Adviye Ergul

Augusta University · Department of Physiology

Diabetes worsens stroke outcomes and cognitive function, but the underlying reasons are not understood. Long-term experimental studies had been limited by greater mortality in diabetic cohorts. Recent studies suggested circadian rhythms may modulate brain ischemia and hence mortality/recovery. The goal of this study was to determine the impact of s...

Cerebrovascular dysfunction leading to brain hypoperfusion is an early event in vascular cognitive impairment & dementia ( VCID ). Postmortem brain levels of endothelin (ET)-1, the most potent vasoconstrictor, closely correlate with blood barrier breakdown and hypoperfusion in individuals with VCID. The prevalence of diabetes in people with dementi...

Increased consumption of a high-fat diet (HFD) is believed to increase the risk for the development and progression of VCID, but the underlying mechanisms of how HFD leads to cognitive impairment are unclear, partly due to the use of different HFD models in preclinical studies. Palmitic acid (PA), the most common form of saturated fatty acid, found...

Both female sex and diabetes increase the risk of poor stroke recovery, but underlying mechanisms are unclear. We reported that inhibition of MMP3 with UK356618 prevents hemorrhagic transformation (HT) in male diabetic rats, and female diabetic rats develop greater HT than males. Emerging evidence suggests that MMP3 may contribute to the regulation...

Diabetes mellitus (DM) is associated with poor stroke outcomes, including high mortality and disability rates. Ischemic injury modeling large artery stroke in diabetic animals also results in high mortality and poor acute and long-term outcomes. In this chapter, we describe middle cerebral artery occlusion (MCAO) in a high-fat diet/low-dose strepto...

Diabetes increases the risk of post-stroke cognitive impairment (PSCI). Greater hemorrhagic transformation (HT) after stroke is associated with vasoregression and cognitive decline in male diabetic rats. Iron chelator deferoxamine (DFX) prevents vasoregression and improves outcomes. While diabetic female rats develop greater HT, its impact on post-...

Diabetes exacerbates hemorrhagic transformation (HT) after stroke and worsens clinical outcomes. Female patients with diabetes are at a greater risk of stroke and worsened recovery. We have shown that activation of matrix metalloprotease 3 (MMP3) in hyperglycemic settings mediates HT in male rats. In light of our recent findings that diabetic femal...

Cellular senescence plays a pivotal role in the aging and progression of neurodegenerative diseases, including vascular cognitive impairment and dementia (VCID). In postmortem brains from individuals with VCID, endothelin-1 (ET-1) levels closely correlate with blood barrier breakdown and cerebral hypoperfusion. Brain microvascular endothelial cells...

Diabetes doubles the risk of vascular cognitive impairment, but the underlying reasons remain unclear. In the current study, we determined the temporal and spatial changes in the brain structure after microemboli (ME) injection using diffusion MRI (dMRI). Control and diabetic rats received cholesterol crystal ME (40-70 µm) injections. Cognitive tes...

We and others have previously shown that angiotensin II receptor type 2 receptor (AT2R) is upregulated in the contralesional hemisphere after stroke in normoglycemic Wistar rats. In this study, we examined the expression of AT2R in type 2 diabetic Goto-Kakizaki (GK) rats and control Wistars after stroke. We also tested the contribution of the contr...

Introduction: Post-stroke cognitive impairment (PSCI) contributes to significant long-term disability in stroke victims. 30% of ischemic stroke victims in the United States also have diabetes, which increases the risk of hemorrhagic transformation as well as PSCI. Ferroptosis, an iron-induced cell death can instigate increased oxidative stress and...

Long-term disability due to stroke is a major global health burden, and there is an urgent need for interventions targeting the post-acute phase of stroke to improve motor and cognitive deficits. Hypertension is a major contributor to overall risk for stroke and is associated with worse functional outcomes and mortality. Previous studies from our l...

OBJECTIVES/GOALS: Vascular cognitive impairment (VCI) is the leading cause of dementia behind Alzheimers Disease (AD) and is often the result of brain hypoxia. Diets rich in polyunsaturated fatty acids (PUFAs) can lower cognitive decline and AD incidence in human patients. Therefore, our goal is to determine the mechanisms that PUFAs influence in a...

