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Thread: Jerry Silver and Other Discussion from ChinaSCINet Update

  1. #381
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    Quote Originally Posted by Wise Young View Post
    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.
    Sould i have my friends and family start taking a Tylenol a day so they never get a SCI?

  2. #382
    Quote Originally Posted by nrf View Post
    Sould i have my friends and family start taking a Tylenol a day so they never get a SCI?
    Ha! Careful not to confuse Tylenol (acetaminophen) with ibuprofen (Motrin).
    Last edited by crabbyshark; 02-05-2013 at 03:12 AM.

  3. #383
    Quote Originally Posted by nrf View Post
    Sould i have my friends and family start taking a Tylenol a day so they never get a SCI?
    Nrf,

    Not all scientific findings should be dismissed because it uses common drugs. Aspirin is one of the most common and cheapest drugs in the Pharmacopea but it is also the most effective drug for preventing stroke that we have. Over 300 studies involving 135,000 individuals have shown that taking an aspirin a day reduces the risk of stroke by about 25%. Of course, many drug companies leaped on this finding and began offering all types of aspirin substitutes for a higher price. As it turns out, aspirin remains the drug of choice because all the higher priced substitutes are not only less effective but have more complications.
    http://abcnews.go.com/Health/story?id=116941&page=1

    Incidentally, I mentioned aspirin because a recent paper [1], studying 2,806 spinal-injured people in Taiwan, showed that stroke is significantly more likely to occur in spinal-injured people than in a non-spinal-injured population. The risk of stroke is 2.93 (p<0.001) times greater than a control group of 28,060 age-, sex-, and propensity- matched control subjects. In other words, the risk of somebody with spinal cord injury getting a stroke is three times higher than the normal population. The paper suggests that low-dose aspirin may be a reasonable prophylactic therapy for people with spinal cord injury for preventing stroke. Aspirin was on my mind when I wrote that post.

    Aspirin, Ibuprofen (Ibu), and Indomethacin (Indo) inhibit a family of enzymes called cyclooxygenase (COX). COX is also known as prostaglandin-endoperoxide synthase and is responsible for forming an important class of biological mediators called prostanoids (prostaglandins, prostacyclin, and thromboxane). COX converts arachidonic acid (a fatty acid that is released in injury or inflammation) into prostanoids, the most powerful vasodilators and inflammatory agents in our body. There are three kinds of COX: COX-1, COX-2, and COX-3. Aspirin, Ibuprofen (Ibu), and Indomethacin (Indo) inhibit all types of COX. Some people may remember COX-2 inhibitors called Vioxx and Celebrex. The former was taken off the market in 2004 because it increases the risk of heart attacks. Note that acetaminophen (Tylenol) may block COX-2 [2].

    The paper by Fu, et al. [3] is of interest because it shows that ibuprofen and indomethacin effectively block rhoA to increase axonal growth whereas naproxen (another COX inhibitor) does not block RhoA and also does not increase neurite growth. Fu, et al. showed that Ibu and Indo both significantly reduced RhoA activity in culture and stimulated neurite outgrowth. Peer reviewers for the Journal of Neuroscience think that the findings are significant. More important, their work has been supported by research from several other laboratories who not only showed that COX inhibitors promote axonal growth [4] but also myelination [5]. This is the way science works. If the Fu, et al. study could not be reproduced by other scientists, it would simply go down the river of irreproducible scientific work. However, it has been reproduced.

    RhoA is the intracellular messenger that mediates the effects of growth inhibitors such as Nogo A and CSPG. 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?

    Wise.

