Tetramethylpyrazine improves rats with sepsis-associated encephalopathy through regulation of autophagy signaling pathway

Abstract

Abstract Background Tetramethylpyrazine, an alkaloid extracted from Ligusticum chuanxiong Hort (Umbelliferae), has been used in China for cardiovascular and cerebrovascular diseases because of its anti-inflammatory and antioxidant properties. Objective To investigate the effect of tetramethylpyrazine (TMP) on sepsis-associated encephalopathy (SAE) and its underlying mechanisms in autophagy regulation. Methods The Sprague-Dawley rat model was established using cecal ligation and puncture (CLP). They were randomly assigned to four groups: sham operation (Sham), (SAE), SAE + TMP (TMP), and SAE + rapamycin (RAPA). Administration of TMP (10 mg/kg/d, i.p.) or RAPA (10 nM/d, i.p.) once daily for 3 days before CLP. Twenty-four h after CLP, we assessed the vital parameters, neurobehavioral scores, water maze tests, hippocampal pathological structure, inflammation factors and autophagy associated proteins. Results TMP or RAPA injection significantly reduce escape latency (28.39%, 38.27%), rises the time spent in the target quadrant (39.29%, 53.57%) and the frequency of crossing the goal platform (100%, 111.76%), inhibit the levels of inflammatory factors IL-1β (49.32%, 50.74%), IL-6 (32.43%, 33.78%) and TNF-α (51.26%, 53.63%), downregulate proteins TLR1 (18.47%, 27.76%) and p62 (90.66%, 97.56%), upregulate proteins LC3II/I ratio (60.96%, 42.93%), ATG5 (58.10%, 15.41%) and Beclin1 (91.82%, 119.71%) compared with SAE group. Further, TMP-activated autophagy was reversed by used of chloroquine (CQ), and increase p62 (66.94%) expression and inhibit LC3II/I ratio (21.94%). Conclusions TMP expressed neuroprotective effects against SAE via activating autophagy, which provide experimental evidence for the clinically beneficial application to treat SAE.