Cyclo(His-Pro) up-regulates heme oxygenase 1 via activation of Nrf2-ARE signalling
Article first published online: 7 SEP 2009
© 2009 The Authors. Journal Compilation © 2009 International Society for Neurochemistry
Journal of Neurochemistry
Volume 111, Issue 4, pages 956–966, November 2009
How to Cite
Minelli, A., Conte, C., Grottelli, S., Bellezza, I., Emiliani, C. and Bolaños, J. P. (2009), Cyclo(His-Pro) up-regulates heme oxygenase 1 via activation of Nrf2-ARE signalling. Journal of Neurochemistry, 111: 956–966. doi: 10.1111/j.1471-4159.2009.06376.x
- Issue published online: 16 OCT 2009
- Article first published online: 7 SEP 2009
- Received March 25, 2009; revised manuscript received July 22, 2009; accepted August 26, 2009.
Article first published online: 13 JUL 2011
- cyclic dipeptide;
- Parkinson’s disease;
- reactive oxygen species
Paraquat (1,1′-dimethyl-4,4′-bipyridinium), a widely used non-selective herbicide, is a redox cycling agent with adverse effects on dopamine systems. Epidemiological data have shown that exposure to paraquat is one of the several risk factors for Parkinson’s disease. We have already shown that cyclo(His-Pro), an endogenous cyclic dipeptide produced by the cleavage of the thyrotropin releasing hormone, has a cytoprotective effect through a mechanism involving Nrf2 activation that decreases production of reactive oxygen species and increases glutathione synthesis. Using primary neuronal cultures and PC12 cells as targets of paraquat neurotoxicity, we addressed whether and how cyclo(His-Pro) causes cellular protective response against paraquat-mediated cell death. We found that cyclo(His-Pro) attenuated reactive oxygen species production, and prevented glutathione depletion by up-regulating Nrf2 gene expression, triggering its nuclear accumulation and activating the expression of heme oxygenase1. These protective effects were abolished by RNA interference-mediated Nrf2 knock down whereas were unaffected by RNA interference-mediated Keap1 knock down. Inhibition of heme oxygenase activity decreased cyclo(His-Pro)-induced neuroprotection. These results suggest that cyclo(His-Pro), acting as a selective activator of the brain modulable Nrf2 pathway, may be a promising candidate as neuroprotective agent that act through induction of phase II genes.