Jerry Silver and Other Discussion from ChinaSCINet Update

[ay2012]

You may remember that Lisa McKerracher developed Cethrin (a form of a bacterial toxin called C3 that enters neurons to block rhoA) as a treatment for spinal cord injury and actually took it to clinical trial, which showed promising results. Since ibuprofen, and indomethacin blocks RhoA, it should have beneficial effects on neurite outgrowth. It does no harm and would be very interesting to include a group in our clinical trial where the patients take some indomethacin or ibuprofen. If it doesn’t help, at least we have tried. If it does restore function, then it is worthwhile, don’t you think?

NO, I don't think so. How about holding off on people until somebody shows that any of these fringe treatments show robust effects in a CHRONIC SCI animal model. By the way how are those chronic CETHRIN experiments progressing that you said you are doing in your lab? Looking forward to hearing about the results IN ANIMALS BEFORE we attempt this in people, don't you think?

Yes, I do hope these experiements are done before it goes to trial. I also hope it is effective. From http://www.twst.com/interview/16847:

TWST: This has to be done soon after the injury?
Dr. McKerracher: The ideal therapeutic window that we have determined is quite small. It is about 24 hours. Nonetheless, our product has potential in chronic spinal cord injury because it has two different effects. One effect is that it is neural-protective which means that it prevents cell death that happens after traumatic or ischemic injury. Of course, for cell protection the drug is best applied early. Cethrin also has effects on promoting and restoring regeneration and growth of damaged axons. So that is an effect where delivery early might not be so important.

[Geoman]

You may remember that Lisa McKerracher developed Cethrin (a form of a bacterial toxin called C3 that enters neurons to block rhoA) as a treatment for spinal cord injury and actually took it to clinical trial, which showed promising results. Since ibuprofen, and indomethacin blocks RhoA, it should have beneficial effects on neurite outgrowth. It does no harm and would be very interesting to include a group in our clinical trial where the patients take some indomethacin or ibuprofen. If it doesn’t help, at least we have tried. If it does restore function, then it is worthwhile, don’t you think?

NO, I don't think so. How about holding off on people until somebody shows that any of these fringe treatments show robust effects in a CHRONIC SCI animal model. By the way how are those chronic CETHRIN experiments progressing that you said you are doing in your lab? Looking forward to hearing about the results IN ANIMALS BEFORE we attempt this in people, don't you think?

Jerry,
Your input is very informative and greatly appreciated. But if you could use the 'Quote' button found at the lower right corner of the post you're responding to it will make your posts a lot clearer. Sometimes it's not clear as to what text is yours and what has been quoted if you do a manual cut and paste.
Thanks,
Clayton

[kivi66]

Jerry,
Your input is very informative and greatly appreciated. But if you could use the 'Quote' button found at the lower right corner of the post you're responding to it will make your posts a lot clearer. Sometimes it's not clear as to what text is yours and what has been quoted if you do a manual cut and paste.
Thanks,
Clayton

Yes, really, not such a "binomial theorem". Must be much easier to accomplish than the big animal clinical trials.

[Skipow]

This ibuprofen study reminds me of a turmeric study published this summer that preserved walking among mice. I didn't read the journal, but does curcumin or omega-3 block rhoA or is it just the anti-inflammatory response, as Turmeric is known to do.

http://http://www.huffingtonpost.com...n_1638769.html

[crabbyshark]

If it does restore function, then it is worthwhile, don’t you think?

NO, I don't think so.

How about holding off on people until somebody shows that any of these fringe treatments show robust effects in a CHRONIC SCI animal model. By the way how are those chronic CETHRIN experiments progressing that you said you are doing in your lab? Looking forward to hearing about the results IN ANIMALS BEFORE we attempt this in people, don't you think?

These drugs have been determined to be safe for use in humans. Ibuprofen and its side effects are very well known. Ibuprofen is easily available. Time is of the essence. It should probably be put to clinical trial in acutes and chronics asap.

[Wise Young]

Dr.Young,
I have been taking 150mg of Indocin SR daily since 1986 for Arthritis, I'm also taking Enbrel for about 10 years. Both drugs have been shown in studies to reverse SCI. Should I start giving my medications to my son to cure his SCI? Should I see if Geeta Shroff is back in business and give her"therapy"a whirl as well?

I assume that you are being sarcastic in your remark concerning Geeta Shroff. Nobody should be taking Indocin for their spinal cord injury based on the animal data presented. That is what clinical trials are for.

The etanercept (Enbrel) and minocycline effects have been reported only for acute spinal cord injury and would not be relevant to the chronic spinal cord injury.