    References
    1. Wu JC, Chen YC, Liu L, Chen TJ, Huang WC, Cheng H and Tung-Ping S (2012). Increased risk of stroke after spinal cord injury: a nationwide 4-year follow-up cohort study. Neurology 78: 1051-7. Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan. OBJECTIVE: Spinal cord injury (SCI) is associated with a higher risk of cardiovascular diseases but whether or not the risk of cerebrovascular disease also increases remains unclear. This study aimed to evaluate the incidence of stroke in patients with disability caused by SCI. METHODS: Study subjects were identified from a nationwide cohort of 18,690,066 people from 1998 to 2002 that was divided into an SCI group (n = 2,806), who were disabled from SCI, and a comparison group (n = 28,060), composed of age-, sex-, and propensity score- matched control subjects. Every subject was followed up for 4 years, unless they died or had a stroke by December 31, 2006. Kaplan-Meier and Cox regression analyses were performed. RESULTS: The incidence rate of stroke in the SCI group (5.96 per 1,000 person-years) was higher than that of the comparison group (p < 0.001). Stroke was more likely to occur in the SCI group than in the comparison group (crude hazard ratio 2.93, p < 0.001; adjusted hazard ratio 2.85, p < 0.001). In the SCI group, the incidence of ischemic stroke was higher than that of hemorrhagic stroke (incidence rate ratio 3.42, p < 0.001). CONCLUSIONS: SCI patients with disability are at a higher risk of stroke, especially the ischemic type. Strategies to prevent stroke are therefore suggested for them.
    2. Hinz, B., Cheremina, O., & Brune, K. (2007). Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man. The FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, 22(2), 383–390. ABSTRACT For more than three decades, acetamin- ophen (INN, paracetamol) has been claimed to be devoid of significant inhibition of peripheral prosta- noids. Meanwhile, attempts to explain its action by inhibition of a central cyclooxygenase (COX)-3 have been rejected. The fact that acetaminophen acts functionally as a selective COX-2 inhibitor led us to investigate the hypothesis of whether it works via preferential COX-2 blockade. Ex vivo COX inhibition and pharmacokinetics of acetaminophen were assessed in 5 volunteers receiving single 1000 mg doses orally. Coagulation-induced thromboxane B2 and lipopolysaccharide- induced prostaglandin E2 were measured ex vivo and in vitro in human whole blood as indices of COX-1 and COX-2 activity. In vitro, acetaminophen elicited a 4.4- fold selectivity toward COX-2 inhibition (IC50=113.7 µmol/L for COX-1; IC50=25.8 µmol/L for COX-2). Following oral administration of the drug, maximal ex vivo inhibitions were 56% (COX-1) and 83% (COX-2). Acetaminophen plasma concentrations remained above the in vitro IC50 for COX-2 for at least 5 h postadmin- istration. Ex vivo IC50 values (COX-1: 105.2 µmol/L; COX-2: 26.3 µmol/L) of acetaminophen compared favorably with its in vitro IC50 values. In contrast to previous concepts, acetaminophen inhibited COX-2 by more than 80%, i.e., to a degree comparable to nonste- roidal antiinflammatory drugs (NSAIDs) and selective COX-2 inhibitors. However, a >95% COX-1 blockade relevant for suppression of platelet function was not achieved. Our data may explain acetaminophen’s anal- gesic and antiinflammatory action as well as its superior overall gastrointestinal safety profile compared with NSAIDs. In view of its substantial COX-2 inhibition, recently defined cardiovascular warnings for use of COX-2 inhibitors should also be considered for acetaminophen.
    3. Fu Q, Hue J and Li S (2007). Nonsteroidal anti-inflammatory drugs promote axon regeneration via RhoA inhibition. J Neurosci 27: 4154-64. Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. After a CNS injury in the adult mammals, axonal regeneration is very limited because of the reduced intrinsic growth capacity and nonpermissive environment for axonal elongation. The growth inhibitions from CNS myelin and astroglial chondroitin sulfate proteoglycans partially account for the lack of CNS repair. Here, we show that the nonsteroidal antiinflammatory drugs (NSAIDs) ibuprofen and indomethacin, the drugs widely used as pain relievers in the clinic, can surmount axon growth restrictions from myelin and proteoglycans by potently inhibiting their downstream pathway RhoA signal. Similar to Rho and Rock inhibitors C3 transferase or Y27632 [(R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide], both NSAID drugs stimulate a significant neurite growth in the cultured dorsal root ganglion neurons exposed to the inhibitory