Effects of antidiabetic agents on Alzheimer’s disease biomarkers in experimentally induced hyperglycemic rat model by streptozocin

Abstract

Background Alzheimer’s disease is the most common cause of dementia in the elderly population. It is characterized by the accumulation of amyloid β and intraneuronal neurofibrillary tangles in the brain. Increasing evidence shows that the disturbance of insulin signalling in the brain may contribute to the pathophysiology of Alzheimer’s disease. In type 1 diabetes, these disruptions are caused by hypoinsulinemia, but in type 2 diabetes, they are caused by insulin resistance and decreased insulin secretion. Multiple studies have shown that diabetes is connected with an increased risk of acquiring Alzheimer’s disease. The aim of this study was to investigate the impact of anti-diabetic agents on Alzheimer’s disease progression and the levels of Alzheimer’s biomarkers in a hyperglycaemic rat model, which was induced by intraperitoneal injection of streptozocin to produce insulin-deficient diabetes. Method Thirty-six male Wistar albino rats were allocated into six groups of six rats each. Group I was the negative control group. Intraperitoneal injections of streptozocin (42mg/kg) were used once for the five experimental groups. Group II served as the positive control group. The rats in Groups III, IV, V, and VI received metformin (300mg/kg), donepezil (10mg/kg), insulin glargine (3 unit/animal), and glibenclamide (10mg/kg), respectively, for 21 days. Results Inducing hyperglycaemia in rats significantly increased the levels of serum glucose, haemoglobin A1c, total cholesterol, triglycerides, high-density lipoprotein, interleukin 6, tumour necrosis factor alpha, amyloid β 42, total plasma tau, and neurofilament light. A significant increase was also found in brain amyloid β 42, nitric oxide, acetylcholinesterase, malondialdehyde, β secretase, and phosphorylated microtubule-associated protein tau. The greatest statistically significant reductions in serum glucose, haemoglobin A1c, triglycerides, amyloid β 42, total plasma tau, brain amyloid β 42, acetylcholinesterase, and malondialdehyde were observed in rats treated with metformin. In contrast, rats treated with donepezil demonstrated the greatest statistically significant reduction in serum tumour necrosis factor alpha, brain nitric oxide, and β secretase. The levels of neurofilament light and phosphorylated microtubule-associated protein tau in the brains of rats treated with insulin glargine were significantly lower than the other treatment groups. The total cholesterol and low-density lipoprotein levels in rats treated with glibenclamide exhibited the most statistically significant reductions of all the treatment groups. Conclusions Metformin and donepezil, when administered at appropriate doses, were shown to successfully lower most plasma and brain biomarkers, including glucose, triglycerides, tumour necrosis factor alpha, amyloid β 42, nitric oxide, acetylcholinesterase, malondialdehyde, and β secretase in rats suffering from Diabetes Mellitus. As a result of this research, we suggest that metformin, either alone or in conjunction with donepezil, might be an excellent drug of choice for neuro-regeneration and risk reduction in Alzheimer’s like disease.

Proteomic Analysis of a Rat Streptozotocin Model Shows Dysregulated Biological Pathways Implicated in Alzheimer’s Disease

“…Peptides were subjected to LC-MS/MS (liquid chromatography with tandem mass spectrometry) analysis with an UltiMate 3000 (Thermo Fisher ® , San José, CA, USA) ultrahigh-performance liquid chromatography (UHPLC) system coupled with an Orbitrap FusionTM LumosTM mass spectrometer (Thermo, San José), as follows: The peptide mixtures were loaded into a column (75 mm i.d., 30 cm long) packed in-house with a 3µm ReproSil-Pur C18-AQ resin (Dr. Maisch) with a flow of 250 nL/min. Subsequently, they were eluted with a flow of 250 nL/min, from 5% to 40% ACN, in 0.1% formic acid in a 140 min gradient (23). The mass spectrometer was set in data-dependent acquisition (DDA) mode to automatically switch between full-scan (MS) and MS/MS (MS2) acquisition.…”

“…Most studies using the ICV-STZ model are focused on the description of the behavioral [ 20 ] and morphological [ 21 ] aspects of the disease. The molecular factors of the ICV-STZ model are often assessed through techniques that target only a few genes, such as qRT-PCR [ 22 ] and Western blot [ 23 ]. Mass spectrometry (MS)-based proteomics is a powerful analytical tool commonly used to study the proteome profile of LOAD’s brain [ 24 ].…”

Exploring the Potential of Antidiabetic Agents as Therapeutic Approaches for Alzheimer's and Parkinson's Diseases: A Comprehensive Review

“…While certain studies have demonstrated favorable results, contrasting outcomes marked by the absence of noteworthy effects or conflicting findings have also been reported. These inconsistencies could potentially be elucidated by disparities in multiple factors, including study architecture, specific patient demographics, variations in drug protocols, and the diverse array of metrics employed to gauge outcomes [56][57][58][59][60][61][62].…”

American Ginseng for the Treatment of Alzheimer’s Disease: A Review

“…Gasparini et al have demonstrated that disruptions in brain insulin signaling may play a contributory role in the pathophysiology of AD [106]. Clinical studies have revealed that AD patients exhibit reduced insulin levels and expression of the insulin receptor in the brain, as well as insulin resistance [107], all of which can trigger Aβ accumulation, tau phosphorylation, neurodegeneration and cerebral glucose metabolism impairment, and cognitive decline [108]. Hence, the perturbations in the insulin signaling pathway are increasingly recognized as a shared characteristic of both AD and diabetes, often referred to as "type 3 diabetes" [109].…”