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Thread: Methylprednisolone soon to be replaced as treatment of choice for Acutes???

  1. #21
    Banned Faye's Avatar
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    Quote Originally Posted by bigbob
    Doctor Young, in all due respect even if MP works, its not a cure but a preventative for further damage.

    I am of course for a cure and for experimentation to try to find one, however, the discovery of MP should not be tauted as the reason to offer hope for a cure, it has nothing at all to do with regeneration. It didn't mean that a cure would follow.

    And, since the use of MP for traumatic sci in the early 90's what other treatment is currently used. In fifteen years where with all the grants, studies, papers, have we really gotten? What pisses me off is hearing schatten attached a email to hwang suggesting how money could be made from the stem cell hubs.
    Carl, how is there no logic in this statement?

    Many CC visitors are concerned about this very issue!

    Holding all researchers accountable as the AIDS activists so poignantly did, is good. Witness what happens when groupthink causes false data to slip into scientific publications, ie. Dr. Hwang.

    Prioritizing research rather than endless basic research is what we need most. Hopefully we are heading there.

    "There’s far too much unthinking respect given to authority,” Molly Ivins explained; “What you need is sustained outrage.”
    Kerr, Keirstead, McDonald, Stice and Jun Yan courageously work on ESCR to Cure SCI.

    Divisiveness comes from not following Christopher Reeve's ESCR lead.
    Young does ASCR.
    [I]I do not tear down CRPA, I ONLY make peopl

  2. #22
    Thanks Faye, I thought my reply was logical also, in addition being a devils advocate is an important function of helping to remove the lock that group think holds on groups like carecure More on Group Think in a new CC thread
    Don't ignore the Reeve Legacy, Remember he and Dana supported open research and fought hard for ESCR

    StemCellBattles

    Support H.R. 810

  3. #23
    What point are y'all trying to make here? Did Dr. Young do something dreadful that you are trying to notify us about?

  4. #24
    Senior Member WM's Avatar
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    A bit off topic, but am saying it anyway. Everytime I read something about MP I get depressed. My relative was injured in 1989. He just missed being injured "at a better time". He told me the other day that after he came out of the coma his leg itched. This was a few days after the accident. He said he couldn't move his legs but it was a definite itch, and when the nurse would scratch the itch for him, he knew she was scratching it. Then, nothing. He had no surgery or anything to his spine because of his other injuries. That makes me think that if he'd been injured a bit later, and had MP, maybe he would have retained and regained more. Oh well, I am happy that MP existed when my friend was injured in July. He got MP and he's getting return, slowly but surely. Can't say if it was the MP, can't say if it was not, but I'm sure glad he got it either way!

    It would be great if something even more effective was coming along. I certainly do believe that Dr. Young would be glad and not sorry for having MP "bumped" for something more effective. To think otherwise is foolish.
    "I just want you to know, it was the best time ever." J.F.F.

  5. #25
    Quote Originally Posted by betheny
    What point are y'all trying to make here? Did Dr. Young do something dreadful that you are trying to notify us about?
    Not at all.

    Would be nice though if some dropped their overprotective ways and allowed for a different point of view without the usual your a culprit innuendos.

    Kinda says alot, that DA gets a big smooooch for saying I'm worse than him. Seems like you encourage this type of behavior.

    As a moderator you seem to lack the skills that applaud openmindedness that a information website like this would/should encourage.
    Don't ignore the Reeve Legacy, Remember he and Dana supported open research and fought hard for ESCR

    StemCellBattles

    Support H.R. 810

  6. #26
    Quote Originally Posted by bigbob
    Doctor Young, in all due respect even if MP works, its not a cure but a preventative for further damage.

    I am of course for a cure and for experimentation to try to find one, however, the discovery of MP should not be tauted as the reason to offer hope for a cure, it has nothing at all to do with regeneration. It didn't mean that a cure would follow.
    And, since the use of MP for traumatic sci in the early 90's what other treatment is currently used. In fifteen years where with all the grants, studies, papers, have we really gotten? What pisses me off is hearing schatten attached a email to hwang suggesting how money could be made from the stem cell hubs.
    Bob,
    If a repair function for a severe SCI were easy..it would already have been here decades ago.
    And MP is a treatment modality...not a cure.

    Vaccines are not a cure either..I can attest to that..but don't want to make a Dr. Salk voodoo doll.

    Repairs will be developed. And they may not be perfect or one size fits all..that's life..live it.
    Life isn't about getting thru the storm but learning to dance in the rain.

  7. #27
    All I'm asking is what your point is, Bob. I understand DA's point. And yes, I lack many many skills.

    Holiday smooches to Bob for being consistent!

  8. #28
    Banned Faye's Avatar
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    Quote Originally Posted by WM
    A bit off topic, but am saying it anyway. Everytime I read something about MP I get depressed. My relative was injured in 1989. He just missed being injured "at a better time". He told me the other day that after he came out of the coma his leg itched. This was a few days after the accident. He said he couldn't move his legs but it was a definite itch, and when the nurse would scratch the itch for him, he knew she was scratching it. Then, nothing. He had no surgery or anything to his spine because of his other injuries. That makes me think that if he'd been injured a bit later, and had MP, maybe he would have retained and regained more.
    WM, there are so many factors that come into play. I wonder what would have happened if he had been able to have the decompression surgery to prevent the cascade of apoptosis.

    I do know what took away the little head movement Jason woke up with after his three day coma........, it was the general anesthesia commonly refered to as "mother's milk" for its color and its supposed "safety". The anesthesia was administered to do a SPECT study AFTER Jason woke up from his coma.

