Cyclo(His-Pro) promotes cytoprotection by activating Nrf2-mediated up-regulation of antioxidant defence.
Hystidyl-proline [cyclo(His-Pro)] is an endogenous cyclic dipeptide produced by the cleavage of thyrotropin releasing hormone. Previous studies have shown that cyclo(His-Pro) protects against oxidative stress, although the underlying mechanism has remained elusive. Here, we addressed this issue and found that cyclo(His-Pro) triggered nuclear accumulation of NF-E2-related factor-2 (Nrf2), a transcription factor that up-regulates antioxidant-/electrophile-responsive element (ARE-EpRE)-related genes, in PC12 cells. Cyclo(His-Pro) attenuated reactive oxygen species production, and prevented glutathione depletion caused by glutamate, rotenone, paraquat and beta-amyloid treatment. Moreover, real-time PCR analyses revealed that cyclo(His-Pro) induced the expression of a number of ARE-related genes and protected cells against hydrogen peroxide-mediated apoptotic death. Furthermore, these effects were abolished by RNA interference-mediated Nrf2 knockdown. Finally, pharmacological inhibition of p-38 MAPK partially prevented both cyclo(His-Pro)-mediated Nrf2 activation and cellular protection. These results suggest that the signalling mechanism responsible for the cytoprotective actions of cyclo(His-Pro) would involve p-38 MAPK activation leading to Nrf2-mediated up-regulation of antioxidant cellular defence.
Minelli
Alba
A
Dipartimento Medicina Sperimentale Scienze Biochimiche, Università di Perugia, Italy. aminelli@unipg.it <aminelli@unipg.it>
Conte
Carmela
C
Grottelli
Silvia
S
Bellezza
Ilaria
I
Cacciatore
Ivana
I
Bolaños
Juan P
JP
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D018698:Glutamic Acid / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D016716:PC12 Cells; D010269:Paraquat / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D034622:RNA Interference; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012402:Rotenone / Q000494:pharmacology; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000975:Antioxidants; D051267:NF-E2-Related Factor 2; D016877:Oxidants; D010456:Peptides, Cyclic; D010879:Piperazines; D017382:Reactive Oxygen Species; D012402:Rotenone; D018698:Glutamic Acid; D006861:Hydrogen Peroxide; D048051:p38 Mitogen-Activated Protein Kinases; D005978:Glutathione; D010269:Paraquat; C015924:histidyl-proline diketopiperazine; D002118:Calcium