Acylated Ghrelin as a Multi-Targeted Therapy for Alzheimer's and Parkinson's Disease

“AG is also involved in the regulation of the adaptive immune system, which is based on the modulation of T-cells.”

“Although to a low degree, GHSR1α is also expressed throughout the cerebral vasculature and a markedly high density of GHS-R1α has been detected in the microvasculature of the granular layer of the cerebellum (Katugampola et al., 2001; Ku et al., 2015, 2016).”

“For example, the genetic deletion of TNF-α and the utility of the microglial inhibitor minocycline attenuated the MPTP-induced permeabilization of the BBB in this PD animal model (Zhao et al., 2007).”

“…for AD and PD, it is no surprise that its early desensitization in the CNS, believed to predominantly occur in response to chronic inflammation, promotes the development of AD and PD (see Holscher, 2019 for further information) (Blazquez et al., 2014; Werner and LeRoith, 2014; Holscher, 2020).”

“For example, the long-term administration of low-doses of IL-2, believed to assist the activity of Tregs (Klatzmann and Abbas, 2015), enhanced the levels of Tregs in the rodent brain, improved the Aß42/40 ratio, stimulated the clearance of Aß plaques, elevated LTP, attenuated spinal degeneration and reversed memory im…”

“In addition, insulin suppresses the activity of GSK-3ß, a wellknown Tau kinase (Lei et al., 2011), hence the loss of insulin signaling initiates Tau hyperphosphorylation and aggregation in AD (Hong and Lee, 1997; Schubert et al.”

“As such, the function of variousmitochondrial master modulators, including AMPK and PGC1α, is disturbed in AD and PD.”

“Furthermore, AG promoted the mitochondrial biogenesis, resulting in increased numbers of nuclear respiratory factor (NRF)1-positive mitochondria (Jiang et al., 2008; Andrews et al., 2009a; Donadelli et al., 2014).”

“…has also recently been identified in AD and PD, believed to sequentially involve Aß accumulation, the Aß-triggered inflammasome activation, inflammasome-induced cytokine production and the onset of Tau pathology in AD (Mamik and Power, 2017; Ising et al., 2019; Stancu et al., 2019).”

“In accord with the animal studies, blood profiling of AD patients indicated heightened adaptive immune responses, such as a total reduction in naive T-cells, a tendency of T-cells to differentiate into CD4 subsets or the elevated activity of pro-inflammatory CD4 Th17 cells (Shalit et al., 1995; Richartz-Salzburger et…”

“In contrast, a dominantnegative role for GHS-R1ß has been suggested, in which heterodimerization of GHS-R1ß with GHS-R1α encourages receptor endocytosis to obstruct intracellular signaling (Leung et al., 2007).”

“The NTS, on the other hand, further projects across the entirety of the CNS, ultimately leading to the intestinal return of immune-suppressing signals through the afferent ends of the vagal nerve.”

“The induction of the cAMP/PKA pathway is highly debated and appears to be conditional and cell-type specific, however (Kohno et al., 2003; Yin et al., 2014; Yanagi et al., 2018).”

“In concert, a study in depression-prone GHS-R1α mice revealed that the deletion of GHS-R1α exacerbated neuronal loss in response to chronic social defeat stress and diminished the proliferation of progenitor cells in the ventral DG (Walker et al., 2015).”

“, 2016) as well as the hypothalamus in adult rodents and mouse models of aging (Velasquez et al., 2011; Fujitsuka et al., 2016).”

“Mechanistically, AG is responsible for the neuroprotective effects of caloric reduction and stimulates AMPK activity in the SN of MPTP-treated rodents (Bayliss et al., 2016).”

“autophagy and, typically in response to stressful cellular conditions and starvation, the activating phosphorylation of the cytoplasmic energy-sensor AMPK results in the AMPK-mediated phosphorylation of TSC1/2 and the inhibition of mTORC1 (Inoki et al., 2003;Manning andCantley, 2003; Demetriades et al., 2016).”

“…of glucose that have been detected in the brains of AD (Lyingtunell et al., 1981, Eberling et al., 1992; Ogawa et al., 1996; Roher et al., 2012; de Eulate et al., 2017) and PD (Huang et al., 2008; Hosokai et al., 2009; Liepelt et al., 2009; Borghammer et al., 2010; Berti et al., 2012) patients.”

“The stimulation of AMPK, which is a highly debated therapeutic option for the treatment of PD, is, in fact, responsible for the large majority of AG’s neuroprotective effects, including (macro)autophagy, mitochondrial enhancement as well as the cellular safeguarding from oxidative stress and inflammation (Bayliss and…”

“Unsurprisingly, in line with the encouraged cerebral trespassing of lymphocytes, BBB leakage has been confirmed in the brains of PD patients (Kortekaas et al., 2005; Pisani et al., 2012).”

