Role of autophagic response in glutamine treatment attenuating inflammation in rats after traumatic brain injury

Abstract

Objective To investigate the effect of glutamine (GLN) treatment on neurobehavioral outcome, brain edema and inflammatory response in rats after traumatic brain injury (TBI), and to find out the role played by autophagic response in this effect. Methods Rat models with TBI in this study were established using Feeney's method. One hundred healthy male SD rats were randomly divided into five groups (n=20) to receive sham operation (group Sham), TBI (group TBI), TBI and glutamine treatment (group TBI+ GLN), TBI amd autophagy inhibitor 3-methyladenine (group TBI+ 3-MA), and TBI, GLN and autophagy inhibitor (group TBI+ GLN+ 3-MA). We measured the rats' behavioral outcomes by modified neurologic severity score (mNSS) tests at day 1, 3, 7 and 14 after intervention. Brain water content was measured with wet-dry weight method. The serum levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1 and IL-4 were tested using enzyme linked immunosorbent assay. The expressions of autophagy-related factors (LC3-Ⅱ, Beclin-1) in TBI cerebral cortex were tested with Western blot. Results Compared with the Sham group, the other four groups had significantly increased levels of brain edema, mNSS, serum inflammatory factors and cerebral LC3-Ⅱ and Beclin-1 (P=0.00). Compared with the TBI group, the TBI+ GLN group had less severe brain edema and improved mNSS, lower levels of TNF-α [(57.71±9.69)pg/ml vs. (83.37±12.81)pg/ml, P=0.01] and IL-1 [(39.46±8.60)pg/ml vs. (69.04±10.48)pg/ml, P=0.00], higher levels of IL-4 [(68.72±11.18)pg/ml vs. (35.75±8.40)pg/ml, P=0.04], and upregulated expressions of LC3-Ⅱ and Beclin-1 (P=0.01). Compared with the TBI+ GLN group, the TBI+ GLN+ 3-MA group had severer neurofunctional impairment, brain edema and inflammation (P<0.05). Conclusions Treatment with GLN markedly reduced brain edema and improved neurobehavioral outcomes in rats with TBI by inhibiting inflammatory response in the central nervous system. The mechanism might have been the activation of the autophagic response. Key words: Traumatic brain injury; Glutamine; Inflammation; Autophagy; Neuroprotection