diseases, overexcites nerve cells and harms them, a process called glutamate excitotoxicity. Excess synaptic glutamate has long been known as a source of nerve damage in neurodegenerative diseases such as ALS, Parkinson's, and multiple sclerosis. Making more transporter molecules, however, seems to counter that. More than a dozen beta-lactam antibiotics were among protective agents identified by a National Institutes of Health-funded project to screen 1,040 Food and Drug Administration-approved drugs and nutritionals for new uses. ``Ceftriaxone was neuroprotective in vitro when used in paradigms of ischemic injury stroke and motor neuron degeneration, both based in part on glutamate toxicity,'' writes principal author Jeffrey D. Rothstein, M.D., Ph.D., director of the Robert Packard Center for ALS Research at Johns Hopkins and Professor of Neurology and Neuroscience at Johns Hopkins. Dr. Rothstein is the scientific founder of Ruxton Pharmaceuticals and is a paid consultant to the company. People with ALS normally experience progressive weakness, paralysis, and death within three to five years of diagnosis. In mouse models of ALS, daily injections of ceftriaxone given after symptoms have developed delayed both nerve damage and the outward signs of the disease. Mice on ceftriaxone also lived significantly longer than those who got no drug. Normal rats and mice that received daily ceftriaxone for up to a week had triple the usual amount of the transporter in cells, an effect that lasted some three months after treatment.
``Overall, these studies document a new property of a very common antibiotic and demonstrate that beta-lactams can activate the gene for a neurotransmitter transporter,'' the researchers write in Nature.
``Although these drugs were tested in a mouse model of ALS, this
discovery is much bigger than ALS,'' said David S. Block, M.D., President and CEO of Ruxton Pharmaceuticals. ``This approach has
potential applications in numerous neurologic and psychiatric conditions that arise from abnormal control of glutamate. In diseases such as ALS, we hope that this approach might eventually deliver drugs that can be used in combination with other approaches, similar to combinations used in HIV and oncology.'' The research was funded by the National Institute of Neurological Disorders and Stroke, the Muscular Dystrophy
Association and the Robert Packard Center for ALS Research at Johns
Hopkins. The ALS mice were provided by Project ALS.

Peter
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Postby OddDuck » Sun Jan 09, 2005 7:11 am

Peter,

That's terrific! At least there is indication that some researchers ARE reaching back into the vast vault of existing medications with properties currently unrealized!

Glutamate..........yep. Wesley is doing some work regarding glutamate, also. We have discussed that in depth in another thread (around here somewhere). :wink:

After protecting cells from degeneration, then all we have to do is find the methods to trigger regeneration!

I think we're real close...........

Deb
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Postby carolsue » Mon Jan 17, 2005 1:54 pm

FYI, from the Dec 17 2004 issue of the journal Science, I found an article regarding a mechanism for remyelination. The citation is:
Arnett, HA, Fancy, SPJ, Alberta, JA, etc...2004. bHLH transcription factor Olig1 is required to repair demyelinated lesions in the CNS. Science 306:2111-2115.

Here's the abstract:
Olig1 and Olig2 are closely related basic helix-loop-helix (bHLH) transcription factors that are expressed in myelinating oligodendrocytes and their progenitor cells in the developing central nervous system (CNS). Olig2 is necessary for the specification of oligodendrocytes, but the biological functions of Olig1 during oligodendrocyte lineage development are poorly understood. We show here that Olig1 function in mice is required not to develop the brain but to repair it. Specifically, we demonstrate a genetic requirement for Olig1 in repairing the types of lesions that occur in patients with multiple sclerosis.

The study had a couple parts, and no, I didn't understand most of it. :? In one part, they induced brain lesions in mice and saw that Olig1 proteins were located in the nucleus of cells (as opposed to the cytoplasm of those cells) around the lesions that were being remyelinated. They also found this nuclear Olig1 pattern in post-mortem examinations of brains of MS patients. So I guess this is supposed to suggest that the mechanism may be similar for mice and people. They then compared the remyelination efficiency of induced lesions in mice populations with and without the gene for Olig1. Several weeks after the induced lesions, the mice with Olig1 had less severe demyelination than the mice without Olig1. This would support the notion that Olig1 is important for remyelination.

Concluding paragraph:
With respect to the human disease, the lesions that define MS are now thought to arise from a number of different mechanisms, mostly immunologic but not always linear or cell-mediated. Accordingly, MS may never be entirely preventable, and new therapeutic approaches must focus on the repair (remyelination) process. At the level of basic science, one important unresolved issue is why remyelination is so limited in patients with MS even though endogenous oligodendrocyte progenitors are often present in abundance. Studies shown in this paper indicate that signals regulating the subcellular localization and/or activity of Olig1 during development may play an additional and critical role in activating oligodendrocyte progenitors in the the adult CNS. Our data show that requirements for Olig1 function are subtle during development, yet striking during the repair of a demyelinating lesion. This would suggest that cell-intrinsic activity of Olig1 can be compensated for during myelination but not remyelination. Further insights into the molecular mechanisms of Olig1 function during development may have practical overtones for future therapeutic interventions in MS.

Any further interpretation will have to come from someone else!
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carolsue
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