Abstract
The gastrointestinal system may be involved in the etiopathogenesis of the insulin-resistant brain state (IRBS) and Alzheimer’s 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 low molecular weight thiols (LMWT), protein sulfhydryls (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.
Highlights
IntroductionAlzheimer’s disease (AD) is the most common type of dementia characterized by progressive neurodegeneration and the development of cognitive deficits
Introduction published maps and institutional affilAlzheimer’s disease (AD) is the most common type of dementia characterized by progressive neurodegeneration and the development of cognitive deficits
Acute inhibition of endogenous GLP-1 receptors (GLP-1R) signaling in the brain with Ex-9 induced peripheral oxidative stress in both control animals and the rat model of sporadic AD (sAD)
Summary
Alzheimer’s disease (AD) is the most common type of dementia characterized by progressive neurodegeneration and the development of cognitive deficits. Etiopathogenesis of the disease is yet to be elucidated, with the exception of a small fraction of cases in which. In the STZ-icv, TBARS and CAT were increased, LMWT amyloid precursor protein (APP), presenilin-1 (PSEN1). Presenilin (PSEN2) is believed to be a causative factor [1]. Many hypotheses have been proposed over the years to explain early molecular mechanisms responsible for the development of the disease. Since its proposal in 1992 [2], the amyloid cascade hypothesis has dominated the field. Other hypotheses are being explored to provide novel therapeutic and diagnostic solutions and address the unmet needs of the increasing burden iations
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