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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Available from: Domenico Gerardo Iacopino, Oct 04, 2015
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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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    • "In addition, some studies have shown that EPO administration reduces the posttraumatic brain edema and inflammation implicated in experimental TBI. (Chen et al., 2007; Grasso et al., 2007). Therefore, treatment with EPO could provide both neuroprotective and neurorestorative effects. "
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    ABSTRACT: Angioneurines are a family of molecules that include vascular growth factors such as VEGF, neurotrophins such as BDNF, IGF-I, and Erythropoietin, among others. They affect both neural and vascular processes. Due to the fact that all of them act over glia, we propose the term angioglioneurins to name them. They play a key role in the neurogliovascular unit that represents the functional core maintaining BBB. Although delivery to CNS is still an unsolved problem nowadays, exogenous angioglioneurin administration represents a promising therapeutic strategy for many neurological pathologies due to their neurotrophic and neurogenic role. In brains, VEGF is produced by neurons and astrocytes in different stages and situation, binding to tyrosine kinase receptors and also to neuropilin family. This fact reinforces its key role in the cross talk between neural and vascular development and activity. Angioglioneurins described in this report might become an important therapeutic resource in CNS restoration, especially in pathologies as stroke or traumatic brain injury.
    International Review of Neurobiology 07/2012; 102:317-46. DOI:10.1016/B978-0-12-386986-9.00012-0 · 1.92 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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