Abstract
BackgroundDiffuse 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.MethodsSprague–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-α (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-1β.ResultsEPO 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-1β to sham levels 2 hours after TAI + Hx, concomitant to a decrease in CD68 positive cells at 7 and 14 days.ConclusionsWhen 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.
Highlights
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
Erythropoietin promotes significant improvement in motor function after traumatic axonal injury (TAI) + Traumatic axonal injury with hypoxia (Hx) Both TAI and TAI + Hx treatment groups demonstrated a severe sensorimotor deficit on the Rotarod 1 day postinjury when compared to sham, with scores of 9.58 ± 1.40 rpm and 9.3 ± 2.09 rpm (Figure 1A,B, respectively)
Untreated TAI + Hx rats showed a plateau in recovery at 8 days post-injury, with scores of 17.25 ± 3.94 rpm, and still maintained a significantly greater deficit compared to sham (28.5 ± 1.50 rpm, P
Summary
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. Epidemiological studies describe post-traumatic hypoxia as common sequelae to diffuse injury, worsening neurological outcome [3,6,7]. More than 20 compounds have been assessed in phase II/III trials, with none showing long-term benefit [16] This lack of success in translation from the laboratory to the clinic has been attributed to several factors, including variations in therapeutic doses and administration windows in animals versus humans, premature passage to the clinic, failure of experimental models to include secondary insults that are commonplace in clinical TBI, and importantly, a lack of research into axonoprotective molecules in diffuse TBI models [17]
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