Abstract
Age-related dementia is one of the most devastating disorders affecting the elderly. Recently, emerging data suggest that impaired insulin signaling is the major contributor in the development of Alzheimer’s dementia (AD), which is the most common type of senile dementia. In the present study, we investigated the potential therapeutic effects of metformin (Met) and saxagliptin (Saxa), as insulin sensitizing agents, in a rat model of brain aging and AD using D-galactose (D-gal, 150 mg/kg/day, s.c. for 90 successive days). Six groups of adult male Wistar rats were used: normal, D-gal, Met (500 mg/kg/day, p.o), and Saxa (1 mg/kg/day, p.o) control groups, as well as D-gal/Met and D-gal/Sax treated groups. Impaired learning and memory function was observed in rats treated with D-gal using Morris water maze test. Biochemical and histopathological findings also revealed some characteristic changes of AD in the brain that include the increased content of acetylcholine, glutamate, and phosphorelated tau, as well as deposition of amyloid plaques and neurofibrillary tangles. Induction of insulin resistance in experimentally aged rats was evidenced by increased blood glycated hemoglobin, brain contents of insulin and receptors for advanced glycated end-products, as well as decreased brain insulin receptor level. Elevation of oxidative stress markers and TNF-α brain content was also demonstrated. Met and Saxa, with a preference to Met, restored the normal memory and learning functions in rats, improved D-gal-induced state of insulin resistance, oxidative stress and inflammation, and ameliorated the AD biochemical and histopathological alterations in brain tissues. Our findings suggest that D-gal model of aging results in a diminishing of learning and memory function by producing a state of impaired insulin signaling that causes a cascade of deleterious events like oxidative stress, inflammation, and tau hyper-phosphorylation. Reversing of these harmful effects by the use of insulin-sensitizing drugs like Met and Saxa suggests their involvement in alleviation insulin resistance as the underlying pathology of AD and hence their potential use as anti-dementia drugs.
Highlights
Aging and geriatric disorders are becoming one of the major concerns of the current medicine as the world’s population is aging at a fast rate probably due to the advances in science and medicine [1]
Met administration resulted in a significant decrease in rats‘weight, while Saxa showed no effect on rats‘weight. On the other hand, treatment of the animals with Met following D-gal injections regained the normal weight of the animals; Sax failed (Fig 1)
The present findings revealed that long-term administration of D-gal decreased the average weight of the animals; a result that could be attributed to aging and loss of muscle mass [29]
Summary
Aging and geriatric disorders are becoming one of the major concerns of the current medicine as the world’s population is aging at a fast rate probably due to the advances in science and medicine [1]. Dementia is one of the most devastating geriatric disorders and characterized by a deterioration of intellectual functions such as cognition, memory, and judgment. Higher cortical functions such as language, reasoning, and the ability to follow directions are impaired. Emerging data demonstrate that there is a strong link between AD and type 2 diabetes mellitus (DM). The pathogenesis of the latter involves a progressive development of insulin resistance leading to hyperglycemia. In the course of developing novel therapeutic agents for AD, anti-diabetic drugs were regarded as potential candidates
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