Ghrelin, the only known orexigenic gut hormone produced primarily in the stomach, has lately gained attention as a potential treatment of anorexia and cachexia. However, its biologic stability is highly limited; therefore, a number of both peptide and nonpeptide ghrelin analogs have been synthesized. In this study, we provide in vitro and in vivo characterization of a series of novel peptide growth hormone secretagogue receptor (GHS-R1a) agonists, both under nonpathologic conditions and in the context of lipopolysaccharide (LPS)-induced anorexia. These analogs were based on our previous series modified by replacing the Ser3 with diaminopropionic acid (Dpr), the N-terminal Gly with sarcosine, and Phe4 with various noncoded amino acids. New analogs were further modified by replacing the n-octanoyl bound to Dpr3 with longer or unsaturated fatty acid residues, by incorporation of the second fatty acid residue into the molecule, or by shortening the peptide chain. These modifications preserved the ability of ghrelin analogs to bind to the membranes of cells transfected with GHS-R1a, as well as the GHS-R1a signaling activation. The selected analogs exhibited long-lasting and potent orexigenic effects after a single s.c. administration in mice. The stability of new ghrelin analogs in mice after s.c. administration was significantly higher when compared with ghrelin and [Dpr3]ghrelin, with half-lives of approximately 2 hours. A single s.c. injection of the selected ghrelin analogs in mice with LPS-induced anorexia significantly increased food intake via the activation of orexigenic pathways and normalized blood levels of proinflammatory cytokines, demonstrating the anti-inflammatory potential of the analogs.

• MeSH
• beta-laktamasy metabolismus   MeSH
• ghrelin analogy a deriváty   metabolismus   farmakokinetika   farmakologie   MeSH
• kompetitivní vazba MeSH
• lipopolysacharidy škodlivé účinky   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nechutenství chemicky indukované   farmakoterapie   metabolismus   patofyziologie   MeSH
• přijímání potravy účinky léků   MeSH
• receptory ghrelinu metabolismus   MeSH
• růstový hormon metabolismus   MeSH
• sekvence aminokyselin MeSH
• signální transdukce účinky léků   MeSH
• stabilita proteinů MeSH
• tkáňová distribuce MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD), are increasing in prevalence. Currently, there are no effective and specific treatments for these disorders. Recently, positive effects of the orexigenic hormone ghrelin on memory and learning were demonstrated in mouse models of AD and PD. In this study, we tested the potential neuroprotective properties of a stable and long-lasting ghrelin analog, Dpr(3)ghrelin (Dpr(3)ghr), in SH-SY5Y neuroblastoma cells stressed with 1.2 mM methylglyoxal (MG), a toxic endogenous by-product of glycolysis, and we examined the impact of Dpr(3)ghr on apoptosis. Pre-treatment with both 10(-5) and 10(-7) M Dpr(3)ghr resulted in increased viability in SH-SY5Y cells (determined by MTT staining), as well as reduced cytotoxicity of MG in these cells (determined by LDH assay). Dpr(3)ghr increased viability by altering pro-apoptotic and viability markers: Bax was decreased, Bcl-2 was increased, and the Bax/Bcl-2 ratio was attenuated. The ghrelin receptor GHS-R1 and Dpr(3)ghr-induced activation of PBK/Akt were immuno-detected in SH-SY5Y cells to demonstrate the presence of GHS-R1 and GHS-R1 activation, respectively. We demonstrated that Dpr(3)ghr protected SH-SY5Y cells against MG-induced neurotoxicity and apoptosis. Our data suggest that stable ghrelin analogs may be candidates for the effective treatment of neurodegenerative disorders.

• MeSH
• apoptóza účinky léků   MeSH
• ghrelin analogy a deriváty   farmakologie   MeSH
• glykolýza účinky léků   MeSH
• L-laktátdehydrogenasa metabolismus   MeSH
• lidé MeSH
• MAP kinasový signální systém účinky léků   MeSH
• membránový potenciál mitochondrií účinky léků   MeSH
• nádorové buněčné linie MeSH
• neuroprotektivní látky farmakologie   MeSH
• neurotoxické syndromy prevence a kontrola   MeSH
• proteiny regulující apoptózu biosyntéza   genetika   MeSH
• pyruvaldehyd toxicita   MeSH
• receptory ghrelinu biosyntéza   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH