Molecular Mechanisms Of Thioredoxin And DARPP-32Expression Induced By Ephedrine

Ephedrine is an alkaloid that has been isolated from the ephedra (ma huang).It can not only directly activate adrenoceptors, but also indirectly activate adrenoceptors through making adrenalin nervous terminal release noradrenalin. Therefore it can activate both α-and β-adrenoceptors. Ephedrine has long been used as a sympathormimetic drug in the treatment of angiocardiopathy. asthma and hypotension. It has functions of anti-fatigue and exciting central nervous system. Long term using ephedrine can result in drug dependence. Thus, ephedrine is also a psychostimulant drug. It can generate the excitation or repression of neurons and influence synaptic plasticity and other sophisticated functions such as study and memory.It is not clearly about the mechanism of ephedrine-induced drug dependence. Studying of ephedrine can further ascertain the mechanism of drug addiction and provide a theory evidence for drug withdrawal. Hence this study is of important significance.Thioredoxin(Trx) is a12-kDa protein which is broadly expressed in prokaryote and eucaryote. It is of the utmost importance for cells maintaining the redox state. Trx is a defensive protein induced by various stress and has functions of anti-apoptotic, anti-inflammatory and regulating transcription factor activity.Dopamine and adenosine3'5'-monophosphate-regulated phospho-protein (DARPP-32) is a protein of having double function. It is not only the inhibitor of phosphoesterase-1(PP-1), but also the inhibitor of protein kinase A(PKA). DARPP-32is high expressed in striatum neurons and is very important in protecting dopaminergic neuron. It plays important roles in drug addiction, depression and schizophrenia.cAMP response element binding protein(CREB) is a transcription factor in eukaryote and plays important roles in the regulations of neurogenesis, synapse formation, learning and memory, drug addiction and depression. However. it is unclear about the effect of ephedrine on Trx-1,DARPP-32and p-CREB.By using PC12as the object of study, we investigated the effect of ephedrine on the expression of Trx-1, DARPP-32and p-CREB. The results showed that ephedrine could promote the growth of PC12cells and induce the expression of Trx-1, DARPP-32and p-CREB in PC12cells. The inhibitors of cAMP/PKA signal pathway and β-adrenoceptor attenuated the increase of Trx-1and DARPP-32expression induced by ephedrine. However, the inhibitor of a-adrenoceptor could not block the expression of Trx-1and DARPP-32. In addition, Trx-1had no influence on the expression of DARPP-32.In conclusion, this study suggests that ephedrine induced the expression of Trx-1and DARPP-32through β-adrenoceptor/cAMP/PKA signal pathway. And ephedrine may phosphorylate CREB through cAMP/PKA signal pathway and up-regulate Trx-1and DARPP-32expression. So ephedrine can regulate the expression of DARPP-32and CREB which are involved in addiction, suggesting association between ephedrine and addiction. The mechanism of ephedrine addiction should be further studied in animals.