School of Clinical Medicine, Ningxia Medical University, Yinchuan 750004, China.
Department of Radiology, General Hospital of Ningxia Medical University, Yinchuan 750004, China.
Brain Res. 2022 Oct 15;1793:148041. doi: 10.1016/j.brainres.2022.148041. Epub 2022 Aug 6.
Minimal hepatic encephalopathy (MHE) is a common neuropsychiatric complication in patients with cirrhosis. Alterations in monoamine neurotransmitters have been associated with the pathogenesis of MHE. We investigated the levels of hippocampal noradrenergic neurotransmitter in a rat model of thioacetamide-induced chronic liver failure-related MHE, and their role in cognitive impairment.
18 male Sprague-Dawley (SD) rats were equally divided in MHE and control groups. A rat model of MHE was established by intraperitoneal injection of thioacetamide (TAA) for 12 weeks. Cognitive function was assessed using the Morris water maze (MWM) test and locomotor activity and exploratory behavior assessed with open field test. The concentration of hippocampal noradrenaline (NE) was detected by ELISA, and the magnetic susceptibility value in the hippocampus was detected by quantitative susceptibility mapping. Hippocampal iron content was quantified by Prussian blue staining.
MHE rats performed significantly poorer than their control counterparts in the MWM test, as seen by decreased number of platform crossings and time in the target quadrant, and increased path length to reach the target zone (P < 0.05 for all parameters). In the open field test, the MHE group exhibited lower locomotor activity and exploratory behavior than the control group (P < 0.05 for all parameters). We detected pronounced iron staining in the hippocampus of MHE rats, whereas no iron-stained particles were found in control rats. We observed an imbalance of inflammatory (increased pro- and decreased anti-) cytokines in the hippocampus of MHE rats. Further analysis of the data showed that the level of hippocampal noradrenaline in MHE rats was significantly lower than that of control rats (P < 0.05). We observed a correlation between the level of inflammatory cytokine and noradrenaline land susceptibility value in the rat hippocampus of the MHE group.
Our results suggest that MHE associated with TAA-induced chronic liver failure is associated with alterations in noradrenergic neurotransmission. We propose that iron imbalance in the brain might lead to reduction in the levels of noradrenaline, and cognitive impairment.
轻微型肝性脑病（MHE）是肝硬化患者常见的神经精神并发症。单胺递质的改变与 MHE 的发病机制有关。我们研究了硫代乙酰胺（TAA）诱导的慢性肝衰竭相关 MHE 大鼠模型中海马去甲肾上腺素能神经递质的水平及其在认知障碍中的作用。
18 只雄性 Sprague-Dawley（SD）大鼠平均分为 MHE 组和对照组。通过腹腔注射 TAA 12 周建立 MHE 大鼠模型。使用 Morris 水迷宫（MWM）测试评估认知功能，使用旷场测试评估运动活动和探索行为。通过 ELISA 检测海马去甲肾上腺素（NE）浓度，通过定量磁化率映射检测海马磁化率值。通过普鲁士蓝染色定量海马铁含量。
与对照组相比，MHE 大鼠在 MWM 测试中表现明显较差，表现在平台穿越次数和目标象限时间减少，到达目标区域的路径长度增加（所有参数 P < 0.05）。在旷场测试中，MHE 组的运动活动和探索行为低于对照组（所有参数 P < 0.05）。我们在 MHE 大鼠的海马中观察到明显的铁染色，而在对照组大鼠中未发现铁染色颗粒。我们观察到 MHE 大鼠海马中炎症（促炎增加和抗炎减少）细胞因子失衡。进一步分析数据显示，MHE 大鼠海马去甲肾上腺素水平明显低于对照组大鼠（P < 0.05）。我们观察到 MHE 组大鼠海马炎症细胞因子水平与去甲肾上腺素和磁化率值之间存在相关性。
我们的结果表明，与 TAA 诱导的慢性肝衰竭相关的 MHE 与去甲肾上腺素能神经传递的改变有关。我们提出，脑内铁失衡可能导致去甲肾上腺素水平降低，并导致认知障碍。
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