Forxiga (dapagliflozin): Plausible role in the treatment of diabetes‐associated neurological disorders

Shaikh, Sibhghatulla; Rizvi, Syed Mohd Danish; Shakil, Shazi; Riyaz, Sania; Biswas, Deboshree; Jahan, Roshan

doi:10.1002/bab.1319

Cited by 49 publications

(37 citation statements)

References 37 publications

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“…In this animal model, improvement in the MWM is attributed to the inhibition of acetylcholinesterase activity and monoamine levels in the brain. Canagliflozin might act as a dual acetylcholinesterase and SGLT2i [55], supporting a dual role for SGLT2i at the central level [56,57] and opening an interesting venue, since acetylcholinesterase inhibitors, and NMDA receptor antagonist memantine, are the only FDAapproved options to treat AD. In our learning and memory studies, we additionally used a very demanding version of the NOD task, which allows the assessment of episodic memory [58].…”

Section: Discussionmentioning

confidence: 96%

Empagliflozin reduces vascular damage and cognitive impairment in a mixed murine model of Alzheimer’s disease and type 2 diabetes

et al. 2020

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Background: Both Alzheimer's disease (AD) and type 2 diabetes (T2D) share common pathological features including inflammation, insulin signaling alterations, or vascular damage. AD has no successful treatment, and the close relationship between both diseases supports the study of antidiabetic drugs to limit or slow down brain pathology in AD. Empagliflozin (EMP) is a sodium-glucose co-transporter 2 inhibitor, the newest class of antidiabetic agents. EMP controls hyperglycemia and reduces cardiovascular comorbidities and deaths associated to T2D. Therefore, we have analyzed the role of EMP at the central level in a complex mouse model of AD-T2D. Methods: We have treated AD-T2D mice (APP/PS1xdb/db mice) with EMP 10 mg/kg for 22 weeks. Glucose, insulin, and body weight were monthly assessed. We analyzed learning and memory in the Morris water maze and the new object discrimination test. Postmortem brain assessment was conducted to measure brain atrophy, senile plaques, and amyloid-β levels. Tau phosphorylation, hemorrhage burden, and microglia were also measured in the brain after EMP treatment. Results: EMP treatment helped to maintain insulin levels in diabetic mice. At the central level, EMP limited cortical thinning and reduced neuronal loss in treated mice. Hemorrhage and microglia burdens were also reduced in EMPtreated mice. Senile plaque burden was lower, and these effects were accompanied by an amelioration of cognitive deficits in APP/PS1xdb/db mice. Conclusions: Altogether, our data support a feasible role for EMP to reduce brain complications associated to AD and T2D, including classical pathological features and vascular disease, and supporting further assessment of EMP at the central level.

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Section: Discussionmentioning

confidence: 96%

Empagliflozin reduces vascular damage and cognitive impairment in a mixed murine model of Alzheimer’s disease and type 2 diabetes

et al. 2020

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“…7 The effects of SGLT2-Is on AD progression have not yet been studied, 5 although certain drugs (i.e., dapagliflozin and canagliflozin) might act as potent dual inhibitors of SGLT2 and acetylcholinesterase (AChE), implying that SGLT2-Is may have some therapeutic potential for DM-associated AD. 9,10 SGLT2/SLC5A2 protein is reported to be exclusively expressed on the brush border membrane (BBM) of proximal tubular epithelial (PTE) cells in the kidney. 11,12 Notably, Bonner et al (2005) reported SGLT2/SLC5A2 expression in the α cells of the human pancreatic islets.…”

Section: Introductionmentioning

confidence: 99%

Sodium/glucose cotransporter 2 is expressed in choroid plexus epithelial cells and ependymal cells in human and mouse brains

et al. 2020

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Diabetes mellitus (DM) is now recognized as one of the risk factors for Alzheimer's disease (AD), and the diseasemodifying effects of anti-diabetic drugs on AD have recently been attracting great attention. Sodium/glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic drugs targeting the SGLT2/solute carrier family 5 member 2 (SLC5A2) protein, which is known to localize exclusively in the brush border membrane of early proximal tubules in the kidney. However, recent data suggest that it is also expressed in other tissues. In the present study, we investigated the expression of SGLT2/SLC5A2 in human and mouse brains. Immunohistochemical staining of paraffin sections from autopsied human brains and C3H/He mouse brains revealed granular cytoplasmic immunoreactivity in choroid plexus epithelial cells and ependymal cells. Immunoblot analysis of the membrane fraction of mouse choroid plexus showed distinct immunoreactive bands at 70 and 26 kDa. Band patterns around 70 kDa in the membrane fraction of the choroid plexus were different from those in the kidney. Reverse transcription-polymerase chain reaction analysis confirmed the expression of Slc5a2 mRNA in the mouse choroid plexus. Our results provide in vivo evidence that SGLT2/ SLC5A2 is expressed in cells facing the cerebrospinal fluid, in addition to early proximal tubular epithelial cells. These findings suggest that SGLT2 inhibitors may have another site of action in the brain. The effects of SGLT2 inhibitors on brain function and AD progression merit further investigation to develop better treatment options for DM patients.

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“…SGLT1s are expressed and are functional in regions of cerebellum, hippocampus, frontal cortex, putamen, amygdala, nucleus caudatus, parietal cortex, and paraventricular nucleus of the hypothalamus in rats . In addition, molecular docking studies demonstrate that SGLT2I may interact and inhibit acetylcholinesterase, which is a primary target for AD treatment . Whether SGLT2Is can cross the blood‐brain barrier and act in the brain remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Obesity as a risk factor for Alzheimer's disease: weighing the evidence

et al. 2017

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Alzheimer's disease (AD) is the sixth leading cause of death in the USA today; therefore, it is imperative that public health initiatives and clinical strategies are developed to prevent and effectively treat AD. Despite the enormous impact that AD has on individuals, families, society, and the health care system, there are no biomarkers to clearly identify those at risk for AD, public health prevention strategies in place, or treatments to address the underlying pathology or stop the progression of AD. There is ample scientific as well as empirical evidence that obesity and its metabolic and vascular comorbidities are related to AD and likely in the causative pathway. Obesity prevention and treatment could prove to be an efficacious and safe approach to preventing AD, a serious and daunting epidemic disease. In this review, we present the current pathophysiological and clinical evidence linking obesity and obesity-related comorbidities (eg, insulin resistance, hyperglycaemia, and type 2 diabetes) with AD. Additionally, we discuss which population to target and when to consider treatment for AD. Finally, we summarize the current evidence regarding the efficacy of anti-obesity and anti-diabetic pharmacotherapeutic agents for the treatment of AD.

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Forxiga (dapagliflozin): Plausible role in the treatment of diabetes‐associated neurological disorders

Cited by 49 publications

References 37 publications

Empagliflozin reduces vascular damage and cognitive impairment in a mixed murine model of Alzheimer’s disease and type 2 diabetes

Empagliflozin reduces vascular damage and cognitive impairment in a mixed murine model of Alzheimer’s disease and type 2 diabetes

Sodium/glucose cotransporter 2 is expressed in choroid plexus epithelial cells and ependymal cells in human and mouse brains

Obesity as a risk factor for Alzheimer's disease: weighing the evidence

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