Wise.
Wise.

[Wise Young]

Why should I know that you think baby aspirin is the best way to reduce the risk of a stroke when the subject at hand is chronic sci? It seems like a red herring to me.

Christopher,

I used the example of aspirin because it is one of the most common and oldest drugs known and it is an NSAID. The tone of the discussion suggest that you and others are dismissing Indomethacin and Ibuprofen because you think that it can't possibly have any effect on spinal cord injury. A similar attitude was present 30 years ago when the first data came out reporting that aspirin has a dramatic effect on stroke prevention. After nearly 3 decades of trials, it has become clear that aspirin is the most effective drug for preventing stroke. Several recent studies indicate that acetylsalicylic acid (aspirin) regulates RhoA [1-2].

In another post, I pointed out another reason why I was thinking about aspirin. I had just read a paper that suggests that the risk of a stroke is 3 times higher in people with spinal cord injury than the normal population in Taiwan and one of the suggested therapies was aspirin. I was thinking that if they do a clinical trial of people with chronic spinal cord injury to assess the effects of NSAIDs to prevent stroke, we can arrange to examine the patients to see if there is any improvement of motor or sensory scores, or walking.

It is good to be skeptical but I think that we should not be dismissing the possibility that indomethacin and ibuprofen block RhoA and stimulates axonal growth. The Fu, et al. paper was published in 2007, over 6 years ago, in Journal of Neuroscience. Peer-reviewers thought that the work is sufficiently interesting and credible to be published in that journal. Several laboratories have confirmed the results and there is growing interest in studying this treatment further. I attach a recent review of the subject by Kopp, et al., indicating that some of the top scientists in the field are taking this therapy seriously.

Wise.

1. Li DB, Fu ZX, Ruan SQ, Hu SJ and Li X (2012). Acetylsalicylic acid regulates overexpressed small GTPase RhoA in vascular smooth muscle cells through prevention of new synthesis and enhancement of protein degradation. Bioscience reports 32: 153-60. Institute of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, People's Republic of China. RhoA has been shown to play a major role in vascular processes and acetylsalicylic acid (aspirin) is known to exert a cytoprotective effect via multiple mechanisms. In the present study, we aimed at investigating the effect of aspirin on RhoA expression under a stress state in rat VSMCs (vascular smooth muscle cells) and the underlying mechanisms. The expression of iNOS (inducible nitric oxide synthase) and iNOS activity as well as NO concentration was significantly promoted by LPS (lipopolysaccharide) accompanying the elevation of RhoA expression, which was blocked by the addition of the iNOS inhibitor L-NIL [L-N6-(1-iminoethyl)lysine dihydrochloride]. Aspirin (30 muM) significantly attenuated the elevation of RhoA, while indomethacin and salicylate had no similar effect. The sGC (soluble guanylate cyclase) inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) showed the same effect as aspirin in down-regulating RhoA but was reversed by the addition of the cGMP analogue 8-Br-PET-cGMP (beta-phenyl-1,N2-ethano-8-bromoguanosine 3',5'-cyclic monophosphorothioate). 8-Br-PET-cGMP solely enhanced the RhoA expression that was abrogated by preincubation with aspirin. Degradation analysis indicated that aspirin enhanced the protein degradation rate of RhoA and GDP-bound RhoA seemed to be more susceptible to aspirin-enhanced degradation compared with the GTP-bound form. Our results indicate that aspirin attenuates the LPS-induced overexpression of RhoA both by inhibiting new synthesis and accelerating protein degradation, which may help elucidate the multiple beneficial effects of aspirin.
   
