Methamphetamine Induces Heme Oxygenase-1 Expression via Activation of PI3K/Akt pathway

• Main Authors: Chin-Yu Lin, 林欽昱
• Other Authors: Jiin-Cherng Yen
• Format: Others
• Language: zh-TW
• Published: 2007
• Online Access: http://ndltd.ncl.edu.tw/handle/92981414369352350564

碩士 === 國立陽明大學 === 藥理學研究所 === 95 === Previous studies indicate that production of reactive oxygen species contributes to neurotoxic effect of methamphetamine (METH). Moreover, we have shown that the antioxidative enzyme heme oxygenase-1 (HO-1) exhibits neuroprotective effect against METH-induced neurotoxicity. However, the molecular mechanism of HO-1 expression induced by METH is still unclear. In this study, I found that METH (3 mM) treatment increased HO-1 expression in human dopaminergic neuroblastoma cell line SH-SY5Y. Pretreatment of dopamine transporter inhibitor GBR12909 did not affect METH-induced HO-1 expression. This suggested that METH increased HO-1 level through a dopamine transporter-independent mechanism. It was found that ERK MAP kinase was activated by METH treatment, while the phosphorylation of JNK and p38 MAPK were not increased by METH. Nevertheless, the increase of HO-1 elicited by METH was not inhibited by the MEK inhibitor PD98059. These results indicated that MAPK signaling pathwat may be not involved in METH-induced HO-1 expression. Furthermore, phospho-Akt level was increased by METH treatment. Pretreatment of antioxidant N-acetylcysteine (NAC) or PI3K inhibitor LY294002 attenuated METH-induced HO-1 expression. In addition, transcription factor NF-E2-related factor-2 (Nrf2) translocated to nucleus after METH treatment. These results suggested that METH-induced HO-1 expression was dependent on activation of PI3K/Akt pathway and nuclear translocation of Nrf2. According to the result from real-time PCR, HO-1 mRNA content was increased after 1 hour exposure of METH. Administration of cycloheximide inhibited METH-induced HO-1 upregulation. These results indicated that HO-1 induction by METH required protein synthesis. HO-1 inhibitor zinc protoporphyrin enhanced oxidative stress produced by METH. It demonstrated the antioxidative effect of HO-1 in this model. In conclusion, oxidative stress generated from METH activated PI3K/Akt signaling pathway and leaded to increased nuclear translocation of Nrf2, thereby upregulated HO-1 expression.