Exposure of human and animals to MPTP

Exposure of human and animals to MPTP can reproduce all the characteristic motor and non-motor signs of PD, in addition to mimicking the same responses and side effects to drugs used to treat PD [37], [38]. Anatomically, intoxication with MPTP induces the same selective loss of substantia nigra DA neurons that occurs in PD. In addition, some of the key biochemical changes elicited by MPTP treatment are the same as those identified in idiopathic and genetic forms of PD, such as deficiency in mitochondrial Complex I activity and induction of oxidative stress in DA neurons [39]. The rodent and nonhuman primate MPTP models have been used to develop both symptomatic and neuroprotective treatments for PD. The aim of this study was to evaluate Dln101 as a potential neuroprotective compound, in comparison with ghrelin, and investigate its GHSR-mediated effects that increase SN DA resilience to MPTP. Although Dln101-mediated neuroprotection of SN DA Carmoxirole hydrochloride was equivalent to that of ghrelin, its effect on electrical activity, dopamine release, locomotor behavior, and modulation of mitochondrial dynamics were very distinct despite the requirement of GHSR in mediating both molecules effects.
Materials and methods
Results
Discussion Ghrelin is mainly produced in the X/A-like gland cells of the gastric fundus mucosa [44] and, to a lesser degree, in the intestines, pancreas, gall bladder, liver, gonads, and breasts [45]. Ghrelin peptide is formed after post-translational processing of the 117-amino-acid peptide preproghrelin. Then, native ghrelin peptide is subject to a unique modification consisting of acylation (addition of an octanoyl group) of the third serine residue (Ser3), a process well conserved among mammalian species [46]. The enzyme responsible for ghrelin acylation, before its secretion, is known as ghrelin-O-acyl-transferase (GOAT), and is predominantly expressed in gastrointestinal organs [47], [48]. According to its acylation status, the peptide can be termed des-acyl or acyl ghrelin. De-acylation process is performed by esterases, including acyl-protein thioesterase-1/lysophospholipase-1 (APT-1), thought to be mainly responsible for ghrelin de-acylation in vivo [49]. Physiological action of acyl ghrelin gene products specifically in the midbrain has been matter of debate as ghrelin does not seem to be expressed in the central nervous system [50], [51] despite immunolabeling in arcuate nucleus neurons [52], [53], and some cells around the third ventricle [54]. On one hand, although only acyl ghrelin is able to activate GHSR, 66–94% of circulating ghrelin is actually found in the des-acyl form [55], [56], [57], due to the activity of esterases and APT-1 [49]. In addition, ghrelin has a limited capacity to cross the blood-brain-barrier [58]. On the other hand, Dln101 emerges as a relevant candidate to maintain GHSR activation due to its increased stability in the acylated residue. Des-acyl ghrelin is the predominant form of ghrelin, but the lack of acylation precludes it from binding to GHSR and subsequent receptor activation. Despite this, there are several reports describing des-acyl ghrelin's biological effects, including neuroprotection [59] and attenuation of proinflammatory cytokines release [60]. Despite the biological importance of des-acyl ghrelin has started to be elucidated, chronic administration of des-acyl ghrelin was shown inefficient in mitigating MPTP-induced SN DA neuronal degeneration in ghrelin KO animals [61], suggesting that the neuroprotective effect of ghrelin over SN DA cells indeed requires GHSR activation. Another possible explanation for midbrain action of ghrelin gene products is based on the local activity of GOAT [62], which mRNA has been shown to have a broad expression among tissues [63], including the central nervous system [64], [65]. This fact supports the idea that ghrelin gene products could potentially be acylated in situ, permitting local activation of GHSR [66].