Research Article: Beneficial effects of novel antagonists of GHRH in different models of Alzheimer’s disease

Date Published: November 29, 2012

Publisher: Impact Journals LLC

Author(s): Miklos Jaszberenyi, Ferenc G. Rick, Luca Szalontay, Norman L. Block, Marta Zarandi, Ren-Zhi Cai, Andrew V. Schally.

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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.

Partial Text

Several etiological factors have been implicated in the pathogenesis of Alzheimer’s disease. These factors, in this most frequent form of dementia, lead to the activation of a cascade process that brings about neuronal death and serious decline in cognitive function. These bed-ridden patients ultimately succumb to death due to inter-current infections related to aspiration, decubitus and stagnation of urine [1].

Our previous studies clearly demonstrated that the GHRH antagonists developed by us [19, 20] had a strong impact on the GHRH – GH – IGF-I axis [21]. The effects of GHRH antagonists on several other physiologic and pathologic conditions have already been demonstrated [19, 22-28]. The role of the GHRH – GH – IGF-I axis in the regulation of learning processes and the development of Alzheimer’s disease, however, has not been completely clarified. Both hyperactivity [29, 30] and hypoactivity [31] of the system have been connected to decreased life-expectancy and impaired cognition. Nevertheless, important recent observations support the view that the suppression of the axis can improve cognition in both physiologic and pathologic conditions [7, 10, 11, 15, 17].

 

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