    Despite administration of high dose MP, Jason did not recover any movement.

    I regret two things: that I allowed them to administer dilantin when he first presented and he was mis-labeled as having "new-onset seizures"
    Dilantin loweres blood pressure which prohibits what little blood can still get past the clot to be pushed through....

    AND after Jason had been on valium for four months in the PICU and in rehab, I found out that rats who had been administered valium never recovered motor function......( valium is routinely used as palliative care to make "patients more manageable").
    Desperately and promptly I weaned Jason off the valium.

    We tried to salvage as many cells as possible that first year post LIS ( apoptosis can continue that long after injury), by doing hyperbaric oxygen treatments and going to the primavera clinic on the island of Cypress.
    Last edited by Faye; 12-23-2005 at 08:26 PM.

    "There’s far too much unthinking respect given to authority,” Molly Ivins explained; “What you need is sustained outrage.”
    Kerr, Keirstead, McDonald, Stice and Jun Yan courageously work on ESCR to Cure SCI.

    Divisiveness comes from not following Christopher Reeve's ESCR lead.
    Young does ASCR.
    [I]I do not tear down CRPA, I ONLY make peopl

  9. #29
    Erythropoietin (EPO) is indeed a promising drug. Several years ago, several groups including Kaptanglu, et al. (2004) and Gorio, et al. (2002) reported that erythropoietin is neuroprotective in rat compression, ischemia, and contusion models of spinal cord injury. This elicited a great deal of excitment in the field and there is consideration of EPO as a promising treatment for acute human spinal cord injury (Fehlings, et al., 2005; Jelkmann, et al., 2005) and other neurological conditions (Juul, 2004)

    Additional papers have come out recently. In addition to the paper that was cited below, Savino, et al. (2005) reported that EPO may be neuroprotective in rat EAE, a model of MS. This had been earlier reported by Li, et al. (2004). Gorio, et al. (2005) found that MP neutralizes the beneficial effects of EPO in rat spinal cord contusion. Demers, et al. (2005) reported that EPO protects dopaminergic neurons in rats after neonatal hypoxia-ischemia. Spinal cord injury upregulated both EPO and EPO receptors in the spinal cord (Grasso, et al., 2005). Kilic, et al. (2005) found that EPO prevents degeneration of retinal ganglionic cells after optic nerve injury. These effects of EPO appears to be mediated not only by EPO but by derivatives of EPO that are not stimulate blood cell production (Doggrell, 2004; Brines, et al. 2004; Leist, et al., 2004). Colman & Brines (2004) suggested that EPO is a protective cytokine in acute critical illnesses, acting on EPO receptors in the central and peripheral nervous system (Gassmann, et al., 2003; Hassan, et al., 2004). Kumrai, et al., (2003) found that EPO is neuroprotective in hypoxic-ischemic brain injury in neonatal rats.

    EPO is already used in humans to stimulate blood cells production. For example, Regis, et al. (2005) and Garcia-Erce, et al. (2005) used EPO to treat children with EPO to stimulate blood production so that blood can be collected from them and then used for autologous transfusions after spinal surgery. Keswani, et al. (2004) found that EPO is neuroprotective in models of HIV-induced sensory neuropathy in patients. Keast & Fraser (2004) reported that EPO is effective in treating chronic skin ulcers in humans. In summary, this EPO is a promising and safe therapy that should be tried in human spinal cord injury, particularly those resulting from ischemia and hypoxia.

