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

BACKGROUND: Alzheimer's disease is the most common cause of dementia in the elderly population. It is characterized by the accumulation of amyloid ß 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 ß 42, total plasma tau, and neurofilament light. A significant increase was also found in brain amyloid ß 42, nitric oxide, acetylcholinesterase, malondialdehyde, ß secretase, and phosphorylated microtubule-associated protein tau. The greatest statistically significant reductions in serum glucose, haemoglobin A1c, triglycerides, amyloid ß 42, total plasma tau, brain amyloid ß 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 ß 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 ß 42, nitric oxide, acetylcholinesterase, malondialdehyde, and ß 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.

Effects of neprilysin-renin inhibition in comparison with neprilysin-angiotensin inhibition on the neurohumoral changes in rats with heart failure.

BACKGROUND: The activation of neurohumoral compensatory mechanisms is a common physiological phenomenon in heart failure in order to make up for a failing heart, which will usually have a deteriorating effect on overall health condition. Many medications, such as neprilysin and angiotensin inhibitors, have recently been introduced to remediate neurohumoral changes. This study was conducted to evaluate the efficacy of the sacubitril-aliskiren combination versus the sacubitril-ramipril combination in the treatment of neurohumoral changes in rats with experimentally induced heart failure. METHOD: Thirty Wister rats were randomly assigned into five groups each of six rats, the first group was the control group. Intraperitoneal isoprenaline injections of 5 mg/kg/day for 1 week were used to induce experimental models of heart failure in rats of the rest of experimental groups. The second group served as a positive control. Rats in the third, fourth, and fifth groups received oral daily dose of sacubitril 30 mg/kg/day, sacubitril-aliskiren 30,10 mg/kg/day, and sacubitril-ramipril 30/10 mg/kg/day respectively, for 2 weeks. RESULTS: Induction of heart failure in rats has significantly increased circulating NT-proBNP (980 ± 116.71 pg/ml), MMP9 (15.85 ± 0.57 ng/ml), troponin-I (3.09 ± 0.147 ng/ml), CK-MB (31.55 ± 1.69 ng/ml), renin (736 ± 45.8 pg/ml), urea (52.1 ± 1.57 mg/dl), and creatinine (0.92 ± 0.04 mg/dl). Significant decreases in glomerular filtration rate (7.031 ± 1.6 ml/hr./kg), urine flow (0.2761 ± 0.06 ml/h/kg), total solute excretion (0.11 ± 0.03 meq/m), and mean blood pressure (83.5 ± 2.6 mm hg) were seen in rats with heart failure. Rats treated with sacubitril combined with aliskiren or ramipril showed a statistically significant reduction of NT-proBNP, MMP9, troponin serum urea, and serum creatinine. Sacubitril-aliskiren or sacubitril-ramipril administration produced a significant increase in renin plasma level, total solute excretion, urine flow, and glomerular filtration rate. CONCLUSION: Sacubitril in combination with aliskiren or with ramipril effectively reduced plasma cardiac biomarkers, such as CK-MB, MMP9, and NT-proBNP, in rats with heart failure. Both combinations showed significant remediation of renal function through increasing GFR, urine flow, and total solute excretion, as well as reducing plasma level of renin. Net results revealed that the sacubitril-aliskiren combination has similar remediating effects on neurohumoral changes compared to the sacubitril-ramipril combination.