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bioRxiv · 10.1101/2021.03.22.436453

Failure of the brain glucagon-like peptide-1-mediated control of intestinal redox homeostasis in a rat model of sporadic Alzheimer's disease

Homolak, J.·Babic Perhoc, A.·Knezovic, A.·Osmanovic Barilar, J.·Salkovic-Petrisic, M.
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Abstract

The gastrointestinal system may be involved in the etiopathogenesis of the insulin-resistant brain state (IRBS) and Alzheimers disease (AD). Gastrointestinal hormone glucagon-like peptide-1 (GLP-1) is being explored as a potential therapy as activation of brain GLP-1 receptors (GLP-1R) exerts neuroprotection and controls peripheral metabolism. Intracerebroventricular administration of streptozotocin (STZ-icv) is used to model IRBS and GLP-1 dyshomeostasis seems to be involved in the development of neuropathological changes. The aim was to explore i) gastrointestinal homeostasis in the STZ-icv model ii) assess whether the brain GLP-1 is involved in the regulation of gastrointestinal redox homeostasis and iii) analyze whether brain-gut GLP-1 axis is functional in the STZ-icv animals. Acute intracerebroventricular treatment with exendin-3(9-39)amide was used for pharmacological inhibition of brain GLP-1R in the control and STZ-icv rats, and oxidative stress was assessed in plasma, duodenum and ileum. Acute inhibition of brain GLP-1R increased plasma oxidative stress. TBARS were increased, and LMWT, SH, and superoxide dismutase (SOD) were decreased in the duodenum, but not in the ileum of the controls. In the STZ-icv, TBARS and CAT were increased, LMWT and SH were decreased at baseline, and no further increment of oxidative stress was observed upon central GLP-1R inhibition. The presented results indicate that i) oxidative stress is increased in the duodenum of the STZ-icv rat model of AD, ii) brain GLP-1R signaling is involved in systemic redox regulation, iii) brain-gut GLP-1 axis regulates duodenal, but not ileal redox homeostasis, and iv) brain-gut GLP-1 axis is dysfunctional in the STZ-icv model.

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Homolak, J., Babic Perhoc, A., Knezovic, A., Osmanovic Barilar, J., Salkovic-Petrisic, M.. 2021-03-23. Failure of the brain glucagon-like peptide-1-mediated control of intestinal redox homeostasis in a rat model of sporadic Alzheimer's disease. https://doi.org/10.1101/2021.03.22.436453

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