“In the 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine (MPTP) mouse model of PD, AG protected from neuronal death in the SNpc, as displayed by the normalized B-cell lymphoma 2 (Bcl-2)/Bax ratio and lowered caspase-3 activity, stimulated the neuronal activity, elevated the production of multiple LCFAs, for instance palmit…”

“Based on the latest evidence, obesity and T2DM seem to encourage the development of ghrelin resistance (Zigman et al., 2016).”

“To recharge NAD+ and FAD+ and to resume ATP generation, the brain relies on glucose as major energy substrate as well as its metabolization in the tricarboxylic acid cycle (TCA) as main bioenergetic pathway (Penicaud et al., 2002; Arun et al., 2016; Martinez-Reyes and Chandel, 2020).”

“Indeed, besides amyloids, AD and PD are characterized by the culminative interplay of oxidative stress, mitochondrial dysfunction and hyperfission, defective autophagy and mitophagy, systemic inflammation, BBB and vascular damage, demyelination, cerebral insulin resistance, the loss of dopamine production in PD, impai…”

“As such, this review will illustrate the wide-ranging neuroprotective properties of acylated ghrelin and critically evaluate the hormone’s therapeutic benefits for the treatment of AD and PD. Keywords: growth hormone secretagogue receptor 1 alpha, mitochondrial dysfunction, inflammation, autophagy, insulin resistance,…”

“Furthermore, components of the insulin pathway were found to be deactivated by inhibitory serine phosphorylation in the SN and basal ganglia, which appeared to precede dopamine neuron death, implying that the functional deterioration of insulin signaling manifests prematurely (Moroo et al., 1994; Takahashi et al., 199…”

“Furthermore, AG promoted the mitochondrial biogenesis, resulting in increased numbers of nuclear respiratory factor (NRF)1-positive mitochondria (Jiang et al., 2008; Andrews et al., 2009a; Donadelli et al., 2014).”

“Other physiological processes that are commanded by ghrelin include the regulation of the gastrointestinal motility and acid secretion, cardiac function, osteoblast proliferation, bone maturation and muscular/myoblast outgrowth, the formation of long-term memory, the control of behaviors such as spontaneity, anxiety,…”

“There is also evidence that proteins involved in autophagosome initiation and formation, for example LC3 or ULK1/2, are sequestered into Lewy bodies in the brain of PD patients (Tanji et al., 2011; Miki et al., 2016).”

“, 2008), which is in line with ghrelin’s physiological role as survival hormone (Mani and Zigman, 2017).”

“In such AD in vivo models, AG rescued from hippocampal atrophy, synaptic damage and the degeneration of cholinergic projections, heightened brain glycogen levels, diminished Aß aggregation and deposition, blocked Aβimparted deficits in LTPs, normalized plasticity-associated p-CREB levels, improved insulin sensitivity,…”

“In the periphery, for example, independent of the hormone’s orexigenic effects, AG stimulated the expression of lipogenic enzymes (fatty acid synthase (FAS), lipoprotein lipase and more) and lessened the transcription of carnitine palmitoyltransferase Ia (CPT1a), a ratelimiting effector necessary to induce fatty acid…”

“Jointly, the PGC1α-induced transcriptional changes in mitochondria-associated genes protect from MPTP oxidative assault in cell and animal models of PD, whereas the deletion of PGC1α exacerbates MPTP-induced injury and excitotoxicity (Scarpulla, 2002, 2006; Kang and Hamasaki, 2005; St.-Pierre et al., 2006; Mudo et al.…”

“lowered plasma levels of AG and total ghrelin as well as decreased gastric synthesis of ghrelin and GOAT, yet also fail to secrete the hormone post-prandially and do not respond to the appetitestimulating effects of administered AG (Martin et al., 2004; Perreault et al., 2004; Briggs et al., 2010; Gardiner et al., 201…”

“…of glucose that have been detected in the brains of AD (Lyingtunell et al., 1981, Eberling et al., 1992; Ogawa et al., 1996; Roher et al., 2012; de Eulate et al., 2017) and PD (Huang et al., 2008; Hosokai et al., 2009; Liepelt et al., 2009; Borghammer et al., 2010; Berti et al., 2012) patients.”

“As such, the induction of UCP2 buffers the glucose/TCA-exacerbated production of ROS by the ETC (see Jezek et al., 2018 for an extensive description of UCP functions), which may be protective in AD and PD. Similar to the SNpc (Andrews et al., 2009a), AG also augmented the induction of UCP2,…”

“The injection of the ghrelin agonist GHRP-6 into healthy, adult rodents elevated the transcription levels of IGF1 in the hypothalamus, the cerebellum and the hippocampus, but not the cortex (Frago et al., 2002).”

