Research Article: Dopamine Burden Induced the Inactivation of Sonic Hedgehog Signaling to Cognitive Decline in Minimal Hepatic Encephalopathy

Date Published: July 21, 2017

Publisher: JKL International LLC

Author(s): Saidan Ding, Jianjing Yang, Xueli Huang, Leping Liu, Jiangnan Hu, Zhu Xu, Qichuan Zhuge.


Minimal hepatic encephalopathy (MHE) is induced by elevated intracranial dopamine (DA). The relationship of the Shh pathway with memory loss in MHE, however, is elusive. In the current study, rats with MHE induced with DA displayed downregulation of the Shh pathway. Additionally, injection of Shh into MHE/DA-treated rats reversed downregulation of BDNF/NT3, whereas administration of cyclopamine (Cyc) enhanced the inhibition of expression of BDNF/NT3. Furthermore, naringin (Nrg) substantially prevented cognitive impairment in MHE/DA-treated rats and upregulated the Shh pathway, paralleling the elevated expression of BDNF/NT3. Overall, our results indicate that the Shh pathway can induce the expression of BDNF/NT3, and DA causes memory loss by inactivation of Shh pathway signaling to BDNF/NT3 in MHE rats, which is reversed by Nrg. Our study may provide new theory basis of pathogenesis and therapeutic target of MHE.

Partial Text

Currently, there is growing interest in the pathogenesis of MHE. We previously found that COMT inhibitor, a protein involved in accumulation of DA, was up-regulated in cirrhotic liver in MHE by 2-DE/MS; we then found increased levels of DA in cirrhotic liver and hippocampus in MHE rats [3]. Our present study further confirmed that elevated DA in the brain from cirrhotic liver could induce the memory impairment of MHE. We here demonstrated that chronic stimulation of cortical astrocytes significantly reduced the expression of proteins in the Shh pathway in MHE rats. Thus, we have provided the first evidence suggesting that the Shh pathway may be important in the pathogenesis of memory impairment in MHE rats. One study found that dopamine agonists impair or have no effect on stimulus-response learning and working memory [20]. Our study also indicated that increased dopamine impairs memory function. Furthermore, changes in DA levels in vivo and in vitro have been shown to regulate the expression of the Shh signaling cascade.




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