Neuroinflammation and endoplasmic reticulum stress are coregulated by cyclo(His-Pro) to prevent LPS neurotoxicity.

Abstract

Many neurological and neurodegenerative diseases are associated with oxidative stress and glial inflammation, all related to endoplasmic reticulum stress. Cyclo(His-Pro) is an endogenous cyclic dipeptide that exerts cytoprotection by interfering with the Nrf2-NF-κB systems, the former presiding the antioxidant and the latter the pro-inflammatory cellular response. Here we investigated whether the cyclic dipeptide inhibits glial inflammation thus reducing the detrimental effect of inflammatory neurotoxins on neurons. We found that systemic administration of cyclo(His-Pro) exerts in vivo anti-inflammatory effects in the central nervous system by down-regulating hepatic and cerebral TNFα expression thereby counteracting LPS-induced gliosis. Mechanistic studies indicated that the cyclic dipeptide-mediated effects are achieved through the activation of Nrf2-driven antioxidant response and the inhibition of the pro-inflammatory NF-κB pathway. Moreover, by up-regulating Bip, cyclo(His-Pro) increases the ER stress sensitivity and triggers the unfolded protein response to alleviate the ER stress. These results unveil a novel potential therapeutic use of cyclo(His-Pro) against neuroinflammatory-related diseases and we might now consider its potential anti-inflammatory role in other neuropathological conditions.

• Authors: Ilaria Bellezza, Silvia Grottelli, Anna Lisa Mierla, Ivana Cacciatore, Erika Fornasari, Luca Roscini, Gianluigi Cardinali, Alba Minelli
• Journal: The international journal of biochemistry & cell biology (Int J Biochem Cell Biol) Vol. 51 Pg. 159-69 (Jun 2014) ISSN: 1878-5875 [Electronic] Netherlands
• PMID: 24699213 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Anti-Infective Agents
• Lipopolysaccharides
• NF-E2-Related Factor 2
• NF-kappa B
• Nfe2l2 protein, mouse
• Peptides, Cyclic
• Piperazines
• Nitric Oxide
• histidyl-proline diketopiperazine

Topics

• Animals
• Anti-Infective Agents (pharmacology)
• Endoplasmic Reticulum Stress (drug effects, physiology)
• Inflammation (chemically induced, metabolism, pathology, prevention & control)
• Lipopolysaccharides
• Male
• Mice
• Mice, Inbred C57BL
• Microglia (drug effects, metabolism, pathology)
• NF-E2-Related Factor 2 (metabolism)
• NF-kappa B (metabolism)
• Neurotoxicity Syndromes (metabolism, pathology, prevention & control)
• Nitric Oxide (antagonists & inhibitors, metabolism)
• Oxidative Stress (drug effects)
• Peptides, Cyclic (pharmacology)
• Piperazines (pharmacology)
• Signal Transduction