Working memory impairment and reduced hippocampal and prefrontal cortex c-Fos expression in a rat model of cirrhosis

Hepatic encephalopathy (HE) is a frequent neurological complication observed in patients with liver malfunction. Previous studies have shown memory impairment in these patients. In order to investigate brain substrates of spatial working memory impairment in chronic HE, neuronal expression of c-Fos protein was studied in an experimental model of cirrhosis. Control and cirrhotic rats were trained on a spatial working memory task in the Morris water maze (MWM). Differences between groups were found in the working memory task. Cirrhotic rats were unable to locate the platform in the retention trial. Neuronal activation, measured by c-Fos protein, was compared between groups. No differences were found in c-Fos expression of control and cirrhotic rats that were not tested in the MWM. Working memory task produced increase in c-Fos positive cells in dorsal hippocampus, CA1 and CA3, and prefrontal cortex in control group compared to thioacetamide group or naïve, which only swam in the maze during a similar time. These findings suggest that cirrhotic rats show spatial working memory impairment that could be linked to dysfunction in neuronal activity in prefrontal cortex and hippocampus.     

岗松挥发油对实验性肝损害的防治作用

本研究表明,岗松油对四氯化碳、硫代乙酰胺、醋酸强的松龙引起的小鼠SGPT升高有明显的降低作用,使BSP潴留量减少,相应肝组织病变减轻。此外,岗松油对四氯化碳损害小鼠和正常小鼠戊巴比妥钠的睡眠时间均能明显缩短。对巴豆油引起小鼠耳部炎症有明显的抗炎作用。岗松油的毒性很低,口服半数致死量(LD_(50)为3,758±539mg/kg,给兔灌胃687～1030mg/kg每天一次,连续30天,一般表现、血象、肝肾功能及病理检查均未见明显的改变。     

急性肝性脑病大鼠脑水肿与脑水通道蛋白-4的相关性

目的 探讨水通道蛋白-4(AQP4)在急性肝衰竭肝性脑病与脑水肿的相关性。方法 采用硫代乙酰胺(TAA)腹腔注射制备急性肝衰竭肝性脑病大鼠模型。将健康雄性SD大鼠随机分为对照组8只和模型组24只,其中模型组根据造模后处死大鼠时间不同,分为24、48、60h组。观察大鼠一般情况,评估HE等级,测定血浆丙氨酸转氨酶、天冬氨酸转氨酶、总胆红素和血氨,观察肝组织病理学,检测脑含水量和脑组织AQP4（包括蛋白和mRNA）表达水平。结果 模型组大鼠表现出典型肝性脑病症状,随着造模后观察时间延长,HE等级进行性升高,肝脏生化和血氨水平较对照组显著升高(P＜0.05),肝组织病理变化与对照组差异有统计学意义。脑含水量和AQP4表达水平（包括蛋白和mRNA）明显高于对照组(P＜0.05),并且AQP4蛋白和mRNA表达水平分别与脑含水量呈正相关(r =0.536,P＜0.01;r=0.566,P=0.01)。结论 急性肝衰竭肝性脑病大鼠脑水通道蛋白-4(AQP4)表达与脑水肿密切相关,因此AQP4是急性肝衰竭肝性脑病脑水肿发生发展的重要分子机制之一。     

TAA诱导大鼠肝硬化模型及内毒素血症在肝硬化中作用的探讨

目的:建立稳定高效的硫代乙酰胺(thioacetamide,TAA)大鼠肝纤维化模型,探讨TAA诱导大鼠肝纤维化模型最佳初始浓度,观察大鼠肝纤维化模型建立成功后肝脏病理、血清ALT、内毒素变化。方法:SD雄性大鼠30只,随机分为两组,对照组15只、TAA组15只,对照组只给予饮用水,TAA组前6周在饮用水中加入0.03%TAA、后6周在饮用水中加入0.04%TAA造模,共12周。结果:TAA组肝硬化形成率95.8%,病死率4.2%;TAA组光镜下见正常肝小叶结构消失,形成大小不等的假小叶;TAA组血浆ALT水平及内毒素明显高于对照组,差异有统计学意义(P0.05)。结论:口服0.03%TAA作为诱导剂量,可成功诱导大鼠肝硬化,且肝硬化形成率高,该剂量大鼠死亡率低;且说明内毒素血症与大鼠肝硬化有一定关系。     

Additive Inhibitory Effect of Experimentally Induced Hepatic Cirrhosis by Agonists of Peroxisome Proliferator Activator Receptor γ and Retinoic Acid Receptor

Peroxisome proliferator activator receptor (PPAR) ligands prevent liver fibrosis, while the role of all-trans retinoic acid (ATRA) and its metabolite 9-cis retinoic acid (9-cis RA) is less clear. We have investigated the ability of the combination of PPARγ ligand rosiglitazone (RSG) and of ATRA to prevent liver fibrosis. In vivo treatment with RSG or ATRA reduced fibrotic nodules, spleen weight, and hydroxyproline levels in rat model of thioacetamide-induced liver fibrosis. The combination of ATRA + RSG caused the strongest inhibition, accompanied by decreased expression of collagen I, α-smooth muscle actin, TGFβ1, and TNFα. In vitro studies showed that PPARγ ligand 15-deoxy-Δ12,14-prostaglandinJ(2)[PJ(2)] and RXR ligand 9-cis RA or PJ(2) and ATRA inhibited proliferation of hepatic stellate cells HSC-T6. 9-cis RA inhibited c-jun levels and also inhibited expression of its receptor RXRα in HSC-T6 cells. The combination of PPAR-γ and RAR agonists demonstrated an additive effect in the inhibition of TAA-induced hepatic fibrosis, due to inhibition of HSC proliferation and reduction of profibrotic TGFβ1 and proinflammatory TNFα.     

