Abstract
IntroductionTraumatic brain injury (TBI) remains a leading cause of disability and death among young people in China. Unfortunately, no specific pharmacological agents to block the progression of secondary brain injury have been approved for clinical treatment. Recently, neuroprotective effects of erythropoietin (EPO) have been demonstrated in addition to its principal function in erythropoiesis, and hence it is viewed as a potential drug for TBI. In this study, we have investigated the neuroprotective effects of EPO associated with immune/inflammatory modulation in a mouse experimental TBI model.Methods EPO (5000 U/kg body weight, i.p.) was injected at 1 hr, 1, 2, and 3 days after TBI, and its effect on cognitive function, brain edema, immune/inflammatory cells including regulatory T cells (Tregs), neutrophils, CD3+ T cells, and microglia, cytokines including interleukin‐10 (IL‐10), transforming growth factor‐β (TGF‐β), interleukin‐1β (IL‐1β), and tumor necrosis factor‐α (TNF‐α) were evaluated at different time points after treatment.Results EPO treatment significantly decreased brain edema and improved cognitive function when compared to Saline‐treated mice (p < .05). EPO treatment also significantly increased Tregs level in spleen and injured brain tissue as well as significantly reduced the infiltration and activation of immune/inflammatory cells (neutrophils, CD3+T cells, and microglia) in the injured hemisphere compared to Saline‐treated control animals (p < .05). In addition, ELISA analysis demonstrated that EPO treatment increased the expression of anti‐inflammatory cytokine IL‐10, but decreased the expression of proinflammatory cytokine IL‐1β and TNF‐α in the injured brain tissue (p < .05).ConclusionsThese findings suggest that EPO could improve neurological and cognitive functional outcomes as well as regulate immune/inflammatory reaction in TBI.
Highlights
Traumatic brain injury (TBI) remains a leading cause of disability and death among young people in China
A multitude of neuroprotective agents have been investigated for TBI treatment in the laboratory, including tumor necrosis factor-α (TNF-α) antagonist (Baratz et al, 2011), free radical scavengers (Aiguo, Zhe, & Gomez-Pinilla, 2010), the nicotinic acetylcholine-receptor activator donepezil and mexiletine (Atalay, Caner, Can, & Cekinmez, 2007; Fujiki et al, 2008), but none have been successful in clinical studies
To our knowledge we are the first to report that EPO treatment significantly increased spleen and brain Tregs and anti-inflammatory factor IL-10 expression, but decreased proinflammatory factor IL-1β and tumor necrosis factor-α (TNF-α) expression as well as decreased neutrophils and CD3+ T-cell infiltration into the injured brain tissue
Summary
Traumatic brain injury (TBI) is a leading cause of mortality, morbidity, and in China it is the highest contributor to mortality in adults under 40 years of age (Wu et al, 2008). A key feature of secondary brain injury is cerebral inflammation, which is characterized by microglial activation, upregulation and secretion of chemokines and cytokines, infiltration of peripheral immune cells including neutrophils, T lymphocytes, B lymphocytes, and NK cells (Roberts et al, 2013). Immune/inflammatory responses play an important role in the pathological process of secondary brain injury. There are only a few studies investigating the role of EPO in the regulation of immune/inflammatory responses following TBI. We demonstrate that EPO treatment can improve neurological functional outcomes in a well-standardized experimental model of TBI in mice, and hypothesize that its protective roles are associated with immune/inflammatory modulation. The therapeutic effects of EPO in TBI model and the changes in regulatory T cells (Tregs), neutrophils, CD3+ T cell, microglia, and some cytokines are investigated in this study
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