The Neuroprotective Effect And Meta-analysis Of Ervthropoietin For Traumatic Brain Injury

In the present study, we first evaluated the effect of EPO on apoptosis of cortex and hippocampus and investigated whether EPO treatment can improve the neurological defects following TBI in rats; Secondly, we investigated the possible role of ERS-induced apoptosis and autophagy in the neuroprotection effect by EPO treatment. Finally, we conducted the first meta-analysis to assess the effectiveness and safety of EPO in patients with TBI. The results demonstrated that TBI can induce apoptosis in the cortex and hippocampus and harm the neurological function of rats, while EPO treatment could attenuated cell apoptosis and improve neurological function. Both suppression of ERS -induced apoptosis and up-regulation of autophagy pathways may participate in the neuroprotective effect of post-TBI EPO treatment EPO is beneficial for patients with TBI in terms of reducing mortality and shortening hospitalization time without increasing the incidence of vegetative state or risk of DVT. However, its effect on improving favorable neurologic outcomes did not reach statistical significance.Prat 1 Neuroprotective effects of erythropoietin treatment for traumatic brain injury in ratsObject:In the present study, we evaluated the effect of EPO on apoptosis in cortex and hippocampus and investigated whether EPO treatment can improve the neurological defects following TBI in rats.Methods:Male SD rats were divided into 4 groups:Sham injury group; Sham injury and EPO group; TBI group; TBI and EPO group. Traumatic brain injury was induced by a fluid percussion TBI device. EPO (5,000U/kg in saline) was administered intraperitoneally at 6 h post injury. Expressions of cleaved caspase-3 and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) positive cells in injured cortex and hippocampus were measured to determine cell apoptosis. Neurological function was assessed using a modified neurological severity score(mNSS).Results:The results showed that TUNEL-positive staining cell density and cleaved caspase-3 expression were increased in the cortex and hippocampus 24 hours after TBI (p< 0.05). This increase was suppressed by post-TBI EPO treatment(p< 0.05). The neurobehavioral results showed that EPO treatment significantly improved long-term neurological functional recovery after TBI on days 7,14,21,28, and 35 compared with saline treatment (p< 0.05). The results demonstrated that EPO could significantly improve neurological function and attenuated cell apoptosis.Conclusions:In summary, our study demonstrated that TBI can induce apoptosis in the cortex and hippocampus and harm the neurological function of rats, while exogenous EPO could attenuated cell apoptosis and improve neurological function.Prat 2 Neuroprotective effects of erythropoietin treatment by attenuating ERS-induced apoptosis after traumatic brain injuryObject:Erythropoietin (EPO) exerts a neuroprotective effect in TBI. However, the concrete mechanisms are not dear completely. ERS-mediated apoptotic pathway may play an important role in TBI pathology. In the present study, we evaluated the changes of ERS and caspase-12-mediated apoptosis after EPO treatment in TBI rats, and investigated the possible role of ERS-induced apoptosis in the neuroprotection effect by EPO treatment.Methods:Male SD rats were divided into 4 groups:Sham injury group; Sham injury and EPO group; TBI group; TBI and EPO group. Traumatic brain injury was induced by a fluid percussion TBI device. EPO (5,000 U/kg in saline) was administered intraperitoneally at 6 h post injury. The expressions of caspase-12, C/EBP-homolo gous protein (CHOP), glucose regulated protein 78 (GRP78)/BIP in cortex were measured by immunohistochemistry and western blotting to assess the changes of ERS after TBI and EPO treatment, and further investigate possible role of ERS-induced apoptosis in the neuroprotection effect by EPO treatment.Results:The results of immunohistochemistry and western blotting of ERS makers show that TBI can induce ERS and EPO treatment can down-regulate the expression of ERS makers(p< 0.05), as show by reduction of caspase-12 and CHOP expression, and further increase