substrates. Systemic administration of ibuprofen to spinal cord-lesioned rodents reverses the active RhoA signal around injury area measured via Rho-GTP binding assay. Subcutaneous injections of ibuprofen via minipumps to rats with a thoracic spinal cord transection or contusion injury result in substantial corticospinal and serotonergic axon sprouting in the caudal spinal cord and promote locomotor functional recovery, even delaying the treatment 1 week after trauma. In contrast, the non-RhoA-inhibiting NSAID naproxen does not have the axon growth-promoting effects on cultured or lesioned neurons. These studies demonstrate the therapeutic potential of RhoA-inhibiting NSAIDs in treating CNS injuries characterized by axonal disconnection including spinal cord injury.
    4. Kopp MA, Liebscher T, Niedeggen A, Laufer S, Brommer B, Jungehulsing GJ, Strittmatter SM, Dirnagl U and Schwab JM (2012). Small-molecule-induced Rho-inhibition: NSAIDs after spinal cord injury. Cell and tissue research 349: 119-32. Department of Neurology and Experimental Neurology, Spinal Cord Injury Research, Charite-Universitatsmedizin Berlin, Chariteplatz 1, 10117 Berlin, Germany. Limited axonal plasticity within the central nervous system (CNS) is a major restriction for functional recovery after CNS injury. The small GTPase RhoA is a key molecule of the converging downstream cascade that leads to the inhibition of axonal re-growth. The Rho-pathway integrates growth inhibitory signals derived from extracellular cues, such as chondroitin sulfate proteoglycans, Nogo-A, myelin-associated glycoprotein, oligodendrocyte-myelin glycoprotein, Ephrins and repulsive guidance molecule-A, into the damaged axon. Consequently, the activation of RhoA results in growth cone collapse and finally outgrowth failure. 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. In addition, RhoA-inhibition reduces apoptotic cell death and secondary damage and improves locomotor recovery in clinically relevant models after experimental spinal cord injury (SCI). Unexpectedly, a subset of "small molecules" from the group of non-steroid anti-inflammatory drugs, particularly the FDA-approved ibuprofen, has recently been identified as (1) inhibiting RhoA-activation, (2) enhancing axonal sprouting/regeneration, (3) protecting "tissue at risk" (neuroprotection) and (4) improving motor recovery confined to realistic therapeutical time-frames in clinically relevant SCI models. Here, we survey the effect of small-molecule-induced RhoA-inhibition on axonal plasticity and neurofunctional outcome in CNS injury paradigms. Furthermore, we discuss the body of preclinical evidence for a possible clinical translation with a focus on ibuprofen and illustrate putative risks and benefits for the treatment of acute SCI.
    5. Xing B, Li H, Wang H, Mukhopadhyay D, Fisher D, Gilpin CJ and Li S (2011). RhoA-inhibiting NSAIDs promote axonal myelination after spinal cord injury. Exp Neurol 231: 247-60. Department of Neurology and Neuroscience Graduate Program, University of Texas Southwestern Medical Center, Dallas, TX 75390-8813, USA. Nonsteroidal anti-inflammatory drugs (NSAIDs) are extensively used to relieve pain and inflammation in humans via cyclooxygenase inhibition. Our recent research suggests that certain NSAIDs including ibuprofen suppress intracellular RhoA signal and improve significant axonal growth and functional recovery following axonal injury in the CNS. Several NSAIDs have been shown to reduce generation of amyloid-beta42 peptide via inactivation of RhoA signal, supporting potent RhoA-repressing function of selected NSAIDs. In this report, we demonstrate that RhoA-inhibiting NSAIDs ibuprofen and indomethacin dramatically reduce cell death of oligodendrocytes in cultures or along the white matter tracts in rats with a spinal cord injury. More importantly, we demonstrate that treatments with the RhoA-inhibiting NSAIDs significantly increase axonal myelination along the white matter tracts following a traumatic contusion spinal cord injury. In contrast, non-RhoA-inhibiting NSAID naproxen does not have such an effect. Thus, our results suggest that RhoA inactivation with certain NSAIDs benefits recovery of injured CNS axons not only by promoting axonal elongation, but by enhancing glial survival and axonal myelination along the disrupted axonal tracts. This study, together with previous reports, supports that RhoA signal is an important therapeutic target for promoting recovery of injured CNS and that RhoA-inhibiting NSAIDs provide great therapeutic potential for CNS axonal injuries in adult mammals.
    Last edited by Wise Young; 02-05-2013 at 08:03 AM.

