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    Originally posted by Christopher Paddon View Post
    Crabbyshark, why do you keep quoting papers at random pretending that you know what you're talking about? Do you seriously believe that ibuprofen is some sort of treatment for sci?
    Scientists seem to think so.
    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.

    Comment


      Please don't take this the wrong way, but after that - I"ll be skipping over your posts. Seriously ...
      Roses are red. Tacos are enjoyable. Don't blame immigrants, because you're unemployable.

      T-11 Flaccid Paraplegic due to TM July 1985 @ age 12

      Comment


        I am surprised to hear your opinion of the Horizon device. The consistency of spinal cord injury is based on many factors, including the device used to injure the spinal cord. The Impactor delivers the most precise and monitored impacts of any device (±1%). When carried out by an experienced surgeon following the model, it produces very small standard errors of means for BBB scores, white matter sparing, and impact parameters. I wish that you had told me of the difficulties that you student had with the model.

        Wise.

        Originally posted by jsilver View Post
        I understand your points about proper use of the BBB rating scale. I've sent several of my students to the Ohio State summer course to learn spinal cord injury techniques where Phil Popovich and Dana McTigue and colleagues do a marvelous job of training students. We have been doing BBB analyses now for a couple of years in the lab so I am getting more familiar with its pros and cons. I'm never impressed anymore with around 2 point improvements in the BBB especially at the low or high end of the scale in terms of potential translational potential. In speaking personally to all of the 3 B's who invented this rating scale (Basso, Breshnahan and Beattie) they suggest a great place to start is at a BBB score of 9-10. This way if a treatment causes harm you can more easily characterize a decline in score and if the treatment is highly potent then you can observe scores that climb above 13. The BBB scale is not linear and this particular part of the scale between 9-13 is especially important because it is more exciting when changes occur in this portion of the range. In this area animals progress form minimal weight bearing steps to fully coordinated walking. I am quite familiar with in vitro assays of neurite elongation and again I caution you that such small changes using low concentrations of inhibitory molecules as substrates worries me. Finally , when I see such small error bars on a plot of BBB scores over time that really concerns me because they used the NYU impactor. We purchased one of these but had quite variable results in terms of our ability to apply highly reproducible impacts to the cord. We had far to much variability in our control animals for my taste in terms of where their BBB scores stabilized over time. One of my students actually did a very careful comparison of the force produced by the NYU impactor versus the computerized Infinite Horizons Device (that we had to purchase at much greater expense) using a mechanical force plate. The data is quite convincing. The Infinite Horizons Device produces far more consistent impacts than does the NYU impactor. So seeing such tiny error bars tells me something is suspicious.

        Comment


          anti inflammatories are not going to cure chronic sci

          There have been a few ways suggested to decrease the inflammation very soon after the accident for example hyperbaric oxygen, anti inflammatories, steroids but how many have proved to be of any practical use?

          but I'll wager everyone on this forum has a chronic injury so these acute studies that keep getting posted are not of much relevance

          Scientists may test something in an acute situation primarly because it may be easier and then move on to a chronic situation more relevant to human injuries but I can't imagine ibuprofen will be of much use.

          But I'm no scientist - just my thoughts

          Comment


            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.

            Originally posted by Christopher Paddon View Post
            anti inflammatories are not going to cure chronic sci

            There have been a few ways suggested to decrease the inflammation very soon after the accident for example hyperbaric oxygen, anti inflammatories, steroids but how many have proved to be of any practical use?

            but I'll wager everyone on this forum has a chronic injury so these acute studies that keep getting posted are not of much relevance

            Scientists may test something in an acute situation primarly because it may be easier and then move on to a chronic situation more relevant to human injuries but I can't imagine ibuprofen will be of much use.

            But I'm no scientist - just my thoughts

            Comment


              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?

              Comment


                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; 5 Feb 2013, 3:12 AM.

                Comment


                  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; 5 Feb 2013, 8:03 AM.

                  Comment


                    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?

                    Comment


                      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??

                      Comment


                        This thread gets increasingly more bizarre

                        Comment


                          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.

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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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                            "what???? , you don't 'all' wear a poop sac?.... DAMNIT BONNIE, YOU LIED TO ME ABOUT THE POOP SAC!!!! "


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                              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; 7 Feb 2013, 6:39 AM. Reason: added quotation commands to distinguish between what Jerry and Wise said

                              Comment


                                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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