Electroacupuncture Synergistically Inhibits Proinflammatory Cytokine Production and Improves Cognitive Function in Rats with Cognitive Impairment due to Hepatic Encephalopathy through p38MAPK/STAT3 and TLR4/NF-κB Signaling Pathways

Abstract

Objective. To investigate the effect of electroacupuncture (EA) on cognitive dysfunction in rats with hepatic encephalopathy and its underlying mechanism. Methods. Fifty Wistar rats were randomly divided into a normal group (n = 10) and model group (n = 40). Rat models of hepatic encephalopathy were established by administration of carbon tetrachloride and thioacetamide for a total of 12 weeks. At the 9th week after modeling, rats with cognitive impairment in the model group were identified by conducting the Morris water maze test, which were then randomly divided into a control group (CCl4) and treatment groups including EA group (CCl4 + EA), lactulose group (CCl4 + Lac), and EA plus lactulose group (CCl4 + CM), with 9 rats in each group. At the end of the 9th week, rats in CCl4 + Lac and CCl4 + CM groups had lactulose gavage at a dose of 10 mL/kg body weight, while normal control and CCl4 groups had gavage with the same volume of normal saline once a day for 21 days until the end of the experiment. Rats in CCl4 + EA and CCl4 + CM groups underwent acupuncture at Baihui (GV[DU]20), Shenting (GV[DU]24), and Zusanli (ST36) acupoints, among which EA at Baihui and Shenting acupoints were given once daily for 30 min lasting for 21 consecutive days. The effect of the treatment was measured by the Morris water maze test for learning and memory ability and magnetic resonance spectroscopy (MRS) for neuronal metabolism in the hippocampus of rats with hepatic encephalopathy. Pathological change in the rat hippocampus was observed by HE staining, while serum ammonia and liver function markers were detected. Western blot and real-time fluorescent quantitative PCR were used to detect the expressions of specific genes and proteins in the brain tissue. Results. Compared with those in the control group, rats undergoing EA had significantly shortened escape latency and increased number of platform crossing. H&E staining confirmed that EA improved brain tissue necrosis and ameliorated nuclear pyknosis in rats with hepatic encephalopathy. Significantly decreased levels of serum ammonia, alanine aminotransferase (ALT), aspartate transaminase (AST), total bilirubin (TBil), and total bile acid (TBA) were observed in rats undergoing EA, as well as improved levels of total protein (TP) and albumin (ALB). In addition, EA inhibited the brain expressions of TNF-α, IL-1β, IL-6, iNOS, TLR4, MyD88, NF-κB, p38MAPK, phosphorylated (p)-p38MAPK, STAT3, and p-STAT3 genes, as well as protein expressions of TNF-α, IL-6, TLR4, MyD88, NF-κB, p38MAPK, p-p38MAPK, STAT3, and p-STAT3. MRS showed increased Glx/Cr and decreased NAA/Cr, Cho/Cr and mI/Cr in the control group, and EA significantly reversed such changes in Glx/Cr and mI/Cr values. Conclusion. EA ameliorated the production of excessive proinflammatory cytokines in the hippocampus of rats with cognitive dysfunction secondary to hepatic encephalopathy, which also gave rise to subsequent changes such as reduced blood ammonia level, brain-protective activated astrocytes, and lower degree of brain tissue injury. The p38MAPK/STAT3 and TLR4/MyD88/NF-κB signaling pathways may be involved. EA can also improve the metabolism of NAA and Cho in the rat hippocampus and thereby improve learning and memory abilities.

The neuroprotective and neural circuit mechanisms of acupoint stimulation for cognitive impairment

“…Acupuncture at GV20 and ST36 suppressed TLR4 expression in the hippocampal microglia of VD rats, accompanied by reduced activation of miR-93 and myeloid differentiation primary response 88 (MyD88)/NF-κB signaling, suggesting that acupuncture may attenuate inflammation-related cognitive impairment by inhibiting miR-93-mediated TLR4/MyD88/NF-κB signaling in VD rats [ 81 ]. Other studies using EA reported similar results, implying that TLR4/MyD88/NF-κB signaling may have mediated EA’s effect in rats with VD and hepatic encephalopathy [ 82 , 83 ].…”

Research on acupuncture and glial cells: A bibliometric analysis

“…Evidence-Based Complementary and Alternative Medicine was the most productive journal in acupuncture and glial cells, and unsurprisingly, this journal was also the most active journal with the maximum number of articles in other acupuncture-related academic fields such as acupuncture and metabolomics, acupuncture and microbiology, and acupuncture and molecular biology. [32,33] In contrast, despite the fact that Korea has no publishers, it is one of the most important countries for acupuncture and glial cell research. Although, China has 3 of the top 10 ranked publishers, it lacks academic journals with a Journal Citation Report partition of Q1.…”

Electroacupuncture improves cognitive impairment in diabetic cognitive dysfunction rats by regulating the mitochondrial autophagy pathway

“…All puncture points were connected to Han's Electroacupuncture instrument. After reviewing the literature [ 22 , 23 ], EA was performed using a stimulation current of 1 mA, frequency of 15 Hz, duration of 30 min, and once a day [ 14 ].…”