Neuroprotection by erythropoietin administration after experimental traumatic brain injury

Department of Clinical Neurosciences, Neurosurgical Clinic, University of Palermo, Italy.
Brain Research (Impact Factor: 2.84). 11/2007; 1182(1):99-105. DOI: 10.1016/j.brainres.2007.08.078
Source: PubMed


A large body of evidence indicates that the hormone erythropoietin (EPO) exerts beneficial effects in the central nervous system (CNS). To date, EPO's effect has been assessed in several experimental models of brain and spinal cord injury. This study was conducted to validate whether treatment with recombinant human EPO (rHuEPO) would limit the extent of injury following experimental TBI. Experimental TBI was induced in rats by a cryogenic injury model. rHuEPO or placebo was injected intraperitoneally immediately after the injury and then every 8 h until 2 or 14 days. Forty-eight hours after injury brain water content, an indicator of brain edema, was measured with the wet-dry method and blood-brain barrier (BBB) breakdown was evaluated by assay of Evans blue extravasation. Furthermore, extent of cerebral damage was assessed. Administration of rHuEPO markedly improved recovery from motor dysfunction compared with placebo group (P<0.05). Brain edema was significantly reduced in the cortex of the EPO-treated group relative to that in the placebo-treated group (80.6+/-0.3% versus 91.8%+/-0.8% respectively, P<0.05). BBB breakdown was significantly lower in EPO-treated group than in the placebo-treated group (66.2+/-18.7 mug/g versus 181.3+/-21 mug/g, respectively, P<0.05). EPO treatment reduced injury volume significantly compared with placebo group (17.4+/-5.4 mm3 versus 37.1+/-5.3 mm3, P<0.05). EPO, administered in its recombinant form, affords significant neuroprotection in experimental TBI model and may hold promise for future clinical applications.

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    • "Although Epo and its cognate receptor EpoR are endogenously expressed and upregulated under injurious conditions such as ischemia, hypoxia or TBI [19-21], their levels of expression rarely appear sufficient to curtail tissue damage and promote neurological recovery [22]. Therefore, pharmacological treatment with exogenous EPO after CNS injury has been a keen area of investigation, particularly with respect to focal brain injury, where EPO has shown to be efficacious in improving sensorimotor and spatial memory after both controlled cortical impact injury (CCI) and cryogenic lesion [22-25], as well as minimising BBB dysfunction and oedema [23,26]. EPO is also a potent immune modulator, and is able to reduce levels of the pro-inflammatory cytokines NFκB, IL-1β, TNF-α, ICAM-1 and CCL-2 in comparison to vehicle-treated rats when assessed post cortical contusion injury or lateral fluid percussion injury [26-29]. "
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    ABSTRACT: Diffuse axonal injury is a common consequence of traumatic brain injury (TBI) and often co-occurs with hypoxia, resulting in poor neurological outcome for which there is no current therapy. Here, we investigate the ability of the multifunctional compound erythropoietin (EPO) to provide neuroprotection when administered to rats after diffuse TBI alone or with post-traumatic hypoxia. Sprague-Dawley rats were subjected to diffuse traumatic axonal injury (TAI) followed by 30 minutes of hypoxic (Hx, 12% O2) or normoxic ventilation, and were administered recombinant human EPO-alpha (5000 IU/kg) or saline at 1 and 24 hours post-injury. The parameters examined included: 1) behavioural and cognitive deficit using the Rotarod, open field and novel object recognition tests; 2) axonal pathology (NF-200); 3) callosal degradation (hematoxylin and eosin stain); 3) dendritic loss (MAP2); 4) expression and localisation of the EPO receptor (EpoR); 5) activation/infiltration of microglia/macrophages (CD68) and production of IL-1beta. EPO significantly improved sensorimotor and cognitive recovery when administered to TAI rats with hypoxia (TAI + Hx). A single dose of EPO at 1 hour reduced axonal damage in the white matter of TAI + Hx rats at 1 day by 60% compared to vehicle. MAP2 was decreased in the lateral septal nucleus of TAI + Hx rats; however, EPO prevented this loss, and maintained MAP2 density over time. EPO administration elicited an early enhanced expression of EpoR 1 day after TAI + Hx compared with a 7-day peak in vehicle controls. Furthermore, EPO reduced IL-1beta to sham levels 2 hours after TAI + Hx, concomitant to a decrease in CD68 positive cells at 7 and 14 days. When administered EPO, TAI + Hx rats had improved behavioural and cognitive performance, attenuated white matter damage, resolution of neuronal damage spanning from the axon to the dendrite, and suppressed neuroinflammation, alongside enhanced expression of EpoR. These data provide compelling evidence of EPO's neuroprotective capability. Few benefits were observed when EPO was administered to TAI rats without hypoxia, indicating that EPO's neuroprotective capacity is bolstered under hypoxic conditions, which may be an important consideration when EPO is employed for neuroprotection in the clinic.
    Journal of Neuroinflammation 12/2013; 10(1):156. DOI:10.1186/1742-2094-10-156 · 5.41 Impact Factor
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    • "By now, numerous techniques have demonstrated the neuroprotective abilities of EPO (e.g. Grasso et al., 2007; Mammis et al., 2009; Y. Zhang et al., 2009). The close association between EPO and blood-related processes originally provoked a primary research focus around the use of EPO in vascular brain injury (e.g. "

    Brain Injury - Functional Aspects, Rehabilitation and Prevention, 03/2012; , ISBN: 978-953-51-0121-5
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    • "Considering the effects of Epotris the impact is likely to be limited as it only reached significance in the thalamus. A beneficial impact of rhEpo on neuronal survival has been described repeatedly in a variety of rodent models with brain injury (Milano and Collomp, 2005; Grasso et al., 2007a; Nadam et al., 2007; Yang et al., 2007; Chu et al., 2008). "
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    ABSTRACT: The design of peptide mimetics offers interesting opportunities to selectively include beneficial and exclude undesirable effects of a parent molecule. Epotris represents a novel erythropoietin mimetic, which lacks an erythropoietic activity. The present study evaluates the potential of this peptide to interfere with the histopathological consequences of electrical-induced status epilepticus in rats. The peptide attenuated status epilepticus-associated expansion of the neuronal progenitor cell population in a significant manner. Moreover, Epotris affected the number of persistent basal dendrites exhibited by neuronal progenitor cells. In contrast, hippocampal cell loss remained unaffected by administration of this peptide mimetic. Status epilepticus resulted in obvious microglial activation in different brain regions involved in seizure generation and spread. Epotris diminished the microglial response caused by prolonged seizure activity in the thalamus but not in other brain regions. The study renders support that the Epotris' sequences from binding site 2 in helix C of Epo play a role in receptor interaction and cytokine function. In addition, the data demonstrate that Epotris can exert limited in vivo effects on the cellular consequences of prolonged seizure activity. When considering further testing it should be taken in mind that Epotris administration only attenuated selected cellular consequences of status epilepticus and did not completely prevent cellular alterations.
    Epilepsy research 07/2011; 96(3):241-9. DOI:10.1016/j.eplepsyres.2011.06.009 · 2.02 Impact Factor
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