2. Ying Z, Giachini FR, Tostes RC and Webb RC (2009). Salicylates dilate blood vessels through inhibiting PYK2-mediated RhoA/Rho-kinase activation. Cardiovascular research 83: 155-62. Department of Physiology, Medical College of Georgia, 1120 15th Street, Augusta, GA 30912, USA. zhekang.ying@osumc.edu. AIMS: Compared with other non-steroid anti-inflammatory drugs (NSAIDs), aspirin is not correlated to hypertension. It has been shown that aspirin has unique vasodilator action in vivo, offering an explanation for the unique blood pressure effect of aspirin. In the present study, we investigate the mechanism whereby salicylates (aspirin and sodium salicylate) dilate blood vessels. METHODS AND RESULTS: Rat aortic or mesenteric arterial rings were used to test the vascular effect of salicylates and other NSAIDs. RhoA translocation and the phosphorylation of MYPT1, the regulatory subunit of myosin light chain phosphatase, were measured by western blot, as evidenced for RhoA/Rho-kinase activation. Salicylates, but not other NSAIDs, relaxed contraction induced by most tested constrictors except for calyculin A, indicating that RhoA/Rho-kinase-mediated calcium sensitization is involved. The involvement of RhoA/Rho kinase in vasodilation by salicylates was confirmed by measurements of RhoA translocation and MYPT1 phosphorylation. The calculated half maximal inhibitory concentration (IC(50)) of vasodilation was apparently higher than that of cyclooxygenase inhibition, but comparable to that of proline-rich tyrosine kinase 2 (PYK2) inhibition. Over-expression of PYK2 induced RhoA translocation and MYPT1 phosphorylation, and these effects were markedly inhibited by sodium salicylate treatment. Consistent with the ex vitro vascular effects, sodium salicylate acutely decreased blood pressure in spontaneous hypertensive rats but not in Wistar Kyoto rats. CONCLUSION: Salicylates dilate blood vessels through inhibiting PYK2-mediated RhoA/Rho-kinase activation and thus lower blood pressure.
   

[Wise Young]

NO, I don't think so. How about holding off on people until somebody shows that any of these fringe treatments show robust effects in a CHRONIC SCI animal model. By the way how are those chronic CETHRIN experiments progressing that you said you are doing in your lab? Looking forward to hearing about the results IN ANIMALS BEFORE we attempt this in people, don't you think?

We have not yet started the Cethrin experiments.

Wise.

[Wise Young]

This ibuprofen study reminds me of a turmeric study published this summer that preserved walking among mice. I didn't read the journal, but does curcumin or omega-3 block rhoA or is it just the anti-inflammatory response, as Turmeric is known to do.

http://http://www.huffingtonpost.com...n_1638769.html

Skipow,

There are many studies of the neuroprotective effects of tumeric on acute spinal cord injury [1-5] and chronic spinal cord injury [6], its beneficial effects on locomotor recovery and cognitive deficits in rats after traumatic brain injury [7], prevention of motoneuronal degeneration [8-11], protection of peripheral nerve injury [2, 12, 13], reduction of neuropathic pain [14, 15], and even enhancement of spinal plasticity [16]. The mechanisms of tumeric or its active ingredient curcumol are not well-understood but several different mechanisms have been proposed, including anti-oxidant effects [7, 17], blockade of NF-kappa [18], inhibition of glycine receptors [19], histone acetylation [20-22], downregulation of CX3CR1 expression [23], attenuation of RANTES [24], and activation of nuclear factor erythroid 2-related factor 2 [3]. I have not seen any studies suggesting that tumeric blocks rhoA.

I first came across this extensive literature on turmeric and its potential effects on spinal cord injury when I noticed that neuropathic pain is less common in patients from India and wondered if there was something in the spices that they eat in India. Tumeric is of course a common spice in India. The effect of indomethacin and ibuprofen is apparently not related to their blockade of cyclooxygenase (COX) but these two drugs act directly on RhoA. Another known cyclooxygenase blocker Naproxen) does not have this effect on RhoA but apparently aspirin inhibits RhoA (see post #397).

Wise.

