الفهرس 
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Abstract
Alzheimer’s disease (AD) is a chronic progressive neurodegenerative disease, it is the sixth-leading reason for fatality, consisting of over two-thirds of all cases of dementia. It is related to multiple risk factors most importantly APOE4 allele genetic predisposition, diabetes mellitus, and chronic exposure to stress leading to learning and memory impairments. The proposed mechanism of AD is accumulation of extra- and intracellular beta-amyloid and neurofibrillary tangles aggregates of phosphorylated tau protein that bind to microtubules.
Chronic stress exposure proved to have negative impact on learning and memory. Numerous lines of evidence pointed out different underlying mechanisms by which chronic stress affects the pathophysiology of AD including insulin resistance, oxidative stress, and mitochondrial dysfunction which are all mediated through chronic glucocorticoids elevation. Thus, a deeper knowledge about the neurobiological basis is warranted to improve the treatment options.
Insulin signaling is important for the development and cognitive function of the hippocampus. Akt and mammalian target of rapamycin (mTOR) are two important components of insulin signaling pathway. chronic activation of unrestrained mTOR by Akt could be responsible for sustaining metabolic dysfunction that causes the breakdown of the blood-brain barrier, tau hyperphosphorylation and senile plaques formation in AD.
Dapagliflozin is a selective SGLT2 inhibitor that lowers the glucose level independently of insulin, by limiting tubular glucose reabsorption. SGLT2 receptor has been identified in the hippocampus, cerebellum, and at blood–brain barrier (BBB) endothelial cells. This particular distribution may be responsible for the evidence suggesting their neuroprotective properties, it has marked antioxidant/antiapoptotic features and it’s a promising neuroprotective agent in murine models of epilepsy and obesity-induced cognitive impairment
For now, no treatment exists for preventing or cure AD, and only few medications have been approved by FDA to treat AD symptoms such as inhibitors of cholinesterase enzyme and antagonists to N-methyl d-aspartate (NMDA). Recently, Dapagliflozin through its insulin sensitizing effect improves insulin signaling by enhancement of BDNF gene expression along with decreasing Akt and mTOR, its antioxidant actions reducing MDA and increasing GSH, mitochondrial function improvement by increasing ATP synthesis and enhances CCO activity expression, has promising effects on ameliorating AD progression and symptoms, improving cognitive functions in AD patients.
Design:
Our study was designed to detect the potential roles of chronic stress exposure on learning and memory abilities, and the effects of chronic treatments with dapagliflozin. Further, assessment of possible underlying molecular mechanisms in chronic restraint stress exposure in male Wistar rats.
Forty-eight male Wister rats were randomly divided into four groups (n= 12); Control group, chronic restraint stress group, CRS-treated group, Dapagliflozin only group. After four weeks, Body weight, Assessment of learning and memory impairment (Morris water maze test, Y maze test), biochemical and histological assessment of hippocampus.
The results could be summarized as follows:
CRS induced learning and memory impairment symptoms (decreased spontaneous alteration ratio in y maze test and decreasing latency with increasing time spent in target quadrant in MWM test) in addition to neurodegenerative changes in CA1 of hippocampus with metabolic disturbances (increased glucose, cortisol, and HOMA-IR with decreased insulin secretion), impairing insulin signaling pathway (increased p-Akt, p-mTOR), oxidative damage (increased MDA and reduced GSH), and mitochondrial dysfunction (decreased ATP synthesis and CCO enzyme activity). This was accompanied by the appearance of AD like changes with increase of amyloid beta and phosphorylated tau along with decreasing BDNF gene expression confirming AD neurodegeneration. chronic dapagliflozin treatment improved cognitive performance in treated rats (increased SAP ratio in y maze test and decreasing latency with increasing time spent in target quadrant in MWM test) with less stress induced neurodegenerative changes in CA1, by correcting the metabolic changes (decreased glucose, cortisol, and HOMA-IR), improving insulin sensitivity with enhancing insulin signaling pathway (decreased p-Akt, p-mTOR), along with its antioxidant effects (decreased MDA and increased GSH) and mitochondrial functions enhancement (decreased ATP synthesis and CCO enzyme activity) with decreasing amyloid beta and phosphorylated tau and increasing BDNF gene expression leading to limiting stress induced AD like changes.
CONCLUSION
This study supports the presence of a biological link between chronic stress, insulin resistance and C.I, and highlights the promising role of DGF in limiting cognitive deficits and neurodegeneration mostly through its insulin sensitizing, antioxidant effects, and improving mitochondrial dysfunction in hippocampus.
RECOMMENDATIONS
• Dapagliflozin may represent a new therapeutic potential in C.I that needs further clinical and experimental studies.
• Further research is needed to investigate different mechanisms of dapagliflozin to enhance cognitive functions in chronic stress.