Oral Antihyperglycemic Therapy with an SGLT2 Inhibitor Reverses Cognitive Impairments in Elderly Diabetics
Description: Diabetes mellitus (DM) is one of the leading risk factors for dementia. The incidence of dementia is up to 2.5 times greater in long-standing DM patient, but the underlying mechanisms are unclear. It is well established that hyperglycemia associated oxidative stress causes cerebral endothelial dysfunction, which increases the susceptibility to brain ischemic injury and cognitive deficits. However, whether endothelial dysfunction induced localized hypoxia is the sole cause of dementia is unclear. In addition, if the dysfunction of other vascular cell types blunting autoregulation of cerebral blood flow (CBF), which superimposes endothelial failure-related hypoxia, blood-brain barrier (BBB) leakage and impairment of neurovascular coupling resulting in dementia in DM remains to be determined. Moreover, although anti-hyperglycemic therapy could reduce cerebrovascular remodeling in young DM, whether normalizing plasma glucose can reverse cerebral vascular dysfunction and dementia in elderly DM has never been addressed. We preliminarily found that impaired myogenic response (MR) in middle cerebral arteries (MCAs) and CBF autoregulation in old diabetic rats were reversed after reducing plasma glucose with a sodium-glucose transporter 2 inhibitor (SGLT2i), which does not cross BBB and did not alter body weight, blood pressure, nor protein excretion. However, BBB leakage and cognitive deficits were rescued. MCAs freshly isolated from DM rats exhibited higher levels of mitochondrial superoxide (mtSOX) and impaired Acetylcholine-induced vasodilation, the MR of MCA was restored after treatment with SOD. Higher levels of mtSOX and reduced oxygen consumption rate were detected in high glucose treated vascular smooth muscle cells (VSMCs), and these cells lost their contractile capability. We HYPOTHESIZE that normalizing plasma glucose with an SGLT2i reduces oxidative stress in cerebral VSMCs and endothelial cells, which reverses the impairment of MR of and parenchymal arterioles (PAs), autoregulation of CBF in the deep brain cortex, and functional hyperemia, providing protect from BBB leakage, neurodegeneration, and cognitive deficit in old diabetes. In this proposal, we will compare the cognitive function, MR of PAs, pial arterioles pressure, functional hyperemia and autoregulation of CBF in deep cortex in elderly control, DM, and SGLT2i treated DM rats. We will also explore BBB integrity using a BBB model co-culture of cerebral endothelial, astrocytes and pericytes.
Funder: American Heart Association
Amount: $62,030
Funding type: training
Funder scheme: Predoctoral Fellowship
Start date: 2020-01-01
End date: 2020-12-31
Investigators: Shaoxun Wang, Shaoxun Wang
Institution: University of Mississippi Medical Center
Funded outputs count: 10
Funder award ID: 20PRE35210043
OpenAlex ID: G3963093339