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

“Anti-inflammatory properties of AG have also been confirmed in various clinical studies (Kodama et al., 2008; Takata et al., 2015; Farokhnia et al., 2020).”

“Thus, obesity and T2DMassociated hyperleptinemia (Maffei et al., 1995; Considine et al., 1996; Okumura et al., 2003; Pandey et al., 2015) may contribute to the desensitization of AG in the hypothalamus.”

“As confirmed with the utility of GHS-R1α, ERK and p38 inhibitors, an in vitro study showed that the interaction of AG with GHS-R1α on oligodendrocytes shields the cells from hydrogen peroxide (H2O2) and apoptosis by potentiating oligoprotective ERK signaling, while attenuating the pro-apoptotic activation of p38 (Lee…”

“GHS-R1α is widely transcribed in multiple key areas of the brain, such as the hippocampus, hypothalamus, cortex, ventral tegmental area (VTA), SN, spinal cord, dorsal and median raphe nuclei, sympathetic preganglionic nerves and endothelial cells of the cerebral vasculature, yet it is also expressed by various immune…”

“Recent reports suggest a possible role for AG in the regulation of the mitochondrial fission and fusion dynamics (Morgan et al., 2018).”

“While it is not entirely evident how AG inhibits NF-κB signaling in GHS-R1α-negative microglia (Moon et al., 2009a; Lee J. Y. et al., 2010; Lee and Yune, 2014), it can be assumed that the prevention of neuronal and oligodendrocyte death, leading to the reduced liberation of DAMPs, indirectly avert inflammatory process…”

“, 2016), dwarf rats (Li et al., 2013), in the 6-OHDA rodent model of PD, although neurogenesis was only enhanced in the non-lesioned brain hemisphere (Elabi et al.”

“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).”

“In a reciprocal manner, inflammation incites the microglial expression and liberation of MMP-3, initiating a wicked cycle of neuronal degeneration and neuroinflammation (Kim et al., 2005; Kim and Hwang, 2011).”

“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…”

“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).”

“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.”

“, the administration of AG results in a phenotype that, despite exhibiting weight gain, displays low systemic inflammation and diminished triglyceride burden (Barazzoni et al., 2011; Garcia-Caceres et al., 2014).”

“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…”

“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.”

“…has consistently performed well in animal models of various inflammatory conditions, guarding against endotoxemia/sepsis, pancreatic, hepatic and kidney disease, cardiovascular conditions, arteriosclerosis, colitis, arthritis, age-induced inflammation and more (Baatar et al., 2011; Deboer, 2011).”

“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 elevated hypothalamic synthesis of IGF-1 was also observed in AG or GHRP-6-injected obese rodents that were placed on a high fat dietary regiment (Garcia-Caceres et al., 2014).”

“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…”

“…APPswe/PS1dE9 mice displayed reduced hippocampal levels of the catalytic α2-subunit of 5’ adenosinemonophosphateactivated protein kinase (AMPK) (Pedros et al., 2014), which is a master effector that upregulates ATP synthesis, curbs ATP utility, maintains the mitochondrial homeostasis and…”

“, 2016), GH (Wu et al., 2009b; Zhou et al., 2017), insulin (Granado et al.”

“Subsequent peripheral inflammatory responses by antigenpresenting cells and lymphocytes (T-cells) then induce immune entry into the CNS in AD and PD (Fisher et al., 2011; Anderson et al., 2014).”

“On the other hand, the injection of AG worsened glucose tolerance directly after administration, yet had rather beneficial metabolic long-term consequences, including weight loss, in T1DM, AD, and HD in vivo models (Granado et al., 2009; Kyoraku et al., 2009; Kunath et al., 2015; Duarte et al., 2018).”

“On the other hand, the injection of AG worsened glucose tolerance directly after administration, yet had rather beneficial metabolic long-term consequences, including weight loss, in T1DM, AD, and HD in vivo models (Granado et al., 2009; Kyoraku et al., 2009; Kunath et al., 2015; Duarte et al., 2018).”

“complex 1 and prevented the toxin-induced drop in the mitochondrial membrane potential, resulting in the lessened leakage of the apoptosis-prompting cytochrome C, reduced caspase-3 activation and diminished cell death (Yu et al., 2016).”

“And indeed, the administration of GHRP-6 to old rats ameliorated the age-associated decline in IGF-1 levels in the cerebellum, inhibited caspase 9/3 and reduced cerebellar apoptosis (Paneda et al., 2003).”

“In agreement, AG elicits AMPK-evoked autophagy in the lymphoblastic Jurkat and Molt-4 cell lines (Heshmati et al., 2020), also considering that autophagy is initiated by the inactivation of mTOR (Lan et al.”

“In stark contrast, AG enhanced fatty acid oxidation and lipolysis in mouse skeletal muscles (Kraft et al., 2019).”

