Gorio, A. et al. Recombinant human erythropoietin counteracts secondary injury and markedly enhances neurological recovery from experimental spinal cord trauma. Proc. Natl. Acad. Sci. USA 99, 9450-9455

University of Milan, Milano, Lombardy, Italy
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 08/2002; 99(14):9450-5. DOI: 10.1073/pnas.142287899
Source: PubMed


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.

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    • "The pharmacological blockade of neuron and/or oligodendrocyte apoptosis using a number of agents promotes functional recovery after SCI. These agents include the following: erythropoietin (Celik et al., 2002; Gorio et al., 2002), inhibitors of purine receptor P2X7 (OxATP and PPADS) (Wang et al., 2004), a neutralizing antibody against CD95 (FAS) antigen (Demjen et al., 2004), and minocycline (Stirling et al., 2004; Teng et al., 2004). Engrafted SHEDs suppress apoptosis in neurons and oligodendrocytes, resulting in the remarkable preservation of neurofilaments and myelin sheaths in the region surrounding the lesion's epicenter (Nosrat et al., 2001; de Almeida et al., 2011). "
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    ABSTRACT: Spinal cord injury (SCI) often leads to persistent functional deficits due to the loss of neurons and glia and to limited axonal regeneration after such injury. Recently, three independent groups have reported marked recovery of hindlimb locomotor function after the transplantation of human adult dental pulp stem cells (DPSCs) and stem cells from human exfoliated deciduous teeth (SHEDs) into rats or mice with acute, sub-acute or chronic SCI. This review summarizes the primary characteristics of human dental pulp stem cells and their therapeutic benefits for treating SCI. Experimental data from multiple preclinical studies suggest that pulp stem cells may promote functional recovery after SCI through multifaceted neuro-regenerative activities.
    Full-text · Article · Nov 2013 · Neuroscience Research
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    • "Early decompressive surgery or high-dose steroid therapy, while long-standing treatments of choice, do not provide recovery from critical sequelae after SCI. Efforts to minimize secondary injury of SCI have included drug management as a neuroprotective effect in many recent studies, including minocycline, erythropoietin, and Nogo-66 receptor antagonist13,23,24). VPA also was investigated35). "
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    ABSTRACT: This study investigates the effect of valproic acid (VPA) on expression of neural stem/progenitor cells (NSPCs) in a rat spinal cord injury (SCI) model. Adult male rats (n=24) were randomly and blindly allocated into three groups. Laminectomy at T9 was performed in all three groups. In group 1 (sham), only laminectomy was performed. In group 2 (SCI-VPA), the animals received a dose of 200 mg/kg of VPA. In group 3 (SCI-saline), animals received 1.0 mL of the saline vehicle solution. A modified aneurysm clip with a closing force of 30 grams was applied extradurally around the spinal cord at T9, and then rapidly released with cord compression persisting for 2 minutes. The rats were sacrificed and the spinal cord were collected one week after SCI. Immunohistochemistry (IHC) and western blotting sample were obtained from 5 mm rostral region to the lesion and prepared. We analyzed the nestin immunoreactivity from the white matter of ventral cord and the ependyma of central canal. Nestin and SOX2 were used for markers for NSPCs and analyzed by IHC and western blotting, respectively. Nestin and SOX2 were expressed significantly in the SCI groups but not in the sham group. Comparing SCI groups, nestin and SOX2 expression were much stronger in SCI-VPA group than in SCI-saline group. Nestin and SOX2 as markers for NSPCs showed increased expression in SCI-VPA group in comparison with SCI-saline group. This result suggests VPA increases expression of spinal NSPCs in SCI.
    Full-text · Article · Jul 2013 · Journal of Korean Neurosurgical Society
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    • "NIH-NINDS has funded 3 major replication centers for SCI in the United States to attempt independent replication of high-profile preclinical therapies. To date, the majority of these replication attempts have been unsuccessful [3], [4], [6]–[8] even though the initial studies were published in high-profile journals [51]–[55] (for exception see [56], [57]). As SCI and other preclinical fields struggle to translate basic research findings to disease syndromes in humans, it may become essential to pool bio-behavioral outcome data across studies to make novel preclinical syndromic discoveries. "
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    ABSTRACT: Spinal cord injury (SCI) and other neurological disorders involve complex biological and functional changes. Well-characterized preclinical models provide a powerful tool for understanding mechanisms of disease; however managing information produced by experimental models represents a significant challenge for translating findings across research projects and presents a substantial hurdle for translation of novel therapies to humans. In the present work we demonstrate a novel 'syndromic' information-processing approach for capitalizing on heterogeneous data from diverse preclinical models of SCI to discover translational outcomes for therapeutic testing. We first built a large, detailed repository of preclinical outcome data from 10 years of basic research on cervical SCI in rats, and then applied multivariate pattern detection techniques to extract features that are conserved across different injury models. We then applied this translational knowledge to derive a data-driven multivariate metric that provides a common 'ruler' for comparisons of outcomes across different types of injury (NYU/MASCIS weight drop injuries, Infinite Horizons (IH) injuries, and hemisection injuries). The findings revealed that each individual endpoint provides a different view of the SCI syndrome, and that considering any single outcome measure in isolation provides a misleading, incomplete view of the SCI syndrome. This limitation was overcome by taking a novel multivariate integrative approach for leveraging complex data from preclinical models of neurological disease to identify therapies that target multiple outcomes. We suggest that applying this syndromic approach provides a roadmap for translating therapies for SCI and other complex neurological diseases.
    Full-text · Article · Mar 2013 · PLoS ONE
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