References

1. Sanli AM, Turkoglu E, Serbes G, Sargon MF, Besalti O, Kilinc K, et al. Effect of curcumin on lipid peroxidation, early ultrastructural findings and neurological recovery after experimental spinal cord contusion injury in rats. Turkish neurosurgery. 2012;22(2):189-95.
2. Noorafshan A, Omidi A, Karbalay-Doust S. Curcumin protects the dorsal root ganglion and sciatic nerve after crush in rat. Pathology, research and practice. 2011;207(9):577-82.
3. Jiang H, Tian X, Guo Y, Duan W, Bu H, Li C. Activation of nuclear factor erythroid 2-related factor 2 cytoprotective signaling by curcumin protect primary spinal cord astrocytes against oxidative toxicity. Biological & pharmaceutical bulletin. 2011;34(8):1194-7.
4. Lin MS, Lee YH, Chiu WT, Hung KS. Curcumin provides neuroprotection after spinal cord injury. The Journal of surgical research. 2011;166(2):280-9.
5. Cemil B, Topuz K, Demircan MN, Kurt G, Tun K, Kutlay M, et al. Curcumin improves early functional results after experimental spinal cord injury. Acta Neurochirurgica. 2010;152(9):1583-90; discussion 90.
6. Holly LT, Blaskiewicz D, Wu A, Feng C, Ying Z, Gomez-Pinilla F. Dietary therapy to promote neuroprotection in chronic spinal cord injury. Journal of neurosurgery Spine. 2012;17(2):134-40.
7. Wu A, Ying Z, Schubert D, Gomez-Pinilla F. Brain and spinal cord interaction: a dietary curcumin derivative counteracts locomotor and cognitive deficits after brain trauma. Neurorehabilitation and neural repair. 2011;25(4):332-42. PMCID: 3258099.
8. Seo JS, Leem YH, Lee KW, Kim SW, Lee JK, Han PL. Severe motor neuron degeneration in the spinal cord of the Tg2576 mouse model of Alzheimer disease. Journal of Alzheimer's disease : JAD. 2010;21(1):263-76.
9. Sakla MS, Lorson CL. Induction of full-length survival motor neuron by polyphenol botanical compounds. Human genetics. 2008;122(6):635-43.
10. Yang Z, Chang YJ, Yu IC, Yeh S, Wu CC, Miyamoto H, et al. ASC-J9 ameliorates spinal and bulbar muscular atrophy phenotype via degradation of androgen receptor. Nature medicine. 2007;13(3):348-53.
11. Ryu H, Smith K, Camelo SI, Carreras I, Lee J, Iglesias AH, et al. Sodium phenylbutyrate prolongs survival and regulates expression of anti-apoptotic genes in transgenic amyotrophic lateral sclerosis mice. Journal of Neurochemistry. 2005;93(5):1087-98.
12. Noorafshan A, Omidi A, Karbalay-Doust S, Aliabadi E, Dehghani F. Effects of curcumin on the dorsal root ganglion structure and functional recovery after sciatic nerve crush in rat. Micron. 2011;42(5):449-55.
13. Li X, Liu RH, Cao H, Li J. [Effects of curcumin on behavior and p-ERK, p-CREB, c-fos expression in dorsal root ganglion in chronic constrictive injury rats]. Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology. 2009;25(3):418-22.
14. Han YK, Lee SH, Jeong HJ, Kim MS, Yoon MH, Kim WM. Analgesic effects of intrathecal curcumin in the rat formalin test. Korean J Pain. 2012;25(1):1-6. PMCID: 3259131.
15. Zhao X, Xu Y, Zhao Q, Chen CR, Liu AM, Huang ZL. Curcumin exerts antinociceptive effects in a mouse model of neuropathic pain: descending monoamine system and opioid receptors are differentially involved. Neuropharmacology. 2012;62(2):843-54.
16. Joseph MS, Ying Z, Zhuang Y, Zhong H, Wu A, Bhatia HS, et al. Effects of Diet and/or Exercise in Enhancing Spinal Cord Sensorimotor Learning. PLoS ONE. 2012;7(7):e41288. PMCID: 3401098.
17. Hall ED, Vaishnav RA, Mustafa AG. Antioxidant therapies for traumatic brain injury. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 2010;7(1):51-61. PMCID: 2818465.
18. Ormond DR, Peng H, Zeman R, Das K, Murali R, Jhanwar-Uniyal M. Recovery from spinal cord injury using naturally occurring antiinflammatory compound curcumin. Journal of neurosurgery Spine. 2012.
19. Wang L, Li WG, Huang C, Zhu MX, Xu TL, Wu DZ, et al. Subunit-specific inhibition of glycine receptors by curcumol. The Journal of pharmacology and experimental therapeutics. 2012;343(2):371-9.
20. Liang DY, Li X, Clark JD. Epigenetic regulation of opioid-induced hyperalgesia, dependence, and tolerance in mice. The journal of pain : official journal of the American Pain Society. 2013;14(1):36-47. PMCID: 3539745.
21. Puglia C, Frasca G, Musumeci T, Rizza L, Puglisi G, Bonina F, et al. Curcumin loaded NLC induces histone hypoacetylation in the CNS after intraperitoneal administration in mice. European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik eV. 2012;81(2):288-93.
22. Dayangac-Erden D, Bora-Tatar G, Dalkara S, Demir AS, Erdem-Yurter H. Carboxylic acid derivatives of histone deacetylase inhibitors induce full length SMN2 transcripts: a promising target for spinal muscular atrophy therapeutics. Arch Med Sci. 2011;7(2):230-4. PMCID: 3258711.
23. Zheng J, Zheng C, Cao H, Li J, Lian Q. [Curcumin down-regulates CX3CR1 expression in spinal cord dorsal horn and DRG in neuropathic pain rats]. Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica. 2011;36(18):2552-6.
24. Lin MS, Sun YY, Chiu WT, Hung CC, Chang CY, Shie FS, et al. Curcumin attenuates the expression and secretion of RANTES after spinal cord injury in vivo and lipopolysaccharide-induced astrocyte reactivation in vitro. Journal of Neurotrauma. 2011;28(7):1259-69.

