Protective role of brain CYP2J in diverse Parkinson disease animal models / 中国药理学与毒理学杂志

ABSTRACT

OBJECTIVE CYP2 family including CYP2C and CYP2J is the predominant arachidonic acid (AA) epoxygenase, and the epoxidation of AA produces four regioisomeric cis-epoxyeicosatrienoic acids (5,6-, 8,9-, 11,12-, and 14,15-EET). Human CYP2J2 is one of the main CYP isoforms expressed in brain, but CYP2C8 was present at a low level. The aim of this study is to investigate the roles of brain CYP2J in Parkinson disease. METHODS Rats received the right-unilaterally injection with concentrated LV-CYP2J3 or LV-EGFP in the substantia nigra (SN) at 3 d before LPS or 6-OHDA treatment. The animals were tested for rotational behavior with the dopaminergic agonist apomorphine dissolved in sterile saline at 14 and 21 d after LPS injection. The influence of CYP2J-dependent derivative, 14,15-EET, on the genes related with oxidative stress was assayed in SH-SY5Y cells. RESULTS CYP2J overexpression or 14,15-EET treatment significantly increased the levels of SOD1, CAT, GPX1, NRF2 and KEAP1 in neurons. TLR4- MyD88 signaling pathway was involved the down- regulation of CYP2J by LPS. The binding of p-CREB with the promoter of CYP2J was inhibited by the LPS treatment. The loss of dopami?nergic neurons in the right SN induced by LPS or 6- OHDA was significantly decreased by CYP2J3 transfection at 21 d after LPS injection. Compared with LPS or 6-OHDA group, the number of the rotation of rats was decreased by 42.6% and 60.7% by CYP2J3 transfection at 14 d after LPS or 6-OHDA injection;meanwhile, the rotation number was decreased by 12.7% and 21.3% at 21 d. The accumulation of alpha synuclein induced by LPS was significantly decreased by CYP2J3 transfection. The mRNA levels of SOD1, CAT, GPX1, NRF2 and KEAP1 in SN were decreased by LPS, which was attenuated by the injection of LV-CYP2J3. CONCLUSION Brain CYP2J can play a protective role in the damage of the inflammation and oxidative stress to the dopaminergic neurons. Brain CYP2J- dependent derivatives from AA may have therapeutic effects in Parkinson disease via the up- regulation of the antioxidant system in neurons.