The Neuroprotective Effects Of Rehmannia And Storesin In Early Hepatic Encephalopathy Rat Model

Hepatic encephalopathy (HE) is defined as a disturbance in central nervous system function because of hepatic insufficiency. This broad definition reflects the existence of a spectrum of neuropsychiatric manifestations from minimal changes in personality or altered sleep-waking cycle to altered cognitive function and motor activity and coordination.The main tenet of all theories of the pathogenesis of HE is firmly accepted: nitrogenous substances derived from the gut adversely affect brain function. These compounds gain access to the systemic circulation as a result of decreased hepatic function. Once in brain tissue, they produce alterations of neurotransmission that affect consciousness and behavior. A large body of work points at ammonia as a key factor in the pathogenesis of HE. Furthermore, the alterations in neurotransmission induced by ammonia also occur after the metabolism of this toxin into astrocytes, resulting in a series of neurochemical events caused by the functioning alteration of this cell. Ammonia activates peripheral-type benzodiazepine receptors with subsequent stimulation of the GABA-ergic system, an effect also induced directly by ammonia. Recent reports support the idea that hyperammonemia and inflammation cooperate in inducing the neurological alterations in HE.At present, the mechanisms of HE are still unclear, and there is no definitive treatment or cure for HE. A large segment of the public findings solace in herbs, in part believing that herbs are natural and hence safer than synthetic drugs, and that a complex mixture of herbs can effectively treat complex diseases. In addition, the metabolite profile of herbal medicine is important for screening its active constituents, thus providing a valuable contribution to the drug discovery process and elucidation of the underlying mechanism of action. In the present study, the neuroprotective effect of RS against CCl4-induced impairment was observed in vivo. We used RS to treat the rats i.g. with CCl4, lactulose as the positive conrol. The results suggested RS could be considered as a potential agent for preventing or retarding the development or progression of HE.1. There were multiple components in RS. The main components of Storesin were analyzed by HPLC.2. The animals were randomly distributed in the following groups:control, model, lactulose (i.g. treated with lactulose6g/kg), RS-L (i.g. treated with R:0.5+S:0.008g/kg), RS-M (i.g. treated with R:1.0+S:0.016g/kg) and RS-H (i.g. treated with R:2.0+S:0.032g/kg). To induce hepatic encephalopathy, all the rats except the ones in control group were treated with a mixture of CCl4and olive oil (1:1vol/vol, at a dose of1ml/kg) by a gavage tube twice a week for12weeks. Control animals were treated with the solvent alone.3. The weight of rats was monitored every week. The body weight changed since the3rd week. There was a significant weight loss in model animals compared with control group (P<0.01). The RS-H treatment significantly reversed the changes of the body weight (P<0.05).4. Total distances, square crossing times, times in inner zone and rearing frequency in open field test revealed a significant decrease (P<0.01) for the model group in comparison to the control group. RS-H-treated rats exhibited longer distance than that of the model (P<0.05). RS treatment inreased the square crossing times and rearing frequeny, but the improvement did not achieve statistical significance. Morris water maze data showed that model animals exhibited obviously longer escape latencies. The lactulose and RS-H significantly shortened escape latenies (P<0.05). The swim speed of model rats slowed down. The model rats exhibited a decreased OE of EPM(P<0.05).5. The hepatosomatic index significantly decreased in model rats compared with control group (P<0.01), and the RS-M and RS-H treatment effectively increased the hepatosomatic index (P<0.05); the spleen index significantly increased in model rats compared with control group (P<0.01), and the RS-M treatment effectively decreased the spleen index (P<0.05).6. The level of serum ALT、Amm、NO、TNOS and iNOS significantly increased in model rats compared with control group (P<0.01), which could be decreased by RS treatment. The level of serum total protein and albumin decreased compared with control group (P<0.05, P<0.01), RS treatment could improve these indexes without statistical significance.7. ELISA results indicated the TNF-a level significantly increased compared with control group (P<0.01), which was decreased by RS-M and RS-H treatment (P<0.05, P<0.01)8. Our findings showed that compared with control group, there was a significant increase in the Bmax value of both PBRs and NMDA-R (P<0.01), which was reduced by RS-H treatment (P<0.01).9. Immunohistostaining results indicated liver cirrhosis in model group, RS treatment reduced the cell degeneration and necrosis. Compared with control group, the number of BrdU, NeuN and GFAP positive cells in model rats hippocampus decreased (P<0.01), RS treatment could increased the number of positive cells.The results of presnet study incicate that RS treatment leads to the increase of spontaneous movement and the improvement of learning and memory ability; mitigates the liver damage induced by CCl4; ablates the toxic effect caused by hyperammonemia, inhibits the increase of both PBRs and NMDA receptors, promotes hippocampal neurogenesis and the proliferation and differentiation of NSC.