Neuroinflammation and endoplasmic reticulum stress are coregulated by cyclo(His-Pro) to prevent LPS neurotoxicity.
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.
Dipartimento di Medicina Sperimentale Università di Perugia, polo Unico S. Andrea delle Fratte, 06123 Perugia, Italy. Electronic address: ilaria.bellezza@unipg.it.
Ilaria
I
Bellezza
Dipartimento di Medicina Sperimentale Università di Perugia, polo Unico S. Andrea delle Fratte, 06123 Perugia, Italy.
Silvia
S
Grottelli
Dipartimento di Medicina Sperimentale Università di Perugia, polo Unico S. Andrea delle Fratte, 06123 Perugia, Italy.
Anna Lisa
AL
Mierla
Dipartimento di Scienze del Farmaco, Università di Chieti, Via dei Vestini, 66013 Chieti, Italy.
Ivana
I
Cacciatore
Dipartimento di Scienze del Farmaco, Università di Chieti, Via dei Vestini, 66013 Chieti, Italy.
Erika
E
Fornasari
Dipartimento di Scienze Farmaceutiche, Borgo XX Giugno 74, Università di Perugia, 06121 Perugia, Italy.
Luca
L
Roscini
Dipartimento di Scienze Farmaceutiche, Borgo XX Giugno 74, Università di Perugia, 06121 Perugia, Italy.
Gianluigi
G
Cardinali
Dipartimento di Medicina Sperimentale Università di Perugia, polo Unico S. Andrea delle Fratte, 06123 Perugia, Italy.
Alba
A
Minelli
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000502:physiology; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D015398:Signal Transduction
D000890:Anti-Infective Agents; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495636:Nfe2l2 protein, mouse; D010456:Peptides, Cyclic; D010879:Piperazines; D009569:Nitric Oxide; C015924:histidyl-proline diketopiperazine
Bip; NF-κB; Nrf2; TNFα; Tunicamycin