Empagliflozin Ameliorates Type 2 Diabetes-Induced Ultrastructural Remodeling of the Neurovascular Unit and Neuroglia in the Female db/db Mouse

Melvin Hayden,Annayya Aroor,DeAna Grant,Vincent DeMarco

doi:10.3390/brainsci9030057

Melvin Hayden, Annayya Aroor + Show 2 more

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https://doi.org/10.3390/brainsci9030057

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Abstract

Type 2 diabetes is associated with diabetic cognopathy. Anti-hyperglycemic sodium glucose transporter 2 (SGLT2) inhibitors have shown promise in reducing cognitive impairment in mice with type 2 diabetes mellitus. We recently described marked ultrastructural (US) remodeling of the neurovascular unit (NVU) in type 2 diabetic db/db female mice. Herein, we tested whether the SGLT-2 inhibitor, empagliflozin (EMPA), protects the NVU from abnormal remodeling in cortical gray and subcortical white matter. Ten-week-old female wild-type and db/db mice were divided into lean controls (CKC, n = 3), untreated db/db (DBC, n = 3), and EMPA-treated db/db (DBE, n = 3). Empagliflozin was added to mouse chow to deliver 10 mg kg−1 day−1 and fed for ten weeks, initiated at 10 weeks of age. Brains from 20-week-old mice were immediately immersion fixed for transmission electron microscopic study. Compared to CKC, DBC exhibited US abnormalities characterized by mural endothelial cell tight and adherens junction attenuation and/or loss, pericyte attenuation and/or loss, basement membrane thickening, glia astrocyte activation with detachment and retraction from mural cells, microglia cell activation with aberrant mitochondria, and oligodendrocyte–myelin splitting, disarray, and axonal collapse. We conclude that these abnormalities in the NVU were prevented in DBE. Empagliflozin may provide neuroprotection in the diabetic brain.

Highlights

Type 2 diabetes mellitus (T2DM) is a chronic metabolic–endocrine disorder characterized by hyperglycemia, insulin resistance or relative lack of insulin, and this glucotoxic state promotes tissue oxidative/nitrosative stress and chronic inflammation
We recently reported cortical gray matter neurovascular unit (NVU), neuroglia, and chronic inflammation, which is associated with multiple diabetic microvascular end-organ myelin injury with US remodeling [1,2,3]
We have previously identified the observational abnormal remodeling associated with the NVU and its supportive cellular constituents [1,2,3]

Summary

Introduction

Type 2 diabetes mellitus (T2DM) is a chronic metabolic–endocrine disorder characterized by hyperglycemia, insulin resistance or relative lack of insulin, and this glucotoxic state promotes tissue oxidative/nitrosative stress and chronic inflammation. T2DM is an independent risk factor for microvascular complications, which include neuropathy, retinopathy, nephropathy, diabetic cognopathy, and age-related neurodegenerative diseases such Alzheimer’s disease (AD) [1,2,3,4,5,6,7]. In this regard, we and others reported cognitive impairment, brain tissue oxidative stress, and ultrastructural (US) remodeling within the neurovascular unit (NVU) of cerebral cortical gray matter and transitional subcortical white matter from db/db mice relative to non-diabetic wild-type age- and gender-matched. As has [1,2,3], been suggested model could[1,2,3], be instrumental in helping whether current anti-hyperglycemic therapies, previously the db/db model couldtobeelucidate instrumental in helping to elucidate whether current including sodium–glucose transporter-2

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