“, 2009a), following various forms of ischemic CNS/spinal cord injury (SCI) in rodents (Ersahin et al., 2010, 2011; Lee J. Y. et al., 2010; Cheyuo et al., 2011; Kenny et al., 2013; Lee et al., 2014b, 2015), as well as drug-induced excitotoxicity (Lee J.”

“To further enhance efficacy, the combination of ghrelin agonists with other growth factors, such as EGF (Barco et al., 2011, del Barco et al., 2011, del Barco-Herrera et al., 2013; Subiros et al., 2016), GH (Wu et al., 2009b; Zhou et al., 2017), insulin (Granado et al., 2011) and GLP-1 (Duarte et al., 2018), or DAG, t…”

“, 2016), rotenone-burdened rat retinal ganglion cells (Liu et al., 2018) and primary hypothalamic neurons during oxygen and glucose withdrawal (Chung et al.”

“Intriguingly, some ghrelin agonists show affinity toward both GHS-R1α and CD36, for example hexarelin or GHRS-6 (Demers et al., 2004; Berlanga-Acosta et al., 2017).”

“In line with this theory, caloric restriction and the associated weight loss ameliorated these inflammatory changes, thus restoring the sensitivity toward AG (Naznin et al., 2018).”

“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).”

“This resulted in markedly enhanced plasma levels of L-dopa and dopamine, indicating that ghrelin may improve the gastrointestinal absorption of dopamine replacement drugs (Wang et al., 2012).”

“Anti-inflammatory properties of AG have also been confirmed in various clinical studies (Kodama et al., 2008; Takata et al., 2015; Farokhnia et al., 2020).”

“In addition, heightened numbers of partially α-synuclein-reactive Th17 cells were discovered in the blood of PD patients (Sulzer et al., 2017); to the degree that PD has been postulated as an α-synuclein-reactive autoimmune disease (Benner et al.”

“Furthermore, cAMP/PKA-signaling is evoked by the physiological release of AG-counteracting and growth-promoting hormones that are associated with nutrient abundance and increased glucose metabolism, such as insulin and leptin (Yang and Yang, 2016).”

“Furthermore, quantitative microarray RNA studies have revealed that AD patients, prior to the appearance of other neuropathological hallmarks, including Aß plaques and Tau neurofibrillary tangles, exhibit a decline in the cerebral expression of insulin-regulated genes that drive TCA and pyruvate metabolism (Zhao et al…”

“Moreover, the injection of SKF 83566 itself did not negatively affect the behavioral performance of the rodents (Jacoby and Currie, 2011).”

“…enhance efficacy, the combination of ghrelin agonists with other growth factors, such as EGF (Barco et al., 2011, del Barco et al., 2011, del Barco-Herrera et al., 2013; Subiros et al., 2016), GH (Wu et al., 2009b; Zhou et al., 2017), insulin (Granado et al., 2011) and GLP-1 (Duarte et al.,…”

“As such, while AG can evidently improve gastrointestinal dysfunction (Hong et al., 2019), the occurrence of unwanted gastrointestinal side-effects in some PD patients may restrict the administration of ghrelin agonists in the long-term.”

“Thus, obesity and T2DMassociated hyperleptinemia (Maffei et al., 1995; Considine et al., 1996; Okumura et al., 2003; Pandey et al., 2015) may contribute to the desensitization of AG in the hypothalamus.”

“, 2017), insulin (Granado et al., 2011) and GLP-1 (Duarte et al.”

“Furthermore, the reduced expression of GHS-R1α was verified in induced pluripotent stem cells with a mutated or disrupted PARK2 gene, which is a mitochondrial gene implicated in mitochondrial quality control, mitophagy, and the development of early-onset PD (Pickrell and Youle, 2015), and in the SNpc of an in vivo mod…”

“…and reduced the TNF-α-incited adhesion of co-cultured monocytes/macrophages to the vascular endothelial cells, which was presumably related to the endothelial downregulation of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) (Li et al., 2004; Zhang, 2017).”

“To further enhance efficacy, the combination of ghrelin agonists with other growth factors, such as EGF (Barco et al., 2011, del Barco et al., 2011, del Barco-Herrera et al., 2013; Subiros et al., 2016), GH (Wu et al., 2009b; Zhou et al., 2017), insulin (Granado et al., 2011) and GLP-1 (Duarte et al., 2018), or DAG, t…”

“, 2017); to the degree that PD has been postulated as an α-synuclein-reactive autoimmune disease (Benner et al., 2008; Hu, 2011).”

“, 2013), in the 6-OHDA rodent model of PD, although neurogenesis was only enhanced in the non-lesioned brain hemisphere (Elabi et al., 2018), and the 5xFAD animal model of AD (Moon et al.”

“…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).”

“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].”