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.
Highlights
Neurodegenerative diseases such as Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD) and Parkinson’s disease (PD), are late-onset multifactorial disorders with a progressive loss of function of neurons, which leads to a progressive functional decline
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
Consistent with this possibility, we showed that cyclo(His-Pro) abolished hydrogen peroxide-mediated reactive oxygen species (ROS) and NO generation and glutathione depletion, which lead to apoptotic cell death [10]
Summary
Neurodegenerative diseases such as Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD) and Parkinson’s disease (PD), are late-onset multifactorial disorders with a progressive loss of function of neurons, which leads to a progressive functional decline. Cyclo(His-Pro) is selectively transported by OCT2 in the brain [36]. The distribution of cyclo(His-Pro) itself in rat brain reveals striking coincidence with both dopaminergic areas and OCT2 consistent with the potential functional link previously reported in the literature [23,40]. Structure/function studies have identified the proline residue and the presence of unsaturated systems as structural elements contributing to the nootropic and cognitive-enhancing properties, as well as the overall neuroprotective action of the natural/synthetic cyclic dipeptides [2,3,4,5,6,11,41,42]. A decline in protective cyclo(His-Pro) may underpin calcium-triggered apoptotic cell death, possibly contributing to the selective chronic nigral degeneration observed in Parkinson’s disease [37]
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