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2016 ; 17
(8
): ä Nephropedia Template TP
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The Role of Cyclo(His-Pro) in Neurodegeneration
#MMPMID27529240
Grottelli S
; Ferrari I
; Pietrini G
; Peirce MJ
; Minelli A
; Bellezza I
Int J Mol Sci
2016[Aug]; 17
(8
): ä PMID27529240
show ga
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-?B 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.
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