During Thioacetamide-Induced Acute Liver Failure, the Proliferative Response of Hepatocytes to Thyroid Hormone Is Maintained, Indicating a Potential Therapeutic Approach to Toxin-Induced Liver Disease

In toxic liver injury, proliferation of preexisting hepatocytes helps restore liver mass and function. While loss of liver mass per se stimulates hepatocyte proliferation, exogenous mitogens have a potential role in enhancing liver regeneration. The aim of this study was to characterize the effects of the mitogen, tri-iodothyonine, on the regenerative capacity of hepatocytes during thioacetamide-induced liver failure. Rats received (two) thioacetamide injections and, 12 hr later, either tri-iodothyonine or vehicle-only control. Liver cell proliferation was assessed and comparison made with other control groups receiving tri-iodothyonine or vehicle only. In rats with thioacetamide-induced hepatitis the proportion of hepatocytes in S-phase was greater in the tri-iodothyonine group (27±3.5%) compared to the vehicle-only group (20±2.5%; P < 0.05), with, notably, a greater number of midzonal (BrdU) positive hepatocytes in the tri-iodothyonine group. We conclude that the ability of hepatocytes in the midzonal areas of rat liver to proliferate in response to tri-iodothyonine is maintained during severe acute toxic injury.     

解毒化瘀方对轻微型肝性脑病大鼠行为学、学习记忆能力、血浆内毒素、血氨、肝功能及肝脏病理影响随机平行对照研究

[目的]观察解毒化瘀方对轻微型肝性脑病大鼠行为学、学习记忆能力、血浆内毒素、血氨、肝功能及肝脏病理的影响。[方法]使用随机平行对照方法,将60只SD雄性大鼠编号按随机数字表法随机分为正常对照组A、模型组B、中药组C、乳果糖组D、中药+乳果糖组E(12只/组)。除正常对照组,各组皆予小剂量硫代乙酰胺(TAA)200mg/kg隔日腹腔注射建立MHE模型,造模前5日至造模后3天B、C、D、E组分别给予生理盐水、解毒化瘀汤剂、乳果糖、解毒化瘀汤剂+乳果糖灌胃10天。观察行为学、学习记忆能力变化,检测血浆内毒素、血氨、肝功能、肝组织病理变化。[结果]模型组大鼠学习和记忆功能下降,血浆内毒素、血氨、肝功等明显升高,出现肝细胞气球样变和中央静脉为中心的肝小叶点状坏死,炎性细胞浸润明显。中药组、乳果糖组、中药+乳果糖组大鼠学习和记忆功能、血浆内毒素、血氨、肝功、肝脏病理等较之明显好转(P<0.05);三者差异无显著性(P>0.05)。[结论]解毒化瘀方对TAA诱导的MHE大鼠有一定的保护作用。     

The effect of melatonin treatment on oxidative and nitrosative stress in rats with thioacetamide-induced hepatic damage.

BACKGROUND:: The following study aimed to clarify the importance of arginase and NOS activities in thioacetamide-induced hepatic damage and to evaluate the underlying mechanism of proposed protection provided by melatonin, using commonly applied therapeutic dose. METHODS:: Rats were randomly assigned to four groups (n=5): control, melatonin (10mg/kg i.p.), thioacetamide (200mg/kg i.p., two doses with a 24h interval) and thioacetamide+three doses of melatonin (10mg/kg i.p., prior- and post-treatment with a 24h interval before thioacetamide administrations) treated groups. RESULTS:: Thioacetamide administration caused hepatic damage creating oxidative and nitrosative stress accompanying perivenous necrosis and eosinophil infiltration. The significant elevation of total nitrite level in livers of thioacetamide treated groups reflected the activation of inducible nitric oxide synthase activity. The decrease in arginase activity indicated hepatic damage. Non-altered specific activity of arginase in the livers of thioacetamide treated groups did not overcome the elevation of NO production. Melatonin treatment did not modulate the levels/activities significantly. CONCLUSIONS:: Our results have indicated that nitrosative stress seems to be essentially critical in thioacetamide-induced hepatic failure in rats. Possible regulatory effect of arginase on NO production and applied dose of melatonin could not prevent hepatic damage.     

Antihepatotoxic activity of monomethyl fumarate isolated from Fumaria indica

Monomethyl fumarate, isolated for the first time from the methanolic extract of the whole plant of Fumaria indica, was characterised and screened for its antihepatotoxic activity in albino rats. The compound showed significant (P<0.01) antihepatotoxic activity against thioacetamide in vitro, and against hepatotoxicities induced by carbon tetrachloride, paracetamol and rifampicin in vivo to an extent almost similar to that of silymarin, a known antihepatotoxic agent.