Publications by authors named "Reece Crumpler"

2 Publications

  • Page 1 of 1

Capillary Stalling: A Mechanism of Decreased Cerebral Blood Flow in AD/ADRD.

J Exp Neurol 2021 ;2(4):149-153

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216, USA.

Alzheimer's Disease (AD) and Alzheimer's Disease-Related Dementias (ADRD) are debilitating conditions that are highly associated with aging populations, especially those with comorbidities such as diabetes and hypertension. In addition to the classical pathological findings of AD, such as beta-amyloid (Aβ) accumulation and tau hyperphosphorylation, vascular dysfunction is also associated with the progression of the disease. Vascular dysfunction in AD is associated with decreased cerebral blood flow (CBF). Impaired CBF is an early and persistent symptom of AD/ADRD and is thought to be associated with deficient autoregulation and neurovascular coupling. Another recently elucidated mechanism that contributes to cerebral hypoperfusion is capillary stalling, or the temporary arrest of capillary blood flow usually precipitated by a stalled leukocyte or constriction of actin-containing capillary pericytes. Stalled capillaries are associated with decreased CBF and impaired cognitive performance. AD/ADRD are associated with chronic, low-level inflammation, which contributes to capillary stalling by increased cell adhesion molecules, circulating leukocytes, and reactive oxygen species production. Recent research has shed light on potential targets to decrease capillary stalling in AD mice. Separate inhibition of Ly6G and VEGF-A has been shown to decrease capillary stalling and increase CBF in AD mice. These results suggest that targeting stalled capillaries could influence the outcome of AD and potentially be a target for future therapies.
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http://dx.doi.org/10.33696/neurol.2.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8754422PMC
January 2021

Luseogliflozin, a sodium-glucose cotransporter-2 inhibitor, reverses cerebrovascular dysfunction and cognitive impairments in 18-mo-old diabetic animals.

Am J Physiol Heart Circ Physiol 2022 Feb 24;322(2):H246-H259. Epub 2021 Dec 24.

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi.

Diabetes mellitus (DM) is a leading risk factor for age-related dementia, but the mechanisms involved are not well understood. We previously discovered that hyperglycemia induced impaired myogenic response (MR) and cerebral blood flow (CBF) autoregulation in 18-mo-old DM rats associated with blood-brain barrier (BBB) leakage, impaired neurovascular coupling, and cognitive impairment. In the present study, we examined whether reducing plasma glucose with a sodium-glucose cotransporter-2 inhibitor (SGLT2i) luseogliflozin can ameliorate cerebral vascular and cognitive function in diabetic rats. Plasma glucose and HbA1c levels of 18-mo-old DM rats were reduced, and blood pressure was not altered after treatment with luseogliflozin. SGLT2i treatment restored the impaired MR of middle cerebral arteries (MCAs) and parenchymal arterioles and surface and deep cortical CBF autoregulation in DM rats. Luseogliflozin treatment also rescued neurovascular uncoupling, reduced BBB leakage and cognitive deficits in DM rats. However, SGLT2i did not have direct constrictive effects on vascular smooth muscle cells and MCAs isolated from normal rats, although it decreased reactive oxygen species production in cerebral vessels of DM rats. These results provide evidence that normalization of hyperglycemia with an SGLT2i can reverse cerebrovascular dysfunction and cognitive impairments in rats with long-standing hyperglycemia, possibly by ameliorating oxidative stress-caused vascular damage. This study demonstrates that luseogliflozin, a sodium-glucose cotransporter-2 inhibitor, improved CBF autoregulation in association with reduced vascular oxidative stress and AGEs production in the cerebrovasculature of 18-mo-old DM rats. SGLT2i also prevented BBB leakage, impaired functional hyperemia, neurodegeneration, and cognitive impairment seen in DM rats. Luseogliflozin did not have direct constrictive effects on VSMCs and MCAs isolated from normal rats. These results provide evidence that normalization of hyperglycemia with an SGLT2i can reverse cerebrovascular dysfunction and cognitive impairments in rats with long-standing hyperglycemia, possibly by ameliorating oxidative stress-caused vascular damage.
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http://dx.doi.org/10.1152/ajpheart.00438.2021DOI Listing
February 2022
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