Erythropoietin is neuroprotective, improves functional recovery, and reduces neuronal apoptosis and inflammation in a rodent model of experimental closed head injury

Abstract

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in young people in industrialized countries. Although various anti-inflammatory and antiapoptotic modalities have shown neuroprotective effects in experimental models of TBI, to date, no specific pharmacological agent aimed at blocking the progression of secondary brain damage has been approved for clinical use. Erythropoietin (Epo) belongs to the cytokine superfamily and has traditionally been viewed as a hematopoiesis-regulating hormone. The newly discovered neuroprotective properties of Epo lead us to investigate its effect in TBI in a mouse model of closed head injury. Recombinant human erythropoietin (rhEpo) was injected at 1 and 24 h after TBI, and the effect on recovery of motor and cognitive functions, tissue inflammation, axonal degeneration, and apoptosis was evaluated up to 14 days. Motor deficits were lower, cognitive function was restored faster, and less apoptotic neurons and caspase-3 expression were found in rhEpo-treated as compared with vehicle-treated animals (P<0.05). Axons at the trauma area in rhEpo-treated mice were relatively well preserved compared with controls (shown by their density; P<0.01). Immunohistochemical analysis revealed a reduced activation of glial cells by staining for GFAP and complement receptor type 3 (CD11b/CD18) in the injured hemisphere of Epo- vs. vehicle-treated animals. We propose that further studies on Epo in TBI should be conducted in order to consider it as a novel therapy for TBI.

Neuroprotection by erythropoietin administration after experimental traumatic brain injury

“…Such a model mimics several pathophysiological characteristics of human focal cortical contusion (Nag, 1996) and produces a reproducible, demarcated lesion to the neocortex that allows evaluation of the efficacy of compounds with a neuroprotective potential (Hortobagyi et al, 2000). The present findings extend previous work by showing that rHuEPO significantly reduces brain injury and improves neurological recovery following traumatic insults (Brines et al, 2000;Lu et al, 2005;Ozturk et al, 2005;Shein et al, 2005;Siren et al, 2006;Verdonck et al, 2007;Yatsiv et al, 2005). In particular, rHuEPO administration improved both functional and cognitive recovery of the rats with an effect that was significantly shown since the early stage after TBI and lasted for 15 days.…”

“…Although the role of EPO as a neuroprotectant has been studied extensively in a wide range of in vitro and in vivo models of brain injury, up to date, there are only few studies evaluating the effect of rHuEPO after experimental TBI (Brines et al, 2000;Lu et al, 2005;Ozturk et al, 2005;Shein et al, 2005;Siren et al, 2006;Verdonck et al, 2007;Yatsiv et al, 2005) and none has used a cryogenic injury paradigm. Neurobehavioral improvement after EPO administration has been reported in other studies where different models of brain injury were used.…”

“…rHuEPO appears to reduce the inflammatory infiltrate and in this manner likely reduces the contribution of late injury to the neurological deficit (Gorio et al, 2002). However, antiapoptotic action and reduced neuroinflammatory response by rHuEPO (Brines et al, 2000;Siren et al, 2001;Yatsiv et al, 2005) are based on mechanisms needing several hours, after the insult, to be effective. Processes occurring in the early stage after TBI, such as release of glutamate, lactate, potassium, calcium, free oxygen radicals, histamine, and kinins by injured cells, seem to be more relevant in the pathophysiological mechanisms underlying brain damage following TBI (Unterberg et al, 2004).…”

“…In this scenario, a large body of evidence has pointed out the efficacy of the hormone erythropoietin (EPO) as neuroprotectant. Although peripherally administered recombinant human EPO (rHuEPO) has shown to penetrate the blood-brain barrier (BBB) and reduce brain injury following a variety of insults (Brines et al, 2000;Digicaylioglu and Lipton, 2001;Grasso et al, 2004), its potential neuroprotective efficacy in an in vivo model of experimental TBI has been scarcely investigated (Brines et al, 2000;Lu et al, 2005;Ozturk et al, 2005;Shein et al, 2005;Siren et al, 2006;Verdonck et al, 2007;Yatsiv et al, 2005). Evidence shows widespread efficacy of rHuEPO in injury models of spinal cord (Celik et al, 2002;Gorio et al, 2002;Grasso et al, 2006), subarachnoid hemorrhage (Buemi et al, 2002a,b;Catania et al, 2002;Grasso, 2001;Grasso et al, 2002a,b;Springborg et al, 2002), retina, and the heart damage (Calvillo et al, 2003;Junk et al, 2002).…”

Erythropoietin regulates immune/inflammatory reaction and improves neurological function outcomes in traumatic brain injury

“…The subsequent accumulation of proinflammatory cytokines further aggravates the impairment (Das, Mohapatra, & Mohapatra, 2012). The ability of EPO to improve cognitive outcome has been demonstrated by our study as well as other researchers (Barichello et al., 2014; Yatsiv et al., 2005). Previous studies have shown that EPO promotes angiogenesis and increases cerebral blood perfusion (Meng et al., 2011).…”