“Furthermore, components of the insulin pathway were found to be deactivated by inhibitory serine phosphorylation in the SN and basal ganglia, which appeared to precede dopamine neuron death, implying that the functional deterioration of insulin signaling manifests prematurely (Moroo et al., 1994; Takahashi et al., 199…”

“, 2018), and the 5xFAD animal model of AD (Moon et al., 2014).”

“Moreover, intestinal inflammation and injury are strikingly pronounced prior to the onset of AD and PD, which, besides the additional inflammatory burden, induce the leakage of Aβ- and α-synuclein-like amyloids that may cross the enteric nervous system (ENS), enter the brain and stimulate cross-seeding (Ambrosini et a…”

“When injected intracerebroventrically or intraVTA, AG further enhanced the locomotor activity of rodents (see Figure 3) (Abizaid et al., 2006; Jerlhag et al., 2007, 2012; Quarta et al., 2009; Skibicka et al., 2011, 2012; Cornejo et al., 2018).”

“Since leptin functions as a physiological and anorexic counteragent to ghrelin in the hypothalamus, blocking intraneuronal AG/GHS-R1α-signaling, some studies have suggested that the elevated plasma pools of leptin during obesity weaken the sensitivity toward AG (Hewson et al., 2002; Kohno et al., 2007; Briggs et al.,…”

“In this context, some genetic variants of TLR4 have been linked to AD and the increased expression of TLR2 has been identified in AD models (Balistreri et al., 2009; Letiembre et al., 2009), whereas the enhanced transcription of TLR2 and TLR4 have been detected in α-synuclein and MPTP mouse models of PD (Panaro et al.”

“AG was shown to induce the synthesis of FoxO1 in the hypothalamus (Lage et al., 2010) and, under conditions of cellular stress, FoxO1 drives the transcription of various anti-oxidant enzymes, such as the PGC1α-co-activated, mitochondrialMnSOD (St.”

“Various studies have testified that the administration of AG boosts adult hippocampal neurogenesis in healthy rodents (Zhao et al., 2014; Kent et al., 2015; Hornsby et al., 2016), dwarf rats (Li et al.”

“Moreover, the prolonged daily injection of the CD36-favoring ghrelin derivate EP 80317 dramatically ameliorated the development of vascular lesions in the apoE animal model of arteriosclerosis by lessening the CD36-driven endocytosis of oxidized low density lipoprotein (oxLDL) by macrophages (Marleau et al., 2005).”

“…a physiological and anorexic counteragent to ghrelin in the hypothalamus, blocking intraneuronal AG/GHS-R1α-signaling, some studies have suggested that the elevated plasma pools of leptin during obesity weaken the sensitivity toward AG (Hewson et al., 2002; Kohno et al., 2007; Briggs et al., 2014).”

“…the driving factor in the maturation of insulin resistance during obesity, T2DM and neurodegenerative diseases, including AD and PD (Tateya et al., 2013; Holscher, 2019), it is implied that AG enhances insulin sensitivity by suppressing systemic inflammation, hyperlipidemia and oxidative assault.”

“Considerably, AG stimulates the activity of the fusion/fissionregulators AMPK and PGC-1α in GHS-R1α-expressing cells, including neurons (Bayliss and Andrews, 2013; Huang et al., 2019).”

“In particular, the vagal nodose ganglion has been shown to desensitize, exhibiting the reduced expression of GHS-R1α, diminished AMPK activation and reduced electric current flow upon exposure to AG (Naznin et al., 2015).”

“, 2020), also considering that autophagy is initiated by the inactivation of mTOR (Lan et al., 2017).”

“Furthermore, AMPK phosphorylates glyceraldehyde 3- phosphate dehydrogenase (GAPDH) at Ser122 during starvation to encourage the nuclear trafficking of GAPDH and the displacement of SIRT1 from its repressor Deleted in Breast Cancer 1 (DBC1) (Chang et al., 2015).”