of BIP expression(p< 0.01). The results demonstrated that TBI can induce ERS and EPO treatment followed TBI can suppress ERS and caspase-12 mediated apoptosis.Conclusions:TBI can induce ERS and EPO treatment can suppress ERS and caspase-12 mediated apoptosis. Combined with the results from part 1 we conclude that EPO could attenuated cell apoptosis and improve neurological function, possibly through suppression of ERS and caspase-12-induced apoptosis.Prat 3 Neuroprotective effects of erythropoietin treatment on traumatic brain injury involving autophagy pathway in ratsObject:We evaluated the changes of autophagy after post-traumatic brain injury (TBI) followed by EPO treatment, and investigate whether autophagy is involved in the neuroprotection effect elicited by EPO treatment in rats.Methods:Adult male Sprague-Dawley rats were randomly divided into Sham group; Sham with EPO group; TBI group; and TBI with EPO group. The traumatic brain injury was induced by a fluid percussion TBI device. EPO (5,000 U/kg in saline) was administered intraperitoneally at 6 h post injury. All rats were killed at 24 h after TBI. Immunohistochemistry and western blotting of autophagy-associated protein including LC3, ATG5, Beclin-1 and P62 were performed to assess changes of autophagy after TBI and EPO treatment, and further investigate possible role of autophagy pathway in the neuroprotection effect by EPO treatment.Results:The Immunohistochemistry and western blotting of autophagy-associated protein show that TBI increased the expression of LC3, ATG5, Beclin-124 h after TBI, and decreased the expression of P62 (p< 0.05); EPO treatment furtherly increased the expression of LC3, ATG5, Beclin-1 and decreased the expression of P62 (p< 0.05). The results demonstrated that TBI can induce autophagy and EPO treatment followed TBI can furtherly up-regulated the level of autophagy.Conclusions:The result showed that EPO treatment can further increased autophagy in injured cortex after TBI. Combined with the results from part 1 we conclude that autophagy pathway participate in the neuroprotective effect of post-TBI EPO treatment.Part 4 Therapeutic effect of erythropoietin in patients with traumatic brain injury:A systematic review and meta-analysis of randomized controlled trialsObject:Erythropoietin (EPO) exerts a neuroprotective effect in animal models of traumatic brain injury (TBI). However, its effectiveness in human patients with TBI is unclear. In this study, we conducted the first meta-analysis to assess the effectiveness and safety of EPO in patients with TBI.Methods:In January 2016, a systematic search was performed of PubMed, Web of Science, MEDLINE, Embase, and Cochrane. Only publications of randomized controlled trials (RCTs) using EPO in patients with TBI were selected for analysis. The assessed outcomes included favorable neurologic outcome, mortality, vegetative state, hospital stay, and associated adverse effects. Continuous variables were presented as mean difference (MD) with a 95% confidence interval (CI). Dichotomous variables were presented as risk ratio (RR) or risk difference (RD) with a 95% CI. Statistical heterogeneity was examined using both I2 and chi-square tests.Results:Of the 346 studies identified in the search,5 RCTs involving 915 patients met the inclusion criterias. The overall results demonstrated that EPO significantly reduced mortality (RR= 0.69; 95% CI= 0.49,0.96; p= 0.03) and shortened the hospitalization time (MD=-7.59; 95%CI=-9.71,-5.46; p< 0.0001) for patients with TBI. Pooled results of favorable outcome (RR=1.00,95%CI=0.88,1.15, p=0.97), vegetative state (RR= 1.13; 95%CI= 0.53,2.42; p= 0.75) and deep vein thrombosis (RD=0.00, 95%CI=-0.05,0.05, p=1.00) did not show significant difference.Conclusions:The results demonstrated that EPO is beneficial for patients with TBI in terms of reducing mortality and shortening hospitalization time without increasing the incidence of vegetative state or risk of DVT. However, its effect on improving favorable neurologic outcomes did not reach statistical significance. Therefore, more well-designed RCTs are necessary in order to ascertain the optimum dosage and time window of EPO treatment for patients with TBI.