  4. #384
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    Quote Originally Posted by Wise Young View Post
    Nrf,

    Not all scientific findings should be dismissed because it uses common drugs. Aspirin is one of the most common and cheapest drugs in the Pharmacopea but it is also the most effective drug for preventing stroke that we have. Over 300 studies involving 135,000 individuals have shown that taking an aspirin a day reduces the risk of stroke by about 25%. Of course, many drug companies leaped on this finding and began offering all types of aspirin substitutes for a higher price. As it turns out, aspirin remains the drug of choice because all the higher priced substitutes are not only less effective but have more complications.
    http://abcnews.go.com/Health/story?id=116941&page=1

    Incidentally, I mentioned aspirin because a recent paper [1], studying 2,806 spinal-injured people in Taiwan, showed that stroke is significantly more likely to occur in spinal-injured people than in a non-spinal-injured population. The risk of stroke is 2.93 (p<0.001) times greater than a control group of 28,060 age-, sex-, and propensity- matched control subjects. In other words, the risk of somebody with spinal cord injury getting a stroke is three times higher than the normal population. The paper suggests that low-dose aspirin may be a reasonable prophylactic therapy for people with spinal cord injury for preventing stroke. Aspirin was on my mind when I wrote that post.

    Aspirin, Ibuprofen (Ibu), and Indomethacin (Indo) inhibit a family of enzymes called cyclooxygenase (COX). COX is also known as prostaglandin-endoperoxide synthase and is responsible for forming an important class of biological mediators called prostanoids (prostaglandins, prostacyclin, and thromboxane). COX converts arachidonic acid (a fatty acid that is released in injury or inflammation) into prostanoids, the most powerful vasodilators and inflammatory agents in our body. There are three kinds of COX: COX-1, COX-2, and COX-3. Aspirin, Ibuprofen (Ibu), and Indomethacin (Indo) inhibit all types of COX. Some people may remember COX-2 inhibitors called Vioxx and Celebrex. The former was taken off the market in 2004 because it increases the risk of heart attacks. Note that acetaminophen (Tylenol) may block COX-2 [2].

    The paper by Fu, et al. [3] is of interest because it shows that ibuprofen and indomethacin effectively block rhoA to increase axonal growth whereas naproxen (another COX inhibitor) does not block RhoA and also does not increase neurite growth. Fu, et al. showed that Ibu and Indo both significantly reduced RhoA activity in culture and stimulated neurite outgrowth. Peer reviewers for the Journal of Neuroscience think that the findings are significant. More important, their work has been supported by research from several other laboratories who not only showed that COX inhibitors promote axonal growth [4] but also myelination [5]. This is the way science works. If the Fu, et al. study could not be reproduced by other scientists, it would simply go down the river of irreproducible scientific work. However, it has been reproduced.

    RhoA is the intracellular messenger that mediates the effects of growth inhibitors such as Nogo A and CSPG. 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?

    Wise.

