| Parkinson disease (PD) is an age-related neurodegenerative disease. Movement disorder is its main clinical features. The selective degeneration of dopaminergic neurons in the substantia nigra of the ventral midbrain results in a gradual reduction of the striatal dopamine levels in Parkinson disease. At present most of the pharmacotherapeutic approaches in PD are aimed at replenishing the striatal dopamine. Although these drugs provide symptomatic relief during early PD, many patients develop motor complications with long-term treatment. Further, PD medications do not effectively tackle tremor, postural instability and cognitive deficits. The most important thing is that most drugs do not have neuroprotective effects. Therefore, choosing natural antioxidants and plant products which have the neuroprotective properties for the primary or secondary treatment strategies has been proposed. Curcumin and resveratrol are the star compounds. Many studies have shown that natural antioxidants such as resveratrol and curcumin have good therapeutic effects on different experimental models of PD.In this paper, we selected the 6-hydroxydopamine (6-OHDA)-induced PC12 cell injury as the Parkinson disease model to investigate the adaptive protective activity, structure-activity relation and mechanism of resveratrol and curcumin analogs against the injury.(1) A series of resveratrol analogs (3,5,4’-THD,3,4-DHS,3,4-DHD,4,4’-DHS,4,4’-DHD, 4,4’-DHT) structurally characterized by ortho-dihydroxyl,para-dihydroxyl groups or/and elongation of the conjugated links which have better antioxidant activity than this parent molecule, were chose to explore their cytoprotective effect on 6-OHDA-induced PC 12 cell injury. It was found that only the compounds (3,4-DHS and 3,4-DHD) bearing ortho-dihydroxyl groups exhibited the cytoprotective activity, and the activity of the latter was higher than that of the former. Moreover, they also inhibited the cell apoptosis and the formation of reactive oxygen species (ROS) induced by 6-OHDA. Treatment with 3,4-DHD significantly increased the cellular GSH and the mRNA expression of GCL, the rate-limiting enzyme of GSH synthesis. However, co-treatment with 3,4-DHD and BSO (a GCL inhibitor) or LY294002 (a PI3K-Akt pathway inhibitor), completely abolished the cytoprotective activity and the mRNA expression of GCL induced by this compound. Therefore, we could conclude that 3,4-DHD enhances nuclear translocation of Nrf2, through either Nrf2 phosphorylation via PI3K-Akt protein kinase pathway or Keapl modification via its oxidative product, ortho-quinone, resulting in the transcription of GCL, a phase Ⅱ enzyme and the increased GSH level to protect against the cellular oxidative stress induced by 6-OHDA.(2) A series of ortho-substituted mono-carbonyl curcumin analogs (2-OH,2-OCH3,2-CF3, 2,2’-OH,2,2’-OCH3,2,2’-CF3) having relatively high Michael acceptor activity in comparison with this parent molecule, were chose to study their cytoprotective activity against 6-OHDA-induced PC 12 cell injury. All the compounds tested exhibited varying degrees of cytoprotective effects and all the mono-carbonyl analogs were more active than this parent molecule. Additionally, all the ortho-disubstituted compounds showed superior cytoprotective activity compared with the corresponding ortho-monosubstituted compounds. In view of the low cytotoxicity and metabolism stability of 2,2’-CF3, we selected this compound to investigate its cytoprotective mechanism. Cellular GSH and real-time quantitative polymerase assay and influence of the GCL and PI3K-Akt pathway inhibitors on the activity of 2,2’-CF3 indicate that this compound may modify Keapl by its Michael acceptor and/or phosphorylate Nrf2 through PI3K-Akt protein kinase pathway. Then Nrf2 dissociates from Keapl and gets into nucleus to regulate the transcription of GCLC and GCLM mRNA. The elevated GCL level promotes the increased GSH content followed by scavenging 6-OHDA-induced ROS and promoting cell survival. |
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