“Further in vivo studies in the MPTP model support the idea that, in conjunction with BBB injury and the loss of tight junction proteins in the nigrostriatal area, the pathological infiltration of lymphocytes and other immune cells as well as the T-cell-driven induction of microglia occur in the SN (Kurkowska-Jastrzebs…”

“Additionally, altered adaptive immune mechanics have been observed in the CNS of several Aß-based in vivo models of AD, displaying hippocampal BBB disruption, the infiltration of peripheral monocytes/macrophages, neutrophils and CD4 T-cells (predominantly Th1 and Th17) as well as the increased transcription of pro-inf…”

“On the other hand, the genetic deletion of ghrelin or knockdown of GHS-R1α lessened the numbers of hippocampal synapses, worsened LTP and impaired long-term memory (Diano et al., 2006; Davis et al., 2011), although discrepancies between spatial and contextual memory have been reported in GHS-R1α-null mice (AlbarranZec…”

“This receptor has been reported to act as an inflammatory conductor for Aß, leading to the production of ROS and proinflammatory cytokines upon the interaction of fibrillar Aß with microglial or macrophage CD36 (Coraci et al., 2002; Bamberger et al., 2003; El Khoury et al., 2003; Demers et al., 2004).”

“Of note, mutational studies in UCP2-modified and MPTPtreated mice revealed that UCP2 is a joint key mediator in the protection of SN-VTA dopaminergic neurons from apoptosis, the decrease of ROS as well as the increase of mitochondrial biogenesis (Andrews et al., 2005; Conti et al., 2005).”

“Conversely, increased circulatory levels of glucose and long-chain fatty acids (LCFA) following meal intake as well as the postprandial release of insulin block the secretion of ghrelin (Gagnon and Anini, 2012; Lu et al., 2012; Sakata et al., 2012).”

“However, clinical studies in healthy, non-obese subjects have shown that the infusion of AG impairs the glucose-stimulated secretion of insulin, diminishes glucose tolerance and worsens insulin sensitivity (Gauna et al., 2004; Vestergaard et al., 2007; Tong et al., 2010, 2014).”

“Furthermore, GHS-R1α antagonists, GOAT inhibitors and the genetic deletion of GHS-R1α enhanced the release of insulin, glucose tolerance, insulin sensitivity and weight loss in in vivo models of obesity (Sun et al., 2006; Esler et al., 2007; Longo et al., 2008; Barnett et al., 2010; Qi et al., 2011).”

“Further in vivo studies in the MPTP model support the idea that, in conjunction with BBB injury and the loss of tight junction proteins in the nigrostriatal area, the pathological infiltration of lymphocytes and other immune cells as well as the T-cell-driven induction of microglia occur in the SN (Kurkowska-Jastrzebs…”

“In an extensive study, it was demonstrated that AG binds to nigral neurons, triggers neuronal firing and enhances dopamine turnover, achieving an impressive three-fold increase in total dopamine levels in the striatum of healthy mice (Shi et al., 2013).”

“Indeed, besides amyloids, AD and PD are characterized by the culminative interplay of oxidative stress, mitochondrial dysfunction and hyperfission, defective autophagy and mitophagy, systemic inflammation, BBB and vascular damage, demyelination, cerebral insulin resistance, the loss of dopamine production in PD, impai…”

“, 2004) and its synthesis by T-cells declined with age, whereas the infusion of AG reversed the age-correlating increase in a large number of pro-inflammatory cytokines and chemokines in old rats (Dixit et al., 2009).”

“To recharge NAD and FAD and to resume ATP generation, the brain relies on glucose as major energy substrate as well as its metabolization in the tricarboxylic acid cycle (TCA) as main bioenergetic pathway (Penicaud et al., 2002; Arun et al., 2016; Martinez-Reyes and Chandel, 2020).”

“As a major metabolic hormone, AG elevates the secretion of growth hormone (GH) by the pituitary gland, reduces insulin, yet increases glucagon secretion by pancreatic cells and promotes the hepatic release of glucose into the blood, thus maintaining steady plasma glucose levels during fasting (Mani et al., 2019).”

“Conversely, increased circulatory levels of glucose and long-chain fatty acids (LCFA) following meal intake as well as the postprandial release of insulin block the secretion of ghrelin (Gagnon and Anini, 2012; Lu et al., 2012; Sakata et al., 2012).”

“Considering the vast neuroprotective properties of AG, it is likely that the insufficient availability of ghrelin and the reduced ghrelin sensitivity in the CNS, such as the temporal lobe (Gahete et al., 2010), contribute to age-related cognitive decline.”

“The NTS, on the other hand, further projects across the entirety of the CNS, ultimately leading to the intestinal return of immune-suppressing signals through the afferent ends of the vagal nerve.”

“, 2012), the basal plasma levels of ghrelin and the postprandial secretion of the hormone were diminished in PD patients (Fiszer et al., 2010; Unger et al., 2011).”

