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Int. J. Mol. Sci. 2016, 17(8), 1332; doi:10.3390/ijms17081332

The Role of Cyclo(His-Pro) in Neurodegeneration

1
Dipartimento di Medicina Sperimentale, Università di Perugia, Polo Unico Sant’Andrea delle Fratte, Piazzale Gambuli, 06132 Perugia, Italy
2
Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano ed Istituto di Neuroscienze, Consiglio Nazionale delle Ricerche, Via Vanvitelli 32, 20129 Milano, Italy
*
Author to whom correspondence should be addressed.
Academic Editor: Katalin Prokai-Tatrai
Received: 4 July 2016 / Revised: 4 August 2016 / Accepted: 8 August 2016 / Published: 12 August 2016
(This article belongs to the Special Issue Neuroprotective Strategies 2016)
View Full-Text   |   Download PDF [1139 KB, uploaded 12 August 2016]   |  

Abstract

Neurodegenerative diseases may have distinct genetic etiologies and pathological manifestations, yet share common cellular mechanisms underpinning neuronal damage and dysfunction. These cellular mechanisms include excitotoxicity, calcium dysregulation, oxidative damage, ER stress and neuroinflammation. Recent data have identified a dual role in these events for glial cells, such as microglia and astrocytes, which are able both to induce and to protect against damage induced by diverse stresses. Cyclo(His-Pro), a cyclic dipeptide derived from the hydrolytic removal of the amino-terminal pyroglutamic acid residue of the hypothalamic thyrotropin-releasing hormone, may be important in regulating the nature of the glial cell contribution. Cyclo(His-Pro) is ubiquitous in the central nervous system and is a key substrate of organic cation transporters, which are strongly linked to neuroprotection. The cyclic dipeptide can also cross the brain-blood-barrier and, once in the brain, can affect diverse inflammatory and stress responses by modifying the Nrf2-NF-κB signaling axis. For these reasons, cyclo(His-Pro) has striking potential for therapeutic application by both parenteral and oral administration routes and may represent an important new tool in counteracting neuroinflammation-based degenerative pathologies. In this review, we discuss the chemistry and biology of cyclo(His-Pro), how it may interact with the biological mechanisms driving neurodegenerative disease, such as amyotrophic lateral sclerosis, and thereby act to preserve or restore neuronal function. View Full-Text
Keywords: oxidative stress; endoplasmic reticulum stress; neuroinflammation oxidative stress; endoplasmic reticulum stress; neuroinflammation
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MDPI and ACS Style

Grottelli, S.; Ferrari, I.; Pietrini, G.; Peirce, M.J.; Minelli, A.; Bellezza, I. The Role of Cyclo(His-Pro) in Neurodegeneration. Int. J. Mol. Sci. 2016, 17, 1332.

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