Divergent effect of central incretin receptors inhibition in a rat model of sporadic Alzheimer’s disease

Abstract

The incretin system is an emerging new field that might provide valuable contributions to the research of both pathophysiology and therapeutic strategies in the treatment of diabetes, obesity, and neurodegenerative disorders. This study aimed to explore the role of central glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) on cell metabolism and energy in the brain as well as on the levels of these incretins, insulin and glucose, by inhibiting the central incretins' receptors following intracerebroventricular administration of the respective antagonists in healthy rats and a streptozotocin-induced rat model of sporadic Alzheimer's disease (sAD). Chemical ablation of the central GIP receptor (GIPR) or GLP-1 receptor (GLP-1R) in healthy and diseased animals indicated a region-dependent role of incretins in the brain cell energy and metabolism and central incretin-dependent modulation of peripheral hormone secretion, markedly after GIPR inhibition, as well as a dysregulation of the GLP-1 system in experimental sAD.

The Effect of the Sodium—Glucose Cotransporter Inhibitor on Cognition and Metabolic Parameters in a Rat Model of Sporadic Alzheimer’s Disease

“…As GLP-1 has neuroprotective effects [ 3 ], the increase in GLP-1 in the CSF could be one of the mechanisms by which SGLTIs induce beneficial effects in the brain. In our previous research, we observed different responses in GLP-1 and GIP levels in plasma and CSF in the STZ-icv rat model of AD after treatment with exenatide (Ex9) [ 64 ]. Based on the highly increased GIP levels in plasma found after acute central GIPR inhibition, and the unchanged plasma GLP-1 levels after central GLP-1R inhibition, we can speculate that the CNS is more dependent on the production of GIP, i.e., more sensitive to a central dysfunction in GIP than GLP-1 homeostasis.…”

Association of Cognitive Deficit with Glutamate and Insulin Signaling in a Rat Model of Parkinson’s Disease

“…For protein isolation and subsequent measurement of protein levels, HPC, HPT and S were homogenized using an ultrasonic homogenizer (Microson Ultrasonic Cell Disruptor XL; Misonix, Farmingdale, NY, USA) in cell lysis buffer solution (1 M Tris (tris(hydroxymethyl)aminomethane) pH 8.0; 1 M NaCl; 0.005 M EDTA; 1 M DTT; 0.01 M sodium vanadate; 1% NP-40) with protease (Roche Holding AG, Basel, Switzerland; Cat.#04693132001) and phosphatase (Roche Holding AG, Basel, Switzerland; Cat.#4906837001) inhibitors. Homogenates were centrifuged for 10 min at 12,500 rpm at 4 °C (Biofuge Fresco Heraeus, Hanau, Germany), and supernatants were stored at −80 °C [ 34 ]. The protein concentration was measured using the Lowry protein assay [ 35 ].…”

“…The ImageJ software (ImageJ; U.S. National Institutes of Health, Bethesda, MD, USA) was used to analyze the bands obtained by the Western blotting method. Total proteins were used as a control of the procedure, and protein intensities were expressed in proportion to the signal of total proteins in the same sample on the corresponding membrane [ 34 ].…”