“Moreover, by increasing blood flow, AG might ameliorate the pathologically diminished cerebral blood flow and deficits in the CNS delivery of glucose that have been detected in the brains of AD (Lyingtunell et al., 1981, Eberling et al., 1992; Ogawa et al., 1996; Roher et al., 2012; de Eulate et al., 2017) and PD (Hua…”

“Furthermore, components of the insulin pathway were found to be deactivated by inhibitory serine phosphorylation in the SN and basal ganglia, which appeared to precede dopamine neuron death, implying that the functional deterioration of insulin signaling manifests prematurely (Moroo et al., 1994; Takahashi et al., 199…”

“MMP-3 is also implicated in BBB damage in PD (Chung et al., 2013) and activates MMP-9 (Lee et al.”

“Various studies have testified that the administration of AG boosts adult hippocampal neurogenesis in healthy rodents (Zhao et al., 2014; Kent et al., 2015; Hornsby et al., 2016), dwarf rats (Li et al.”

“Moreover, AG downregulated the transcription of IL-1 and/or the inflammasome-activating cytokine TNF-α in face of MPTPinjury (PD), threohydroxyaspartate (THA)/kainic acid-assault (excitotoxicity), subarachnoid hemorrhage and SCI (Moon et al., 2009a; Ersahin et al., 2010; Lee J. et al., 2010; Lee et al., 2012, 2014b; A…”

“Ultimately, the latter changes led to reduced glucose uptake, elevated glutamate uptake and the steadily rising lactate levels in the cell culture medium (Fuente-Martin et al., 2016).”

“Generally, functional deficits in complex 1 are associated with PD and defects in complex IV are implicated in AD (Cottrell et al., 2002; Arun et al., 2016).”

“The promitochondrial impact of PGC1α in PD, whose expression levels were found to be decreased in the brains of PD patients, has been made evident in knockdown studies, in which the suppression or conditional knockdown of PGC1α led to the selective atrophy of dopaminergic neurons in the SNpc and lessened dopamine pool…”

“, 2012), the basal plasma levels of ghrelin and the postprandial secretion of the hormone were diminished in PD patients (Fiszer et al., 2010; Unger et al., 2011).”

“On the other hand, it is plausible that the initial, inflammationdriven desensitization of insulin and other growth factors during obesity, T2DM, AD and PD (Maldonado-Ruiz et al., 2017; Holscher, 2019, 2020), which negatively affect the rate of cellular protein translation though the loss of Akt/mTORC1-signaling (Hols…”

“…deactivated by inhibitory serine phosphorylation in the SN and basal ganglia, which appeared to precede dopamine neuron death, implying that the functional deterioration of insulin signaling manifests prematurely (Moroo et al., 1994; Takahashi et al., 1996; Tong et al., 2009; Morris et al., 2014).”

“Moreover, a recent study revealed a cytoprotective function of AG in palmitate- and glucose-stressed human microvascular endothelial cells, in which AG rescued apoptosis and caspase-3 activity by inhibiting the stress kinases p38 and JNK1/2, diminishing the mitochondrial generation of ROS and normalizing the rate of o…”

“It has been proposed that the PD-related Lewy body pathology in the myenteric plexus of the stomach and in the DMV, which innervates the gut and navigates the gastrointestinal motility, might impair the release of ghrelin (Stoyanova, 2014).”

““Perhaps there is a field of treasures right there, waiting to be discovered” (Gault and Holscher, 2018).”

“4 h, respectively, have been reported for AG in human plasma and∼27min in rat serum, whereas the degradation t1/2 of total circulatory ghrelin has been estimated to be as short as ∼9-11min (De Vriese et al., 2004; Liu et al., 2008; Tong et al., 2013).”

“Likewise, chronically increased plasma ghrelin levels did not lead to any complications in adult rodents, although it might promote hyperglycemia with age (Iwakura et al., 2005; Reed et al., 2008).”

“In such AD in vivo models, AG rescued from hippocampal atrophy, synaptic damage and the degeneration of cholinergic projections, heightened brain glycogen levels, diminished Aß aggregation and deposition, blocked Aβimparted deficits in LTPs, normalized plasticity-associated p-CREB levels, improved insulin sensitivity,…”

“, 2002), it is likely that the binding of DAG sterically hinders the proinflammatory interaction of CD36 with Aß (Bulgarelli et al., 2009).”

“Hexarelin was demonstrated to interact with both GHS-R1α and CD36 on cultured THP-1 monocytes and primary peritoneal macrophages derived from apoE mice (Avallone et al., 2006).”

