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C5a is an important mediator and chemokine of inflammation, which plays an important role in the process of traumatic brain injury (TBI) pathogenesis.To investigate the effect of human umbilical cord mesenchymal stem cells (hUC-MSCs) transplantation and C5a receptor antagonist on TBI.Sprague-Dawley rats were prepared to the heavy-duty hydraulic traumatic brain injury models and they were randomly divided into three groups: TBI group, hUC-MSCs transplantation group and hUC-MSCs transplantation plus C5a receptor antagonist group (C5a+hUC-MSCs group).At 1–4 weeks after transplantation, the modified neurological severity scores (mNSS) were lower in the hUC-MSCs and C5a+hUC-MSCs groups than in the TBI group (P< 0.05, 0.01), while mNSS were decreased significantly in the C5a+hUC-MSCs group. The average time of escape latency was gradually decreased in each group; however, it was much shorter in the C5a+hUC-MSCs group than in the other two groups at 3–5 days (P < 0.05). The frequency of platform passing and the percentage of swimming distance traveled in the previous target quadrant in the C5a+hUC-MSCs group were significantly greater than those in the TBI group and hUC-MSCs group. It is indicated that UC-MSCs transplantation combined with C5a receptor antagonist can significantly improve the neurological function in the rats.