    Publications cited
    1. Kaptanoglu E, Solaroglu I, Okutan O, Surucu HS, Akbiyik F and Beskonakli E (2004). Erythropoietin exerts neuroprotection after acute spinal cord injury in rats: effect on lipid peroxidation and early ultrastructural findings. Neurosurg Rev 27: 113-20. Lipid peroxidation has been reported to play an important role in spinal cord injury (SCI). Erythropoietin (EPO) is a hematopoietic growth factor that stimulates proliferation and differentiation of erythroid precursor cells and is also known to exert neurotrophic activity in the central nervous system. The purpose of this study was to investigate the effectiveness of recombinant human EPO in attenuating the severity of experimental SCI. Rats were divided into seven groups. Controls (1) received only laminectomy. The trauma-only group (2) underwent 50-g/cm contusion injury and had no medication. In group 3, 30 mg/kg of methylprednisolone was introduced. The vehicle group (4) received vehicle solution containing human serum albumin, which is a solvent of EPO. Groups 5, 6, and 7 received 100 IU/kg, 1,000 IU/kg, and 5,000 IU/kg of EPO, respectively. All treatments were given as single doses, intraperitoneally, immediately after injury. Thiobarbituric acid-reactive substances were estimated to demonstrate lipid peroxidation, and ultrastructure was evaluated by electron microscopy. The results showed that lipid peroxidation by-products increased after injury. Administration of EPO and methylprednisolone sodium succinate (MPSS) reduced thiobarbituric acid-reactive substances after trauma. The best biochemical results were obtained with 5,000 IU/kg of EPO. Electron microscopic findings showed that EPO protected the spinal cord from injury. Although 1,000 IU/kg and 5,000 IU/kg of EPO inhibited lipid peroxidation better than MPSS, ultrastructural neuroprotection was similar. Department of Neurosurgery, Ankara Numune Education and Research Hospital, Ankara, Turkey. erkankaptanoglu@yahoo.com http://www.ncbi.nlm.nih.gov/entrez/q..._uids=12920606
    2. Gorio A, Gokmen N, Erbayraktar S, Yilmaz O, Madaschi L, Cichetti C, Di Giulio AM, Vardar E, Cerami A and Brines M (2002). Recombinant human erythropoietin counteracts secondary injury and markedly enhances neurological recovery from experimental spinal cord trauma. Proc Natl Acad Sci U S A 99: 9450-5. Erythropoietin (EPO) functions as a tissue-protective cytokine in addition to its crucial hormonal role in red cell production. In the brain, for example, EPO and its receptor are locally produced, are modulated by metabolic stressors, and provide neuroprotective and antiinflammatory functions. We have previously shown that recombinant human EPO (rhEPO) administered within the systemic circulation enters the brain and is neuroprotective. At present, it is unknown whether rhEPO can also improve recovery after traumatic injury of the spinal cord. To evaluate whether rhEPO improves functional outcome if administered after cord injury, two rodent models were evaluated. First, a moderate compression of 0.6 N was produced by application of an aneurysm clip at level T3 for 1 min. RhEPO (1,000 units per kg of body weight i.p.) administered immediately after release of compression was associated with partial recovery of motor function within 12 h after injury, which was nearly complete by 28 days. In contrast, saline-treated animals exhibited only poor recovery. In the second model used, rhEPO administration (5,000 units per kg of body weight i.p. given once 1 h after injury) also produced a superior recovery of function compared with saline-treated controls after a contusion of 1 N at level T9. In this model of more severe spinal cord injury, secondary inflammation was also markedly attenuated by rhEPO administration and associated with reduced cavitation within the cord. These observations suggest that rhEPO provides early recovery of function, especially after spinal cord compression, as well as longer-latency neuroprotective, antiinflammatory and antiapoptotic functions. Laboratory of Pharmacology, Department of Medicine, Surgery and Odontoiatry, Faculty of Medicine, University of Milan, Milan 20142, Italy. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=12082184
    3. Gorio A, Madaschi L, Di Stefano B, Carelli S, Di Giulio AM, De Biasi S, Coleman T, Cerami A and Brines M (2005). Methylprednisolone neutralizes the beneficial effects of erythropoietin in experimental spinal cord injury. Proc Natl Acad Sci U S A 102: 16379-84. Inflammation plays a major pathological role in spinal cord injury (SCI). Although antiinflammatory treatment using the glucocorticoid methyprednisolone sodium succinate (MPSS) improved outcomes in several multicenter clinical trials, additional clinical experience suggests that MPSS is only modestly beneficial in SCI and poses a risk for serious complications. Recent work has shown that erythropoietin (EPO) moderates CNS tissue injury, in part by reducing inflammation, limiting neuronal apoptosis, and restoring vascular autoregulation. We determined whether EPO and MPSS act synergistically in SCI. Using a rat model of contusive SCI, we compared the effects of EPO [500-5,000 units/kg of body weight (kg-bw)] with MPSS (30 mg/kg-bw) for proinflammatory cytokine production, histological damage, and motor function at 1 month after a compression injury. Although high-dose EPO and MPSS suppressed proinflammatory cytokines within the injured spinal cord, only EPO was associated with reduced microglial infiltration, attenuated scar formation, and sustained neurological improvement. Unexpectedly, coadministration of MPSS antagonized the protective effects of EPO, even though the EPO receptor was up-regulated normally after injury. These data illustrate that the suppression of proinflammatory cytokines alone does not necessarily prevent secondary injury and suggest that glucocorticoids should not be coadministered in clinical trials evaluating the use of EPO for treatment of SCI. Pharmacological Laboratories, Departments of Medicine, Surgery, and Dentistry, Polo Ospedale San Paolo, Faculty of Medicine, University of Milan, Via Celoria 26, 20133 Milan, Italy. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16260722