“The decreased sensitivity toward AG could be related to an age-induced decline in the transcriptional levels of GHS-R1α, as reported for the anterior pituitary in 24-month-old Lou C/Jall rats, the vagal nerve in aged Fischer-344 rats and the brainstem in rats and dwarf rats (Katayama et al., 2000; Kappeler et al., 200…”

“Over time, prolonged neuroinflammation encourages various other secondary complications, such as impairments in protein degradation, amyloid misfolding, Tau hyperphosphorylation (in conjunction with the inflammationperpetuating activation of the inflammasome), permeabilization of the BBB, peripheral immune cell infilt…”

“, 2014), it must be noted that wt α-synuclein, in fact, promotes fusion and its expression may be a compensatory and protective mechanism to prevent hyperfission in PD (Berthet et al., 2014; Guardia-Laguarta et al., 2014; Menges et al., 2017).”

“In contrast, the limited amount of cerebral studies with AG, at the very least, have verified the induction of autophagy via mTOR inhibition in cortical neurons (Ferreira-Marques et al., 2016).”

“Since leptin functions as a physiological and anorexic counteragent to ghrelin in the hypothalamus, blocking intraneuronal AG/GHS-R1α-signaling, some studies have suggested that the elevated plasma pools of leptin during obesity weaken the sensitivity toward AG (Hewson et al., 2002; Kohno et al., 2007; Briggs et al.,…”

“Immune cell invasion into the spinal cord was only blocked by AG in some of these studies, however, which might have been related to the choice of the EAE-initiating antigen used for immunization (Theil et al., 2009; Souza-Moreira et al., 2013; Liu F. et al., 2019).”

“In concert, the area postrema, the nucleus tractus solitarius and the dorsal motor nucleus of the vagus (DMV) form the dorsal vagal complex (DVC) that serves as a commanding platform for the autonomic nervous system, navigating gastrointestinal motility, secretory activity and pancreatic hormone release (Price et al.,…”

“Furthermore, AMPK phosphorylates glyceraldehyde 3- phosphate dehydrogenase (GAPDH) at Ser122 during starvation to encourage the nuclear trafficking of GAPDH and the displacement of SIRT1 from its repressor Deleted in Breast Cancer 1 (DBC1) (Chang et al., 2015).”

“Various studies have testified that the administration of AG boosts adult hippocampal neurogenesis in healthy rodents (Zhao et al., 2014; Kent et al., 2015; Hornsby et al., 2016), dwarf rats (Li et al.”

“, 2010) and, under conditions of cellular stress, FoxO1 drives the transcription of various anti-oxidant enzymes, such as the PGC1α-co-activated, mitochondrialMnSOD (St.-Pierre et al., 2006; Hsu et al., 2010; Tong et al., 2012).”

“, 2013) and the stimulation of AMPK was proven to trigger the AMPKconveyed activating phosphorylation of eNOS at Ser1177 in cultured human and rat endothelial cells, thus strengthening vasodilation in vivo (Morrow et al., 2003; Suzuki et al., 2008), it is highly likely that the AG-evoked liberation of NO is”

“, 2009), whereas the enhanced transcription of TLR2 and TLR4 have been detected in α-synuclein and MPTP mouse models of PD (Panaro et al., 2008; Letiembre et al., 2009), indicating that immune regulation is harmfully altered in AD and PD.”

“AG-evoked autophagy ismainly connected to the downstream activation of the phospho-AMPK/mTOR axis, as it has been welldescribed for the initiation of autophagy in peripheral tissue (Tong et al., 2012; Mao et al., 2015; Ruozi et al., 2015; Ezquerro et al., 2016; Xu et al., 2017).”

“5 dopaminergic cells (Dong et al., 2009; Yu et al., 2016), rotenone-burdened rat retinal ganglion cells (Liu et al., 2018) and primary hypothalamic neurons during oxygen and glucose withdrawal (Chung et al., 2007).”

“When injected intracerebroventrically or intraVTA, AG further enhanced the locomotor activity of rodents (see Figure 3) (Abizaid et al., 2006; Jerlhag et al., 2007, 2012; Quarta et al., 2009; Skibicka et al., 2011, 2012; Cornejo et al., 2018).”

“…the combinatorial administration of the ghrelin agonist HM01 or AG with the dopamine-replacing drugs Ldopa or L-dopa/levodopa prevented the L-dopa- and 6-OHDAassociated slowing of the gastric motility and constipation in the 6-OHDA rodent model of PD (Wang et al., 2012; Karasawa et al., 2014).”

“In such AD in vivo models, AG rescued from hippocampal atrophy, synaptic damage and the degeneration of cholinergic projections, heightened brain glycogen levels, diminished Aß aggregation and deposition, blocked Aβimparted deficits in LTPs, normalized plasticity-associated p-CREB levels, improved insulin sensitivity,…”

“lowered plasma levels of AG and total ghrelin as well as decreased gastric synthesis of ghrelin and GOAT, yet also fail to secrete the hormone post-prandially and do not respond to the appetitestimulating effects of administered AG (Martin et al., 2004; Perreault et al., 2004; Briggs et al., 2010; Gardiner et al., 201…”

“The binding of plasma AG to GHS-R1α on the afferent vagal ends mutes vagal firing, contributing to the initiation of feeding and GHrelease (Date, 2012).”