[Christopher Paddon]

I still can't see what taking aspirin has to do with chronic spinal cord injury. It may help reduce the chance of having a stroke (BEFORE a stroke happens, possibly by thinning the blood or reducing blood pressure? I don't know).

Where is the laboratory evidence that aspirin or ibuprofen etc etc can do anything to deal with the massive neurological deficit and scar tissue left that exist in a chronic sci or stroke for that matter?

Saying something helps prevent a disease or works in an acute injury situation and then extrapolating it to apply to a chronic injury situation seems illogical to me.

[paolocipolla]

Christopher,

What the authors found was that these NSAID's appear to block rho. Those results were very clear. I don't share Jerry's skepticism of all the results in the paper. Nor did the peer reviewers of the paper share his views. Finally, you should know that the most effective way to reduce stroke in people is a baby aspirin a day.

Wise.

Wise,

this post here above reminds me that in the past I had several times the impression that, sometimes, you don't fully realise the perspective of people living in chair.
For example, in this context, I don't see why did you say:
"Finally, you should know that the most effective way to reduce stroke in people is a baby aspirin a day" ?

It's more or less like if you go at W2W and give a presentation about preventimng stroke.. that is not exactly what the audience is interested in, who cares?

Anyway, don't worry, it has happened to me many times to listen to scientists talking to me about his/her wonderfull research and then I had to ask him/her "is that going to get me out of chair somehow"? Tipically the answer is "not really... bla bla" and the face of the individual turns red. If I don't see a red face in a few seconds then I usually ask something like "Why should I get excited hearing what you are telling me"?

Hope you understand what I mean and how bad people in chair may feel hearing researchers sometimes.

Paolo

[crabbyshark]

When axons approach the inhibitory environment, RhoA is activated in the axon.
When RhoA is activated in the axon, the axon freezes.
Evidence suggests that ibuprofen inhibits, or turns off, RhoA.

In turn, the inhibition of RhoA-activation blinds the injured axon to its growth inhibitory environment resulting in enhanced axonal sprouting and plasticity. This has been demonstrated in various CNS-injury models for direct RhoA-inhibition and for downstream/upstream blockade of the RhoA-associated pathway.

Axons regrow at ~1 mm per day.
Perhaps a dose of ibuprofen, or another similar NSAID, taken every day, would inhibit RhoA and allow regrowing axons to overcome the inhibitory environment in chronic SCI.

[ay2012]

These drugs have been determined to be safe for use in humans. Ibuprofen and its side effects are very well known. Ibuprofen is easily available. Time is of the essence. It should probably be put to clinical trial in acutes and chronics asap.

What?! Sorry but this is nonsense. Animal studies are significantly shorter than human trials. Every potential therapy (if possible) should be tested in a complete, chronic model before going to trial, in my opinion. Your view would only make sense if everything could go to trial collectively at the same time... Obviously the animal models wouldn't occur that way either, but a whole hell of a lot faster. If you want simply any therapy to go to trial, even if it hasn't demonstrated efficacy in a comparable animal model, I hope you're ready to sit through a bunch of failures or that you're ok with rolling the dice and waiting 5+ years per trial to even see what lands.

[cripwalk]

Wise,

this post here above reminds me that in the past I had several times the impression that, sometimes, you don't fully realise the perspective of people living in chair.
For example, in this context, I don't see why did you say:
"Finally, you should know that the most effective way to reduce stroke in people is a baby aspirin a day" ?

It's more or less like if you go at W2W and give a presentation about preventimng stroke.. that is not exactly what the audience is interested in, who cares?

Anyway, don't worry, it has happened to me many times to listen to scientists talking to me about his/her wonderfull research and then I had to ask him/her "is that going to get me out of chair somehow"? Tipically the answer is "not really... bla bla" and the face of the individual turns red. If I don't see a red face in a few seconds then I usually ask something like "Why should I get excited hearing what you are telling me"?

Hope you understand what I mean and how bad people in chair may feel hearing researchers sometimes.

Paolo

Please feel free to correct me if I'm wrong but Dr young's point was simply that a drug's usefulness shouldn't be dismissed because it is common, as it may have yet unexplored but effective alternative uses.

[GRAMMY]

We have not yet started the Cethrin experiments.

Wise.

A perfect opportunity to do a side by side comparison of Cethrin and aspirin in chronic rats!