    4. Fehlings MG and Baptiste DC (2005). Current status of clinical trials for acute spinal cord injury. Injury 36 Suppl 2: B113-22. Acute spinal cord injury (ASCI) occurs as a result of physical disruption of spinal cord axons through the epicenter of injury leading to deficits in motor, sensory, and autonomic function. This is a debilitating neurological disorder common in young adults that often requires life-long therapy and rehabilitative care, placing a significant burden on our healthcare system. While no cure exists, research has identified various pharmacological compounds that specifically antagonize primary and secondary mechanisms contributing to the etiology of ASCI. Several compounds including methylprednisolone (MPSS), GM-1 ganglio-side, thyrotropin releasing hormone (TRH), nimodipine, and gacyclidine have been tested in prospective randomized clinical trials of ASCI. MPSS and GM-1 ganglioside have shown evidence of modest benefits. Clearly trials of improved neuroprotective agents are required. Promising potential therapies for ASCI include riluzole, minocycline, erythropoietin, and the fusogen polyethylene glycol, as well as mild hypothermia. Division of Neurosurgery and Cell and Molecular Biology, Toronto Western Research Institute and Krembil Neuroscience Centre, Toronto Western Hospital, University Health Network, University of Toronto, Ontario, Canada. Michael.Fehlings@uhn.on.ca http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15993112
    5. Jelkmann W (2005). Effects of erythropoietin on brain function. Curr Pharm Biotechnol 6: 65-79. This article is a selective extension of a review on recombinant human erythropoietin (rHu-EPO) as an anti-anaemic drug, published in this journal in 2000. It summarises the recent advances in understanding the molecular mechanisms by which the hypoxia-inducible transcription factor 1 (HIF-1) regulates O(2)-dependent genes, including the EPO gene in brain. With respect to brain integrity, EPO exerts positive effects in two different ways. First, rHu-EPO raises the blood haemoglobin concentration and, hence, the O(2) capacity of the blood in anaemic patients. The restored O(2) supply ameliorates attention difficulties and psychomotor slowing, improves memory capacities and normalises neuroendocrine functions. Second, EPO can act as a neurotrophic and neuroprotective factor directly in brain. EPO and its receptor are expressed in the cerebral cortex, cerebellum, hippocampus, pituitary gland and spinal cord. In vitro EPO protects against glutamate-induced cell death in a dose-dependent way. In animal models it reduces volumes of brain ischaemia, protects the cortex from hypoxic damage and leads to survival of neurons and synapses. One can expect that in the near future rHu-EPO will be used therapeutically in cerebral ischaemia, brain trauma, inflammatory diseases, and neural degenerative disorders. A first clinical trial has shown the neuroprotective effectiveness of the drug in cerebral ischaemia. Institut fur Physiologie, Medizinische Universitat zu Lubeck, Ratzeburger Allee 160, 23538 Lubeck, Germany. jelkmann@physio.uni-luebeck.de http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15727557
    6. Juul S (2004). Recombinant erythropoietin as a neuroprotective treatment: in vitro and in vivo models. Clin Perinatol 31: 129-42. The biologic effects of erythropoietin in the central and peripheral nervous system involve the activation of its specific cell surface receptor and corresponding signal transduction pathways. This article reviews the neuroprotective effects of erythropoietin in brain, emphasizing the progress made using in vitro and in vivo research models. Division of Neonatology, Department of Pediatrics, University of Washington, PO Box 356320, Seattle, WA 98195, USA. sjuul@u.washington.edu http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15183662
    7. Savino C, Pedotti R, Baggi F, Ubiali F, Gallo B, Nava S, Bigini P, Barbera S, Fumagalli E, Mennini T, Vezzani A, Rizzi M, Coleman T, Cerami A, Brines M, Ghezzi P and Bianchi R (2005). Delayed administration of erythropoietin and its non-erythropoietic derivatives ameliorates chronic murine autoimmune encephalomyelitis. J Neuroimmunol Erythropoietin (EPO) mediates a wide range of neuroprotective activities, including amelioration of disease and neuroinflammation in rat models of EAE. However, optimum dosing parameters are currently unknown. In the present study, we used a chronic EAE model induced in mice by immunization with the myelin oligodendrocyte glycoprotein peptide (MOG(35-55)) to compare the effect of EPO given with different treatment schedules. EPO was administered intraperitoneally at 0.5, 5.0 or 50 mug/kg three times weekly starting from day 3 after immunization (preventive schedule), at the onset of clinical disease (therapeutic schedule) or 15 days after the onset of symptoms (late therapeutic schedule). The results show that EPO is effective even when given after the appearance of clinical signs of EAE, but with a reduced efficacy compared to the preventative schedule. To determine whether this effect requires the homodimeric EPO receptor (EPOR(2))-mediated hematopoietic effect of EPO, we studied the effect of carbamylated EPO (CEPO) that does not bind EPOR(2). CEPO, ameliorated EAE without changing the hemoglobin concentration. Another non-erythropoietic derivative, asialoEPO was also effective. Both EPO and CEPO equivalently decreased the EAE-associated production of TNF-alpha, IL-1beta and IL-1Ra in the spinal cord, and IFN-gamma by peripheral lymphocytes, indicating that their action involves targeting neuroinflammation. The lowest dosage tested appeared fully effective. The possibility to dissociate the anti-neuroinflammatory action of EPO from its hematopoietic action, which may cause undesired side effects in non-anemic patients, present new avenues to the therapy of multiple sclerosis. "Mario Negri" Institute for Pharmacological Research, 20157, Milan, Italy. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16337691