“In accord with insulin resistance, glucose hypometabolism in the CNS, for instance within the cortex, has been linked to the transition from MCI to AD and cognitive dysfunction (Lyingtunell et al., 1981; Hoyer et al., 1988; Ogawa et al., 1996; Drzezga et al., 2003; Mosconi et al., 2008).”

“Thus, by diminishing total inflammation, the secretion of pro-inflammatory DAMPs and inflammation-driven BBB injury, AG was capable of preventing neutrophil infiltration into the CNS (Ersahin et al., 2010, 2011; Lopez et al., 2012a,b, Mohaddes et al., 2017).”

“Interestingly, AG equally appears to elevate the synthesis of IGF-1 in some brain regions.”

“In the brains of these AD-like mice, AG further suppressed glycogen synthase kinase 3β (GSK-3β) activity and Tau hyperphosphorylation (Kang et al., 2015).”

“Furthermore, in vitro studies have shown that the administration of AG downregulated the synthesis of IL-1β, IL-6, and TNFα in human peripheral blood mononuclear cells following irritation with the mitogen phytohemagglutinin (Dixit et al., 2004).”

“While no relevant alterations in the blood levels of ghrelin have been observed in AD patients (Proto et al., 2006; Theodoropoulou et al., 2012), the basal plasma levels of ghrelin and the postprandial secretion of the hormone were diminished in PD patients (Fiszer et al.”

“, 2011), inflammation-driven intestinal permeabilization and atrophy (Wu et al., 2008, 2009a; Bansal et al., 2010).”

“Furthermore, GHS-R1α antagonists, GOAT inhibitors and the genetic deletion of GHS-R1α enhanced the release of insulin, glucose tolerance, insulin sensitivity and weight loss in in vivo models of obesity (Sun et al., 2006; Esler et al., 2007; Longo et al., 2008; Barnett et al., 2010; Qi et al., 2011).”

“, 2009), and serum-derived or locally released TNFα and IFN-γ, whose combinatorial action was shown to be a crucial inflammatory mediator of dopaminergic cell death in a rodent model of PD (Mir et al., 2008; Barcia et al., 2011).”

“Notably, the presence of GOAT has been detected in human serum, the hippocampus and the temporal gyrus (Gahete et al., 2010; Goebel-Stengel et al., 2013; Murtuza and Isokawa, 2018).”

“Interestingly, various studies have indicated that PD patients also exhibit cortical glucose hypometabolism and diminished blood flow in this area (Huang et al., 2008; Hosokai et al., 2009; Liepelt et al., 2009; Borghammer et al., 2010; Berti et al., 2012), a decreased rate of glucose consumption in the frontal lobe a…”

“In the brains of these AD-like mice, AG further suppressed glycogen synthase kinase 3β (GSK-3β) activity and Tau hyperphosphorylation (Kang et al., 2015).”

“, 2017; Holscher, 2019, 2020), which negatively affect the rate of cellular protein translation though the loss of Akt/mTORC1-signaling (Holscher, 2019; Liu and Sabatini, 2020), might be responsible for the reduced cerebral expression of GHS-R1α and GOAT in the cortex, hypothalamus and, potentially, further brain regi…”

“For instance, the administration of AG succeeded in the animal model of colitis, showing downregulated local and systemic release of pro-inflammatory modulators, reduced inflammatory Th 1 activity, elevated action of immunosuppressive regulatory T-cells (Tregs), diminished oxidative stress, ameliorated intestinal tiss…”

“Notably, the presence of GOAT has been detected in human serum, the hippocampus and the temporal gyrus (Gahete et al., 2010; Goebel-Stengel et al., 2013; Murtuza and Isokawa, 2018).”

“In such AD in vivo models, AG rescued from hippocampal atrophy, synaptic damage and the degeneration of cholinergic projections, heightened brain glycogen levels, diminished Aß aggregation and deposition, blocked Aβimparted deficits in LTPs, normalized plasticity-associated p-CREB levels, improved insulin sensitivity,…”

“However, clinical studies in healthy, non-obese subjects have shown that the infusion of AG impairs the glucose-stimulated secretion of insulin, diminishes glucose tolerance and worsens insulin sensitivity (Gauna et al., 2004; Vestergaard et al., 2007; Tong et al., 2010, 2014).”

