Cyclo(His-Pro) up-regulates heme oxygenase 1 via activation of Nrf2-ARE signalling

J Neurochem. 2009 Nov;111(4):956-66. doi: 10.1111/j.1471-4159.2009.06376.x. Epub 2009 Sep 7.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / pharmacology*
  • Brain / cytology
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Electrophoretic Mobility Shift Assay / methods
  • Embryo, Mammalian
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Female
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / metabolism*
  • Herbicides / pharmacology
  • Intracellular Signaling Peptides and Proteins
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • Neurons / drug effects
  • Paraquat / pharmacology
  • Peptides, Cyclic / pharmacology*
  • Peroxiredoxins / metabolism*
  • Piperazines / pharmacology*
  • Pregnancy
  • Proteins / genetics
  • Proteins / metabolism
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / metabolism
  • RNA, Small Interfering / pharmacology
  • Rats
  • Rats, Wistar
  • Signal Transduction / drug effects*
  • Signal Transduction / physiology
  • Time Factors
  • Transfection / methods
  • Up-Regulation / drug effects*


  • Antioxidants
  • Enzyme Inhibitors
  • Herbicides
  • Intracellular Signaling Peptides and Proteins
  • KEAP1 protein, rat
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • Peptides, Cyclic
  • Piperazines
  • Proteins
  • RNA, Messenger
  • RNA, Small Interfering
  • Peroxiredoxins
  • Heme Oxygenase-1
  • Paraquat
  • histidyl-proline diketopiperazine