Protective effect of growth hormone-releasing hormone (GHRH) agonist MR-409 in Alzheimer’s disease

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the formation of amyloid-β (Aβ) plaques and Tau neurofibrillary tangles, leading to neuronal loss, inflammation, reduced neurogenesis, and cognitive impairment. Currently, there is no effective cure for AD, highlighting the urgent need for novel therapeutic strategies. Growth hormone-releasing hormone (GHRH) and its agonistic analog MR-409 exhibit several peripheral functions, including neuroprotection and protection against skeletal muscle atrophy. However, the role of GHRH in AD remains to be elucidated. Our in vitro findings indicated that GHRH(1-44)NH2 attenuates Aβ(1-42)-induced toxicity in neural stem cells, while promoting neurogenesis and neuronal differentiation. Thus, we investigated the potential protective effect of MR-409 in the 5xFAD mouse model of AD. 3-month-old male mice were assigned to the following groups: wild type (WT)-vehicle (VH) (n=6); WT-MR-409 (n=4); 5xFAD-VH (n=10); 5xFAD-MR-409 (n=10). Mice were subcutaneously treated daily with 0.8 mg/kg MR-409 or VH for 3 months. Compared with untreated, MR-409-treated 5xFAD mice showed i) increased body weight; ii) reduced brain astrogliosis (assessed by immunohistochemistry), reduced mRNA levels of inflammatory cytokines, in brain tissues, and increased brain-derived neurotrophic factor (BDNF) (real-time PCR analysis); iii) reduced phosphorylated Tau and nuclear factor-κB (NF-κB), increased phosphorylated glycogen synthase kinase-3 beta (GSK-3β) (Western blot analysis) in brain tissues; iv) decreased markers of atrophy (atrogin, MuRF1) in skeletal muscle. Ongoing studies include in vivo behavioral tests and ex vivo amyloid-β plaque analysis, neurogenesis, and oxidative stress. Overall, these results, combined with our previous in vitro findings, suggest a protective role for MR-409 in AD.