    8. Demers EJ, McPherson RJ and Juul SE (2005). Erythropoietin protects dopaminergic neurons and improves neurobehavioral outcomes in juvenile rats after neonatal hypoxia-ischemia. Pediatr Res 58: 297-301. Brain injury as a result of hypoxia-ischemia remains a common cause of morbidity and mortality in neonates. No effective therapy is currently available. The hematopoietic cytokine erythropoietin (Epo) provides neuroprotection in many adult models of brain injury and is currently being investigated as a therapeutic agent for human stroke and spinal cord injury. We tested the hypothesis that recombinant Epo (rEpo) would improve neurobehavioral outcomes after neonatal hypoxic-ischemic brain injury. Postnatal day 7 rats underwent right common carotid artery occlusion followed by a 90-min exposure to 8% oxygen. Rats were subsequently treated with rEpo or placebo. Sensory neglect and apomorphine-induced rotation were measured at P27 and P28. Rats were killed at P30, blood was drawn, and the brains were perfusion-fixed for histology and immunohistochemistry. No differences in gross brain injury between rEpo and placebo-treated rats were found. Neonatal rEpo treatment protected dopamine neurons as indicated by the preservation of tyrosine hydroxylase-positive cells in the substantia nigra pars compacta and ventral tegmental area. rEpo treatment also improved functional outcomes by reducing sensory neglect and preventing the rotational asymmetry seen in control animals. No differences in hematocrit, white blood cell counts, neutrophil counts, or platelet counts were measured. We observed that rEpo treatment protected mesencephalic dopamine neurons and reduced the degree of behavioral asymmetries at 4 wk of life. On the basis of these findings, we conclude that further studies investigating the safety and efficacy of high-dose rEpo as a neuroprotective strategy are indicated in neonatal models of hypoxic-ischemic brain injury. Department of Pediatrics, University of Washington, Seattle, Washington 98195, USA. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16055937
    9. Demers EJ, McPherson RJ and Juul SE (2005). Erythropoietin protects dopaminergic neurons and improves neurobehavioral outcomes in juvenile rats after neonatal hypoxia-ischemia. Pediatr Res 58: 297-301. Brain injury as a result of hypoxia-ischemia remains a common cause of morbidity and mortality in neonates. No effective therapy is currently available. The hematopoietic cytokine erythropoietin (Epo) provides neuroprotection in many adult models of brain injury and is currently being investigated as a therapeutic agent for human stroke and spinal cord injury. We tested the hypothesis that recombinant Epo (rEpo) would improve neurobehavioral outcomes after neonatal hypoxic-ischemic brain injury. Postnatal day 7 rats underwent right common carotid artery occlusion followed by a 90-min exposure to 8% oxygen. Rats were subsequently treated with rEpo or placebo. Sensory neglect and apomorphine-induced rotation were measured at P27 and P28. Rats were killed at P30, blood was drawn, and the brains were perfusion-fixed for histology and immunohistochemistry. No differences in gross brain injury between rEpo and placebo-treated rats were found. Neonatal rEpo treatment protected dopamine neurons as indicated by the preservation of tyrosine hydroxylase-positive cells in the substantia nigra pars compacta and ventral tegmental area. rEpo treatment also improved functional outcomes by reducing sensory neglect and preventing the rotational asymmetry seen in control animals. No differences in hematocrit, white blood cell counts, neutrophil counts, or platelet counts were measured. We observed that rEpo treatment protected mesencephalic dopamine neurons and reduced the degree of behavioral asymmetries at 4 wk of life. On the basis of these findings, we conclude that further studies investigating the safety and efficacy of high-dose rEpo as a neuroprotective strategy are indicated in neonatal models of hypoxic-ischemic brain injury. Department of Pediatrics, University of Washington, Seattle, Washington 98195, USA. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16055937
    10. Li W, Maeda Y, Yuan RR, Elkabes S, Cook S and Dowling P (2004). Beneficial effect of erythropoietin on experimental allergic encephalomyelitis. Ann Neurol 56: 767-77. We have known for a long time that erythropoietin signaling plays a key role in bone marrow erythrocyte proliferation. However, recent studies have indicated that erythropoietin also may have protective effects on the nervous system. This unexpected role remains incompletely characterized. To investigate the potential neuroprotective role of erythropoietin in the central nervous system, we assessed its effects on a well-characterized autoimmune demyelinating model of multiple sclerosis-myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE) in the mouse. We found that erythropoietin administered intravenously for 14 days after the onset of symptoms reduced both disease severity and duration of maximum impairment at dose levels as low as 50U/kg (p < 0.001). We assessed the neuropathology of diseased spinal cords and found that erythropoietin-treated EAE animals had reduced axonal damage, inflammatory cell infiltration and demyelination, and diminished blood-brain barrier leakage when compared with saline-treated EAE controls. Moreover, the pronounced upregulation of spinal cord major histocompatibility complex (MHC) class II expression found in saline-treated EAE was significantly reduced in erythropoietin-treated animals, a finding we replicated in vitro, using microglial cultures. The notion that short-term erythropoietin therapy might be of clinical benefit in human autoimmune demyelinating diseases needs investigation. Neurology Service (127), Department of Veterans Affairs, New Jersey Health Care System, East Orange, NJ, USA. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15562412
