Na-K-2Cl cotransporters contributes to IL-1-induced neuronal damage during traumatic brain injury

Abstract

Traumatic brain injury (TBI) is one of the most prevalent causes of morbidity and mortality all over the world. One characteristic feature of patients with severe TBI is brain edema. The cerebral spinal fluid (CSF) is secreted by the epithelial cell of the choroid plexuses and Na+-K+-2Cl- cotransporter (NKCC1) has a major role in the secretory process in the CSF secretion. Our previous results demonstrated that IL-1 plays an important role in TBI-induced neuronal loss. This study assessed the effect of NKCC1 on TBI-induced brain edema and neuron damage and the relationship between NKCC1 and IL-1 induced neuronal loss. TBI model was induced by the calibrated weight-drop device (450 g weight, 2 m height) and the animals were divided into sham operation and different time course after TBI (0 h, 2 h, 4 h, 8 h, 12 h, 24 h, 48 h, 96 h). The infarction volume and neuronal damage was verified by hematoxylin and eosin staining and TTC staining. NKCC1 and IL-1 mRNA expression was detected by RT-PCR and the protein expression was measured by Western blot. IL-1 antogonist or antibody and NKCC1 blocker, bumetanide were locally injected into lateral ventricle to elucidate the effect of NKCC1 on IL-1 induced neuronal loss. In this study, we found that NKCC1 and IL-1 mRNA expression in choroid plexus started to detect at 2 h after TBI and lasted for 24 h after TBI. NKCCl protein significantly elevated after TBI 2 h and lasted for 24 h. After TBI, animals displayed severe brain edema and neuron loss. There is a sustained up-regulation of NKCC1 in choroid plexus was detected from 2 h to 24 h after TBI. Infarction volume was significantly increased after TBI and bumetanide treatment significantly decreased infarct volume after TBI. Administration of IL-1 antibody significantly reduced the NKCC1 expression. Theses results evidenced that NKCC1 plays an essential roles in IL-1 induced neuron damage in TBI.