title: Beneficial effects of novel antagonists of GHRH in different models of Alzheimer's disease.
abstract: Alzheimer's disease is the most frequent debilitating disorder of the central nervous system. Neuroendocrine mechanisms appear to play an important role in this insidiously developing disease. In the present study, the effects of a recently developed growth hormone-releasing hormone (GHRH) antagonist (MIA-690) were evaluated in vivo observing the behavior of genetically modified "Alzheimer's" 5XFAD mice in a Morris water maze (MWM). The effects of the antagonist were also evaluated in vitro using HCN2 human cortical cell cultures treated with amyloid-β1-42. In vivo, the indices of cognitive performance (latency, cumulative index etc.) were followed up for 6 months. In vitro, the formation of reactive oxygen species, markers of inflammatory and neurohormonal signaling were measured by fluorescent detection, PCR, and ELISA. Accumulation of amyloid-β1-42 rafts and τ filaments in necropsied brain samples was verified with the help of ELISA. In the MWM experiments, MIA-690 decreased escape latency, and, in the brain samples, it inhibited the concentration of amyloid-β1-42 and τ filaments. In cell cultures, the GHRH analog showed anti-oxidative and neuro-protective properties and inhibited the GHRH-growth hormone-insulin like growth factor axis. Our data strongly suggest the merit of further studies with GHRH analogs in models of Alzheimer's disease and in elementary clinical trials.
authors.affiliation: Endocrine, Polypeptide, and Cancer Institute, Miami Veterans Affairs Medical Center and South Florida VA Foundation for Research and Education, Miami, FL 33125, USA.
authors.forename: Miklos
authors.initials: M
authors.lastname: Jaszberenyi
authors.forename: Ferenc G
authors.initials: FG
authors.lastname: Rick
authors.forename: Luca
authors.initials: L
authors.lastname: Szalontay
authors.forename: Norman L
authors.initials: NL
authors.lastname: Block
authors.forename: Marta
authors.initials: M
authors.lastname: Zarandi
authors.forename: Ren-Zhi
authors.initials: RZ
authors.lastname: Cai
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Schally
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D013007:Growth Hormone-Releasing Hormone / Q000037:antagonists & inhibitors*; D006801:Humans; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D018696:Neuroprotective Agents; D013007:Growth Hormone-Releasing Hormone