    References
    1. Wu JC, Chen YC, Liu L, Chen TJ, Huang WC, Cheng H and Tung-Ping S (2012). Increased risk of stroke after spinal cord injury: a nationwide 4-year follow-up cohort study. Neurology 78: 1051-7. Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan. OBJECTIVE: Spinal cord injury (SCI) is associated with a higher risk of cardiovascular diseases but whether or not the risk of cerebrovascular disease also increases remains unclear. This study aimed to evaluate the incidence of stroke in patients with disability caused by SCI. METHODS: Study subjects were identified from a nationwide cohort of 18,690,066 people from 1998 to 2002 that was divided into an SCI group (n = 2,806), who were disabled from SCI, and a comparison group (n = 28,060), composed of age-, sex-, and propensity score- matched control subjects. Every subject was followed up for 4 years, unless they died or had a stroke by December 31, 2006. Kaplan-Meier and Cox regression analyses were performed. RESULTS: The incidence rate of stroke in the SCI group (5.96 per 1,000 person-years) was higher than that of the comparison group (p < 0.001). Stroke was more likely to occur in the SCI group than in the comparison group (crude hazard ratio 2.93, p < 0.001; adjusted hazard ratio 2.85, p < 0.001). In the SCI group, the incidence of ischemic stroke was higher than that of hemorrhagic stroke (incidence rate ratio 3.42, p < 0.001). CONCLUSIONS: SCI patients with disability are at a higher risk of stroke, especially the ischemic type. Strategies to prevent stroke are therefore suggested for them.
    2. Hinz, B., Cheremina, O., & Brune, K. (2007). Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man. The FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, 22(2), 383–390. ABSTRACT For more than three decades, acetamin- ophen (INN, paracetamol) has been claimed to be devoid of significant inhibition of peripheral prosta- noids. Meanwhile, attempts to explain its action by inhibition of a central cyclooxygenase (COX)-3 have been rejected. The fact that acetaminophen acts functionally as a selective COX-2 inhibitor led us to investigate the hypothesis of whether it works via preferential COX-2 blockade. Ex vivo COX inhibition and pharmacokinetics of acetaminophen were assessed in 5 volunteers receiving single 1000 mg doses orally. Coagulation-induced thromboxane B2 and lipopolysaccharide- induced prostaglandin E2 were measured ex vivo and in vitro in human whole blood as indices of COX-1 and COX-2 activity. In vitro, acetaminophen elicited a 4.4- fold selectivity toward COX-2 inhibition (IC50=113.7 µmol/L for COX-1; IC50=25.8 µmol/L for COX-2). Following oral administration of the drug, maximal ex vivo inhibitions were 56% (COX-1) and 83% (COX-2). Acetaminophen plasma concentrations remained above the in vitro IC50 for COX-2 for at least 5 h postadmin- istration. Ex vivo IC50 values (COX-1: 105.2 µmol/L; COX-2: 26.3 µmol/L) of acetaminophen compared favorably with its in vitro IC50 values. In contrast to previous concepts, acetaminophen inhibited COX-2 by more than 80%, i.e., to a degree comparable to nonste- roidal antiinflammatory drugs (NSAIDs) and selective COX-2 inhibitors. However, a >95% COX-1 blockade relevant for suppression of platelet function was not achieved. Our data may explain acetaminophen’s anal- gesic and antiinflammatory action as well as its superior overall gastrointestinal safety profile compared with NSAIDs. In view of its substantial COX-2 inhibition, recently defined cardiovascular warnings for use of COX-2 inhibitors should also be considered for acetaminophen.
    3. Fu Q, Hue J and Li S (2007). Nonsteroidal anti-inflammatory drugs promote axon regeneration via RhoA inhibition. J Neurosci 27: 4154-64. Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. After a CNS injury in the adult mammals, axonal regeneration is very limited because of the reduced intrinsic growth capacity and nonpermissive environment for axonal elongation. The growth inhibitions from CNS myelin and astroglial chondroitin sulfate proteoglycans partially account for the lack of CNS repair. Here, we show that the nonsteroidal antiinflammatory drugs (NSAIDs) ibuprofen and indomethacin, the drugs widely used as pain relievers in the clinic, can surmount axon growth restrictions from myelin and proteoglycans by potently inhibiting their downstream pathway RhoA signal. Similar to Rho and Rock inhibitors C3 transferase or Y27632 [(R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide], both NSAID drugs stimulate a significant neurite growth in the cultured dorsal root ganglion neurons exposed to the inhibitory substrates. Systemic administration of ibuprofen to spinal cord-lesioned rodents reverses the active RhoA signal around injury area measured via Rho-GTP binding assay. Subcutaneous injections of ibuprofen via minipumps to rats with a thoracic spinal cord transection or contusion injury result in substantial corticospinal and serotonergic axon sprouting in the caudal spinal cord and promote locomotor functional recovery, even delaying the treatment 1 week after trauma. In contrast, the non-RhoA-inhibiting NSAID naproxen does not have the axon growth-promoting effects on cultured or lesioned neurons. These studies demonstrate the therapeutic potential of RhoA-inhibiting NSAIDs in treating CNS injuries characterized by axonal disconnection including spinal cord injury.
    4. Kopp MA, Liebscher T, Niedeggen A, Laufer S, Brommer B, Jungehulsing GJ, Strittmatter SM, Dirnagl U and Schwab JM (2012). Small-molecule-induced Rho-inhibition: NSAIDs after spinal cord injury. Cell and tissue research 349: 119-32. Department of Neurology and Experimental Neurology, Spinal Cord Injury Research, Charite-Universitatsmedizin Berlin, Chariteplatz 1, 10117 Berlin, Germany. Limited axonal plasticity within the central nervous system (CNS) is a major restriction for functional recovery after CNS injury. The small GTPase RhoA is a key molecule of the converging downstream cascade that leads to the inhibition of axonal re-growth. The Rho-pathway integrates growth inhibitory signals derived from extracellular cues, such as chondroitin sulfate proteoglycans, Nogo-A, myelin-associated glycoprotein, oligodendrocyte-myelin glycoprotein, Ephrins and repulsive guidance molecule-A, into the damaged axon. Consequently, the activation of RhoA results in growth cone collapse and finally outgrowth failure. 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. In addition, RhoA-inhibition reduces apoptotic cell death and secondary damage and improves locomotor recovery in clinically relevant models after experimental spinal cord injury (SCI). Unexpectedly, a subset of "small molecules" from the group of non-steroid anti-inflammatory drugs, particularly the FDA-approved ibuprofen, has recently been identified as (1) inhibiting RhoA-activation, (2) enhancing axonal sprouting/regeneration, (3) protecting "tissue at risk" (neuroprotection) and (4) improving motor recovery confined to realistic therapeutical time-frames in clinically relevant SCI models. Here, we survey the effect of small-molecule-induced RhoA-inhibition on axonal plasticity and neurofunctional outcome in CNS injury paradigms. Furthermore, we discuss the body of preclinical evidence for a possible clinical translation with a focus on ibuprofen and illustrate putative risks and benefits for the treatment of acute SCI.
    5. Xing B, Li H, Wang H, Mukhopadhyay D, Fisher D, Gilpin CJ and Li S (2011). RhoA-inhibiting NSAIDs promote axonal myelination after spinal cord injury. Exp Neurol 231: 247-60. Department of Neurology and Neuroscience Graduate Program, University of Texas Southwestern Medical Center, Dallas, TX 75390-8813, USA. Nonsteroidal anti-inflammatory drugs (NSAIDs) are extensively used to relieve pain and inflammation in humans via cyclooxygenase inhibition. Our recent research suggests that certain NSAIDs including ibuprofen suppress intracellular RhoA signal and improve significant axonal growth and functional recovery following axonal injury in the CNS. Several NSAIDs have been shown to reduce generation of amyloid-beta42 peptide via inactivation of RhoA signal, supporting potent RhoA-repressing function of selected NSAIDs. In this report, we demonstrate that RhoA-inhibiting NSAIDs ibuprofen and indomethacin dramatically reduce cell death of oligodendrocytes in cultures or along the white matter tracts in rats with a spinal cord injury. More importantly, we demonstrate that treatments with the RhoA-inhibiting NSAIDs significantly increase axonal myelination along the white matter tracts following a traumatic contusion spinal cord injury. In contrast, non-RhoA-inhibiting NSAID naproxen does not have such an effect. Thus, our results suggest that RhoA inactivation with certain NSAIDs benefits recovery of injured CNS axons not only by promoting axonal elongation, but by enhancing glial survival and axonal myelination along the disrupted axonal tracts. This study, together with previous reports, supports that RhoA signal is an important therapeutic target for promoting recovery of injured CNS and that RhoA-inhibiting NSAIDs provide great therapeutic potential for CNS axonal injuries in adult mammals.

    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?

  5. #385
    Dr Silver and Dr Young,
    Back in 2004 we were discussing the Glial scar and using Chase in a Baclofen Pump in a thread titled Dream Combination, I was understanding that Suzanne Poon was going to ask Dr Houng to try it in his combination he was working on....Do you think a pump like that could work as a delivery system??

  6. #386
    This thread gets increasingly more bizarre

  7. #387
    Quote Originally Posted by Wise Young View Post
    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.
    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.

  8. #388
    Senior Member lunasicc42's Avatar
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    papa joe, I too have a baclofan pump and had asked dr. Young that same question a long time ago. His answer was something to this effect:
    The baclofan pump delivers medicine into the CSF flow surrounding the Spinal cord and if you put some cocktail or something in the baclofan attempting to do something for you SCI, that cocktail would not get to it's intended target because the CSF flows downward and all the cells would just flow down and collect in the cuada equina.... My apologies to wise if I butchered that, it was a long time ago

    I was thinking theoretically, what if a person like jawaid with such a low injury had a baclofan pump, could a cocktail inserted into that do anything?

    I guess most of the cells would die before they reached the target anyway
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  9. #389
    Quote Originally Posted by Wise Young
    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?
    Last edited by Wise Young; 02-07-2013 at 06:39 AM. Reason: added quotation commands to distinguish between what Jerry and Wise said

  10. #390
    Quote Originally Posted by Christopher Paddon View Post
    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.
    Chris, it's incurable form of logorrea.

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