Stress-induced premature senescence can contribute to the accelerated metabolic aging process in diabetes. Progressive accumulation of senescent cells in the brain, especially those displaying the harmful inflammatory senescence-associated secretory phenotype (SASP), may lead to cognitive impairment linked with metabolic disturbances. In this conte...

Hypertension and aging are leading risk factors for stroke and cognitive decline. Animal models fail to capture the complex interplay between these two pathophysiologic processes, limiting human translation of interventions. In the current study, we investigated the development of cognitive impairment in 18-month-old spontaneously hypertensive rats...

Diabetes doubles the risk of VCID, but underlying reasons for this are not understood and preventive therapeutic strategies are lacking. We showed that diabetic but not control rats develop progressive cognitive decline in a microemboli (ME) model of VCID. Given that cerebrovascular dysfunction is a common pathology between diabetes and VCID, we hy...

Introduction: Endothelin (ET) system contributes to cerebrovascular dysfunction and acute neurovascular injury after ischemic stroke. While some clinical and preclinical studies suggests, dual inhibition of ET receptors prevent poststroke cognitive impairment (PSCI), also recent advances suggests systemic ETB receptor agonism improves PSCI. Current...

There is a very complex interaction between the brain and the cerebral vasculature to meet the metabolic demands of the brain for proper function. Preservation of vascular networks and cerebrovascular function ultimately plays a key role in this intricate communication within the brain in health and disease. Experimental evidence showed that diabet...

Diabetes and cognitive dysfunction, ranging from mild cognitive impairment to dementia, often coexist in individuals over 65 years of age. Vascular contributions to cognitive impairment/dementia (VCID) are the second leading cause of dementias under the umbrella of Alzheimer’s disease and related dementias (ADRD). Over half of dementia patients hav...

Significant innovations in the management of acute ischemic stroke have led to an increased incidence in the long-term complications of stroke. Therefore, there is an urgent need for improvements in and refinement of rehabilitation interventions that can lead to functional and neuropsychological recovery. The goal of this review is to summarize the...

Angiotensin signaling is known to be sexually dimorphic. Although it is a well-studied target for intervention in stroke and cognitive impairment, female studies are rare. With females suffering a disproportionately greater negative impact of stroke and dementia vs. males, effective interventions are of utmost urgency. The aim of the current study...

It is a clinically well-established fact that patients with diabetes have very poor stroke outcomes. Yet, the underlying mechanisms remain largely unknown. Our previous studies showed that male diabetic animals show greater hemorrhagic transformation (HT), profound loss of cerebral vasculature in the recovery period, and poor sensorimotor and cogni...

Diabetes increases risk and severity of post-stroke cognitive impairment (PSCI), a major cause of disability worldwide. While it is known that females suffer more from PSCI, psychological outcomes and underlying reasons are poorly understood. From a preclinical perspective, potential explanations include 1) use of otherwise healthy animals in exper...

Diabetes doubles the risk of VCID but underlying reasons remain unclear. We reported that diabetic animals are more prone to microemboli (ME)-mediated tissue damage/demyelination and progressive cognitive decline. The goal of the current study was to determine the temporal and spatial changes in cerebral blood flow (CBF) and brain structure after M...

Introduction: We have shown that iron chelation with deferoxamine (DFX) prevents stroke-induced cerebral vasoregression and improves sensorimotor and cognitive deficits after ischemic stroke in diabetic male rats. Diabetic female rats, on the other hand, develop greater hemorrhagic transformation (HT) but no vasoregression and DFX improves outcomes...

Introduction: Females patients with diabetes suffer from poor outcomes of ischemic stroke but underlying reasons are not fully understood. We have shown that 1) adult female diabetic rats develop greater infarct and hemorrhagic transformation (HT) leading to poorer outcomes after ischemic stroke, and 2) MMP3 activity is increased to a greater exten...

About 70% of stroke victims present with comorbid diseases such as diabetes and hypertension. The integration of comorbidities in pre-clinical experimental design is important in understanding the mechanisms involved in the development of stroke injury and recovery. We recently showed that administration of compound C21, an angiotensin II type 2 re...

Post-stroke cognitive impairment (PSCI) is a major source of disability, affecting up to two thirds of stroke survivors with no available therapeutic options. The condition remains understudied in preclinical models due to its delayed presentation. Although hypertension is a leading risk factor for dementia, how ischemic stroke contributes to this...