    11. Grasso G, Sfacteria A, Passalacqua M, Morabito A, Buemi M, Macri B, Brines ML and Tomasello F (2005). Erythropoietin and erythropoietin receptor expression after experimental spinal cord injury encourages therapy by exogenous erythropoietin. Neurosurgery 56: 821-7; discussion 821-7. OBJECTIVE: Erythropoietin (EPO) is a pleiotropic cytokine originally identified for its role in erythropoiesis. Recent studies have demonstrated that EPO and its receptor (EPO-R) are expressed in the central nervous system, where EPO exerts neuroprotective functions. Because the expression of the EPO and EPO-R network is poorly investigated in the central nervous system, the aim of the present study was to investigate whether the resident EPO and EPO-R network is activated in the injured nervous system. METHODS: A well-standardized model of compressive spinal cord injury in rats was used. EPO and EPO-R expression was determined by immunohistochemical analysis at 8 hours and at 2, 8, and 14 days in the spinal cord of injured and noninjured rats. RESULTS: In noninjured spinal cord, weak immunohistochemical expression of EPO and EPO-R was observed in neuronal and glial cells as well as in endothelial and ependymal cells. In injured rats, a marked increase of expression of EPO and EPO-R was observed in neurons, vascular endothelium, and glial cells at 8 hours after injury, peaking at 8 days, after which it gradually decreased. Two weeks after injury, EPO immunoreactivity was scarcely detected in neurons, whereas glial cells and vascular endothelium expressed strong EPO-R immunoreactivity. CONCLUSION: These observations suggest that the local EPO and EPO-R system is markedly engaged in the early stages after nervous tissue injury. The reduction in EPO immunoexpression and the increase in EPO-R staining strongly support the possible usefulness of a therapeutic approach based on exogenous EPO administration. Department of Neurosurgery, University of Messina, Messina, Italy. Giovanni.Grasso@unime.it http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15792521
    12. Kilic U, Kilic E, Soliz J, Bassetti CI, Gassmann M and Hermann DM (2005). Erythropoietin protects from axotomy-induced degeneration of retinal ganglion cells by activating ERK-1/-2. Faseb J 19: 249-51. Apart from its hematopoietic function, erythropoietin (Epo) exerts neuroprotective activity upon reduced oxygenation or ischemia of brain, retina, and spinal cord. To examine whether Epo has an impact on the retrograde degeneration of retinal ganglion cells (RGCs) following optic nerve transection in vivo, we made use of our transgenic mouse line tg21 that constitutively expresses human Epo preferentially in neuronal cells without inducing polycythemia. We show that the tg21 retina expresses human Epo and that RGCs in this mouse line carry the Epo receptor. Upon axotomy, the RGCs of Epo transgenic tg21 mice were protected against degeneration, as compared with wild-type control animals. Western blot analysis revealed decreased phosphorylation levels of STAT-5 and reduced expression of Bcl-XL in RGCs of axotomized tg21 animals, suggesting that the corresponding pathways are not crucial for Epo's neuroprotective activity. Increased phosphorylation levels of ERK-1/-2 and Akt, as well as decreased caspase-3 activity, however, were observed in injured tg21 retinae. Injection of selective inhibitors of ERK-1/-2 (PD98059) or Akt (Wortmannin) pathways into the vitreous space revealed that transgenic Epo protected the RGCs by a pathway involving ERK-1/-2 but not Akt. In view that axotomy-induced degeneration of RGC occurs slowly, and considering the earlier data on the safety and efficacy of Epo in human stroke patients, we predict the clinical implementation of recombinant human Epo not only in patients with acute ischemic stroke, but also with more delayed degenerative neurological diseases. Department of Neurology, University Hospital Zurich, Switzerland. uelkan.kilic@usz.ch http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15556972
    13. Doggrell SA (2004). A neuroprotective derivative of erythropoietin that is not erythropoietic. Expert Opin Investig Drugs 13: 1517-9. In addition to its well-known erythropoetic effect, erythropoietin (EPO) has also been shown to be neuroprotective in various animal models. In contrast to EPO, carbamylated EPO (CEPO) does not bind to the EPO receptor on UT7 cells or have any haematopoietic/proliferative activity on these cells. In vivo studies in mice and rats showed that even high doses of CEPO for long periods are not erythropoietic. However, in common with EPO, CEPO does inhibit the apoptosis associated with glutamate toxicity in hippocampal cells. Like EPO, CEPO is neuroprotective in a wide range of animal models of neurotoxicity: middle cerebral artery occlusion model of ischaemic stroke, sciatic nerve compression, spinal cord depression, experimental autoimmune encephalomyelitis and peripheral diabetic neuropathy. To date, EPO and CEPO have been exciting developments in the quest for the treatment of various types of neurotoxicity. The development of CEPO should continue. School of Biomedical Sciences, University of Queensland, Australia. s.doggrell@xtra.com http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15500399
    14. Brines M, Grasso G, Fiordaliso F, Sfacteria A, Ghezzi P, Fratelli M, Latini R, Xie QW, Smart J, Su-Rick CJ, Pobre E, Diaz D, Gomez D, Hand C, Coleman T and Cerami A (2004). Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor. Proc Natl Acad Sci U S A 101: 14907-12. The cytokine erythropoietin (Epo) is tissue-protective in preclinical models of ischemic, traumatic, toxic, and inflammatory injuries. We have recently characterized Epo derivatives that do not bind to the Epo receptor (EpoR) yet are tissue-protective. For example, carbamylated Epo (CEpo) does not stimulate erythropoiesis, yet it prevents tissue injury in a wide variety of in vivo and in vitro models. These observations suggest that another receptor is responsible for the tissue-protective actions of Epo. Notably, prior investigation suggests that EpoR physically interacts with the common beta receptor (betacR), the signal-transducing subunit shared by the granulocyte-macrophage colony stimulating factor, and the IL-3 and IL-5 receptors. However, because betacR knockout mice exhibit normal erythrocyte maturation, betacR is not required for erythropoiesis. We hypothesized that betacR in combination with the EpoR expressed by nonhematopoietic cells constitutes a tissue-protective receptor. In support of this hypothesis, membrane proteins prepared from rat brain, heart, liver, or kidney were greatly enriched in EpoR after passage over either Epo or CEpo columns but covalently bound in a complex with betacR. Further, antibodies against EpoR coimmunoprecipitated betacR from membranes prepared from neuronal-like P-19 cells that respond to Epo-induced tissue protection. Immunocytochemical studies of spinal cord neurons and cardiomyocytes protected by Epo demonstrated cellular colocalization of Epo betacR and EpoR. Finally, as predicted by the hypothesis, neither Epo nor CEpo was active in cardiomyocyte or spinal cord injury models performed in the betacR knockout mouse. These data support the concept that EpoR and betacR comprise a tissue-protective heteroreceptor. Kenneth S. Warren Institute, Ossining, NY 10563, USA. mbrines@kswi.org http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15456912