“There is also evidence that proteins involved in autophagosome initiation and formation, for example LC3 or ULK1/2, are sequestered into Lewy bodies in the brain of PD patients (Tanji et al., 2011; Miki et al., 2016).”

“It has been proposed that chronic inflammation provokes NTS dysfunction, which, in turn, propagates neuroinflammation and death across the brain in AD (Daulatzai, 2012; Wang J. T. et al., 2018).”

“In such AD in vivo models, AG rescued from hippocampal atrophy, synaptic damage and the degeneration of cholinergic projections, heightened brain glycogen levels, diminished Aß aggregation and deposition, blocked Aβimparted deficits in LTPs, normalized plasticity-associated p-CREB levels, improved insulin sensitivity,…”

“In the periphery, AG has been deemed as the most powerful stimulator of the GH/IGF-1 axis (Nass et al., 2011).”

“Thus, by diminishing total inflammation, the secretion of pro-inflammatory DAMPs and inflammation-driven BBB injury, AG was capable of preventing neutrophil infiltration into the CNS (Ersahin et al., 2010, 2011; Lopez et al., 2012a,b, Mohaddes et al., 2017).”

“In such AD in vivo models, AG rescued from hippocampal atrophy, synaptic damage and the degeneration of cholinergic projections, heightened brain glycogen levels, diminished Aß aggregation and deposition, blocked Aβimparted deficits in LTPs, normalized plasticity-associated p-CREB levels, improved insulin sensitivity,…”

“Likewise, chronically increased plasma ghrelin levels did not lead to any complications in adult rodents, although it might promote hyperglycemia with age (Iwakura et al., 2005; Reed et al., 2008).”

“The activation of SIRT1 via AG has been confirmed in the periphery (Fujimura et al., 2014; Tamaki et al., 2015; Fujitsuka et al., 2016; Yang et al., 2016) as well as the hypothalamus in adult rodents and mouse models of aging (Velasquez et al.”

“This is in line with the Mfn2-upregulating and Drp1-impeding function of PGC-1α (Peng et al., 2017), suggesting that AG stimulates the AMPK/PGC-1α axis to ameliorate mitochondrial fragmentation in response to cellular stress (Sirago et al., 2017).”

“Moreover, AG downregulated the transcription of IL-1 and/or the inflammasome-activating cytokine TNF-α in face of MPTPinjury (PD), threohydroxyaspartate (THA)/kainic acid-assault (excitotoxicity), subarachnoid hemorrhage and SCI (Moon et al., 2009a; Ersahin et al., 2010; Lee J. et al., 2010; Lee et al., 2012, 2014b; A…”

“lowered plasma levels of AG and total ghrelin as well as decreased gastric synthesis of ghrelin and GOAT, yet also fail to secrete the hormone post-prandially and do not respond to the appetitestimulating effects of administered AG (Martin et al., 2004; Perreault et al., 2004; Briggs et al., 2010; Gardiner et al., 201…”

“AG is also involved in the regulation of the adaptive immune system, which is based on the modulation of T-cells.”

“Furthermore, pathogen-associated molecular patterns (PAMPs) that originate from cerebral infections, such as LPS, or, in the case of AD, infections with members of the Herpesviridae family and Hepatitis C virus, may further potentiate neuroinflammation (Morales et al., 2014; Sochocka et al., 2017; Cortes et al., 2018;…”

“Additionally, clinical studies indicate that AG, in an endothelial nitic oxide synthase (eNOS)-mediated and GH-independent manner, enhances the bioavailability of NO and elicits vasorelaxation, hence improving blood flow and decreasing blood pressure (Nagaya et al., 2001, 2004; Shimizu et al., 2003; Tesauro et al., 20…”

“In such AD in vivo models, AG rescued from hippocampal atrophy, synaptic damage and the degeneration of cholinergic projections, heightened brain glycogen levels, diminished Aß aggregation and deposition, blocked Aβimparted deficits in LTPs, normalized plasticity-associated p-CREB levels, improved insulin sensitivity,…”

“, 2014b, 2015), as well as drug-induced excitotoxicity (Lee J. et al., 2010; Lee et al., 2012).”

“Moreover, under physiological conditions, AG was shown to discourage, rather than elevate, fatty acid oxidation in the hypothalamic ARC and in the cortex (Lage et al., 2010; Gao et al., 2013; Mir et al., 2018).”

“Ghrelin has shown efficacy for the treatment of several mouse models of neurodegenerative disease consistent with the neuroprotective effects of AMPK signaling [208,209].”

“Moreover, ghrelin can enhance several energy metabolic pathways like beta oxidation [133] and alleviate neuronal inflammation by reducing proinflammatory cytokines [134].”