A disabling consequence of stroke is cognitive impairment, occurring in 12%–48% of patients, for which there is no therapy. A critical barrier is the lack of understanding of how post-stroke cognitive impairment (PSCI) develops. While 70% of stroke victims present with comorbid diseases such as diabetes and hypertension, the limited use of comorbid...

The endothelin (ET) system has been implicated to contribute to the pathophysiology of cognitive impairment and stroke in experimental diabetes. Our goals were to test the hypotheses that 1) circulating and/or peri-infarct ET-1 levels are elevated after stroke in both sexes and this increase is greater in diabetes, 2) ET receptors are differentiall...

Introduction: Unfortunately, over 40% of stroke victims have pre-existing diabetes which not only increases their risk of stroke up to 2-6 fold, but also worsens both functional recovery and the severity of cognitive impairment. Our lab has recently linked the chronic inflammation in diabetes to poor functional outcomes and exacerbated cognitive i...

Diabetes increases the risk and severity of cognitive impairment, especially after ischemic stroke. It is also known that the activation of ET system is associated with cognitive impairment and microglia around periinfarct area produce ET-1. However, little is known about the effect of ET-1 on microglial polarization, especially under diabetic cond...

Diabetes exacerbates hemorrhagic transformation and worsens survival/recovery after ischemic stroke, especially in female patients. Brain microvascular endothelial cells (BMECs) are early targets in diabetes and ischemic injury. Differences in survival and reparative properties of BMECs may contribute to sex differences seen in stroke recovery. Rec...

Diabetes increases the risk of VCID but underlying reasons remain unclear. We reported that diabetes-mediated early cerebrovascular dysfunction facilitates the entrapment of microemboli (ME) and results in demyelination/neurodegeneration 6 weeks after ME injection in male diabetic but not control rats. Cognitive decline became apparent by week 8 an...

Post-stroke cognitive impairment (PSCI) occurs in up to 48% of patients, for which there is no therapy. Although 70% of stroke victims present with comorbid diseases such as diabetes and hypertension, the inadequate integration of these comorbidities into experimental studies limited our understanding of the mechanisms involved in the development o...

We have shown that 1) poor recovery in diabetes is associated with greater hemorrhagic transformation and significant loss of the cerebrovasculature, and 2) iron chelation therapy with deferoxamine (DFX) improves sensorimotor and cognitive outcomes while preventing vasoregression in male diabetic animals after stroke. This study tested the hypothes...

Unfortunately, over 40% of stroke victims have pre-existing diabetes which not only increases their risk of stroke up to 2-6 fold, but also worsens both functional recovery and the severity of cognitive impairment. Our lab has recently linked the chronic inflammation that persists in diabetic animals to their poor functional outcomes and exacerbate...

We recently reported that diabetes negates the cerebrovascular protection typically seen in adult female rats resulting in cognitive impairment, which is worsened by increased parenchymal bleeding and edema after ischemic stroke. Although women experience more severe diabetes and suffer from a higher rate of diabetic complications, including stroke...

Experimental studies have demonstrated protective effects of NHE-1 inhibition on cardiac function; however, clinical trials utilizing NHE-1 antagonists found an increase in overall mortality attributed to thromboembolic strokes. NADPH oxidase-derived reactive oxygen species (ROS) from microglial cells have been shown to contribute to injury followi...

Diabetes increases the risk of occurrence and poor functional recovery after ischemic stroke injury. Previously, we have demonstrated greater hemorrhagic transformation (HT), edema, and more severe functional deficits after stroke in diabetic animals that also presented with cerebral vasoregression and endothelial cell death in the recovery period....

The angiotensin II type 2 receptor (AT 2 R) agonist, compound 21 (C21), has been shown to be neurovascularly protective after ischemic stroke in male rats. In the current study, we aim to study the impact of C21 treatment on female rats. Young female Wistar rats were subjected to different durations of middle cerebral artery occlusion (MCAO) (3 h,...

OBJECTIVES/SPECIFIC AIMS: The study aim was to 1) elucidate mechanisms contributing to the evolution of PSCI using a clinically relevant model of diabetes, a major risk factor for stroke and cognitive impairment, and 2) develop angiotensin type 2 receptor (AT2R) agonism as a therapeutic target. METHODS/STUDY POPULATION: Diabetes was induced in male...