    15. Leist M, Ghezzi P, Grasso G, Bianchi R, Villa P, Fratelli M, Savino C, Bianchi M, Nielsen J, Gerwien J, Kallunki P, Larsen AK, Helboe L, Christensen S, Pedersen LO, Nielsen M, Torup L, Sager T, Sfacteria A, Erbayraktar S, Erbayraktar Z, Gokmen N, Yilmaz O, Cerami-Hand C, Xie QW, Coleman T, Cerami A and Brines M (2004). Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science 305: 239-42. Erythropoietin (EPO) is both hematopoietic and tissue protective, putatively through interaction with different receptors. We generated receptor subtype-selective ligands allowing the separation of EPO's bioactivities at the cellular level and in animals. Carbamylated EPO (CEPO) or certain EPO mutants did not bind to the classical EPO receptor (EPOR) and did not show any hematopoietic activity in human cell signaling assays or upon chronic dosing in different animal species. Nevertheless, CEPO and various nonhematopoietic mutants were cytoprotective in vitro and conferred neuroprotection against stroke, spinal cord compression, diabetic neuropathy, and experimental autoimmune encephalomyelitis at a potency and efficacy comparable to EPO. H. Lundbeck A/S, 2500 Valby, Denmark. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15247477
    16. Coleman T and Brines M (2004). Science review: recombinant human erythropoietin in critical illness: a role beyond anemia? Crit Care 8: 337-41. Erythropoiesis usually fails during severe illness because of a blunting of the kidney-erythropoietin (EPO)-bone marrow axis. In this setting, clinical studies have shown that recombinant human erythropoietin (rhEPO), administered in pharmacological amounts, significantly reduces the need for blood transfusions. In addition to the kidney, however, EPO is also produced locally by other tissues in a paracrine-autocrine manner. Here, similar to its role in the bone marrow, EPO rescues cells from apoptosis. Additionally, EPO reduces inflammatory responses, restores vascular autoregulation, and promotes healing. The results of many studies (including a phase II clinical trial in ischemic stroke) demonstrate that rhEPO protects the brain, spinal cord, retina, heart, and kidney from ischemic and other types of injury. Although rhEPO is efficacious in the treatment of EPO-deficient anemia during illness, inadequate effort has been devoted to determining whether direct tissue protection might also result from its administration. Here, we speculate on the potential utility of EPO as a protective cytokine in the context of acute critical illness and suggest key parameters required for a proof-of-concept clinical study. The Kenneth S Warren Institute, Kitchawan, New York, USA. tcoleman@kswi.org http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15469595
    17. Gassmann M, Heinicke K, Soliz J, Ogunshola OO, Marti HH, Hofer T, Grimm C, Heinicke I and Egli B (2003). Non-erythroid functions of erythropoietin. Adv Exp Med Biol 543: 323-30. The oxygen-dependent, renal cytokine eythropoietin (Epo) is well known to increase red cell production. Binding of Epo to the Epo receptor (EpoR) represses apoptosis of erythroid progenitor cells, thereby allowing their final maturation. We and others showed that Epo and its receptor are expressed in many other tissues, including brain, spinal cord, retina and testis. The presence of a blood barrier suggests that Epo plays a local role in these organs. Indeed, therapeutically applied or hypoxically induced Epo has been shown to reduce the infarct volume in various stroke animal models, to prevent retinal degeneration, and to ameliorate spinal cord injury. In a study conducted by Ehrenreich and colleagues, stroke patients treated with Epo showed reduced infarct volume, fast neurological recovery and improved clinical outcome. In analogy to its function on erythroid progenitor cells, this neuroprotective effect of Epo might be explained by repression of programmed cell death. Apart from neuroprotection, there is an assumption that Epo present in breast milk has the potential to protect against mother-to-infant transmission of HIV. When using Epo at high doses for longer time periods; however, care has to be taken to control the resulting chronic polycythemia that most probably caused enlarged cerebral infarct volumes in a transgenic mouse model that due to Epo-overexpression reached hematocrit levels of about 0.8. Overall, these data strongly support the notion that Epo will soon find new applications in the clinic. Institute of Veterinary Physiology, University of Zurich, Switzerland. maxg@access.unizh.ch http://www.ncbi.nlm.nih.gov/entrez/q..._uids=14713131
    18. Hassan K, Gross B, Simri W, Rubinchik I, Cohen H, Jacobi J, Shasha SM and Kristal B (2004). The presence of erythropoietin receptors in the human peripheral nervous system. Clin Nephrol 61: 127-9. Erythropoietin (EPO) is a well-known hematopoietic factor and a major determinant of tissue oxygenation. EPO receptors have been identified on a wide variety of non-erythroid cell types including human central nervous system and peripheral nervous system of animal models. The presence or function of EPO receptors in human peripheral nervous system is unknown. By examining nerve segments from radicular and autonomic nerves using immunohistochemical methods, we demonstrated the presence of EPO receptors on myelin sheath of radicular nerves in the human peripheral nervous system. Nephrology and Hypertension Department, Western Galilee Hospital, Nahariya, Israel. drkamalh@hotmail.com http://www.ncbi.nlm.nih.gov/entrez/q..._uids=14989632
    19. Kumral A, Ozer E, Yilmaz O, Akhisaroglu M, Gokmen N, Duman N, Ulukus C, Genc S and Ozkan H (2003). Neuroprotective effect of erythropoietin on hypoxic-ischemic brain injury in neonatal rats. Biol Neonate 83: 224-8. Erythropoietin (Epo) prevents ischemia and hypoxia-induced neuronal death in vitro. Recent studies have shown that this cytokine also has in vivo neuroprotective effects in cerebral and spinal ischemia in adult rodents. In this study, we aimed to investigate the effect of systemically administered recombinant human Epo on infarct volume and apoptotic neuronal death in a newborn rat hypoxic-ischemic brain injury model. Our results showed that a single dose of intraperitoneal Epo treatment (1,000 U/kg) significantly decreased the mean infarct volume as compared to the control group. In contrast to the Epo-treated group, histopathological examination by positive terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling of the affected brain in control animals revealed widespread neuronal injury associated with numerous apoptotic cells. Morphometric analysis to determine the extent of damage quantitatively ascertained that the mean infarct volume was significantly lower in the Epo-treated group (p < 0.003). These results suggest the beneficial neuroprotective effect of Epo in this model of neonatal hypoxic-ischemic brain injury. To our knowledge, this is the first study that demonstrates a protective effect of Epo against hypoxia-ischemia in the developing brain. Department of Pediatrics, School of Medicine, Dokuz Eylul University, Izmir, Turkey. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=12660442
    20. Regis D, Franchini M, Corallo F and Bartolozzi P (2004). Recombinant human erythropoietin in pediatric patients: efficacy in facilitating autologous blood donation in spinal deformity surgery. Chir Organi Mov 89: 299-303. Preoperative autologous blood donation (PABD) is a widely used practice in orthopaedic elective surgery, but many pediatric patients are unable to complete the program of pre-deposit. Twenty-three consecutive patients undergoing spinal surgery for scoliosis received 6 administrations of 10000U of recombinant human erythropoietin (rHuEpo). Preop hemoglobin (Hb) levels and the numbers of collected and of autologous and allogeneic blood transfused units were determined. These results were compared with a previously-operated group of 28 patients, who differed only by the absence of concomitant erythropoietin therapy. Significant higher numbers of collected blood units and Hb levels were measured, and all of the patients completed the PABD program. A significantly lower requirement for allogeneic blood in the <<rHuEpo-treated>> group was observed: 1 vs 9 patients (4.3%-32.1%; p < 0.001). The study documents the efficacy of rHuEpo in facilitating the completion of a PABD program and in reducing exposure to allogeneic blood in pediatric patients undergoing corrective spinal surgery. Istituto di Clinica Ortopedica e Traumatologica-Universita degli Studi di Verona. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16048051
    21. Garcia-Erce JA, Solano VM, Saez M and Muoz M (2005). Recombinant human erythropoietin facilitates autologous blood donation in children undergoing corrective spinal surgery. Transfusion 45: 820-1; author reply 821-2. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15847676
    22. Keswani SC, Leitz GJ and Hoke A (2004). Erythropoietin is neuroprotective in models of HIV sensory neuropathy. Neurosci Lett 371: 102-5. HIV-associated sensory neuropathy (HIV-SN) is the most common neurological complication of HIV infection. Presently, there are no effective therapies for this painful neuropathy. The pathology of HIV-SN is characterized by 'dying back' sensory axonal degeneration and a more modest loss of dorsal root ganglion (DRG) sensory neurons. It has been hypothesized that HIV-SN results from neurotoxicity by secreted viral proteins, such as the HIV envelope glycoprotein gp120. Furthermore, neurotoxicity by dideoxynucleoside (DDX) agents, results in the observed higher incidence of HIV-SN in HIV-infected patients taking these antiretroviral drugs. In this study we show that administration of picomolar amounts of the hormone erythropoietin (EPO) prevents sensory axonal degeneration and in vitro DRG neuronal death by both gp120 and ddC (a neurotoxic DDX drug). Our results suggest that EPO may be useful in the treatment of HIV-SN. Department of Neurology, The Johns Hopkins Hospital, 600 North Wolfe Street, Pathology 627A, Baltimore, MD 21287, USA. skeswani@jhmi.edu http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15519737
    23. Keast DH and Fraser C (2004). Treatment of chronic skin ulcers in individuals with anemia of chronic disease using recombinant human erythropoietin (EPO): a review of four cases. Ostomy Wound Manage 50: 64-70. Patients with hemoglobin greater than or equal to 100 g/L may have difficulty healing pressure ulcers because of impaired tissue oxygenation. Decreased hemoglobin is often anemia of chronic disease and may be due to the effects of inflammatory cytokines on erythroid progenitor cells. Recombinant human erythropoietin has been found to reverse anemia of chronic disease and may act as a growth factor in wound healing. To review the effect of 6 weeks of subcutaneous recombinant human erythropoietin 75 IU/kg administered 3 times weekly to resolve refractory anemia of chronic disease and heal Stage IV pressure ulcers, a retrospective chart review was conducted of four spinal cord injured patients (all men, mean age 59 years +/- 19) with Stage IV pressure ulcers and multiple comorbid conditions. The patients received recombinant human erythropoietin either through an inpatient spinal cord rehabilitation unit or an outpatient wound management clinic as part of interdisciplinary care. Mean hemoglobin increased from 88 +/- 7.4 g/L to 110 +/- 3.7 g/L. Mean ulcer surface area decreased from 42.3 cm2 (+/- 40.2) to 37.3 cm2 (+/- 44.3) despite extensive deroofing of one ulcer and subsequent increase in size. Mean ulcer depth decreased from 2.3 cm (+/- 1.2) to 1.2 cm (+/- 1.0). Human recombinant erythropoietin shows promise in resolving the refractory anemia of chronic disease associated with Stage IV pressure ulcers. Further study is suggested. University of Western Ontario, Canada. david.keast@sympatico.ca http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15509883

  10. #30
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    Hypothetically would EPO be of any benefit in in-utero treatment of spina bifida Wise? for that matter has anybody tried in-utero transplant of stem cells to correct sb lesions?

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