There is a complex interaction between the brain and the cerebral vasculature to meet the metabolic demands of the brain for proper function. Preservation of cerebrovascular function and integrity has a central role in this sophisticated communication within the brain, and any derangements can have deleterious acute and chronic consequences. In alm...

Diabetes increases the risk & severity of hemorrhagic transformation (HT) after ischemic stroke, worsening the functional outcomes & recovery. Women experience more severe strokes and suffer from a higher rate of stroke & diabetic-related complications including cognitive impairment. Yet, experimental data on sex differences in cerebrovascular comp...

Introduction: Diabetic female patients are at greater risk of stroke and worsened recovery. We have previously shown that matrix metalloprotease 3 (MMP3) exacerbates hemorrhagic transformation (HT) in hyperglycemic stroke in male rats while high glucose and hypoxia increases MMP3 activity in brain microvascular endothelial cells (BMVECs). Furthermo...

Introduction: The angiotensin type 2 receptor (AT2R) agonist, compound 21 (C21), has been shown to be neuroprotective and neurorestorative after stroke in male rats. Here, we aim to determine the long-term impact of C21 treatment on hypertensive female rats after stroke. Methods: Twenty female ovariectomized spontaneously hypertensive rats (SHRs),...

Introduction: Cognitive deficits are a common occurrence in both patients and experimental models of stroke. However, there is still a gap in our understanding of the time course and mechanisms involved in the progression of cognitive dysfunction after stroke in part due to the insufficient integration of risk factors for vascular cognitive impairm...

Diabetes increases the risk and worsens the progression of cognitive impairment via the greater occurrence of small vessel disease and stroke. While NLRP3 inflammasome signaling has been implicated in the development of neurodegenerative diseases, little is known about the impact of NLRP3 activation on functional and structural interaction within t...

Introduction: We have shown that 1) poor recovery in diabetes is associated with greater hemorrhagic transformation (HT) and significant loss the cerebrovasculature, and 2) iron chelation therapy with deferoxamine (DFX) improves functional outcomes while preventing vasoregression in diabetic animals after embolic stroke. However, underlying mechani...

30 million Americans of the United States population have diabetes. Additional 90 million people in the pre-diabetic stage. Insulin resistance and obesity are the hallmarks of prediabetes. Understanding the effect of obesity on cerebrovasculature is crucial to identify novel therapies to prevent cerebrovascular complications of diabetes including v...

Diabetes doubles the risk of vascular cognitive impairment and dementia (VCID), a disease is associated with small vessel disease (SVD) of the brain. Given that diabetes mediates early cerebrovascular dysfunction, and microemboli are common in the cerebral circulation and can penetrate into the brain parenchymal arterioles without causing an infarc...

A disabling consequence of stroke is cognitive impairment, occurring in 12%-48% of patients, for which there is NO therapy. A critical barrier is the lack of understanding of how vascular cognitive impairment & dementia (VCID) develops. While 70% of stroke victims present with comorbid diseases such as diabetes & hypertension, the limited use of co...

Diabetes increases the risk and worsens the progression of cognitive impairment via the greater occurrence of small vessel disease and stroke. Yet, the underlying mechanisms are not fully understood. It is now accepted that cardiovascular health is critical for brain health and any neurorestorative approaches to prevent/delay cognitive deficits sho...

We have previously shown that diabetes causes dysfunctional cerebral neovascularization that increases the risk for cerebrovascular disorders such as stroke and cognitive impairment. Pericytes (PCs) play a pivotal role in the angiogenic process through their interaction with the endothelial cells (EC). Yet, the role of PCs in dysfunctional cerebral...

The pro-survival effect of VEGF-B has been documented in different in vivo and in vitro models. We have previously shown an enhanced VEGF-B expression in response to candesartan treatment after focal cerebral ischemia. In this study, we aimed to silence VEGF-B expression to assess its contribution to candesartan's benefit on stroke outcome. Silenci...

Post stroke cognitive impairment (PSCI) is an understudied, long-term complication of stroke, impacting nearly 30–40% of all stroke survivors. No cure is available once the cognitive deterioration manifests. To our knowledge, this is the first study to investigate the long-term effects of C21 treatment on the development of PSCI in aged animals. Tr...

Diabetes is associated with increased risk and worsened outcome of stroke. Previous studies showed that male diabetic animals had greater hemorrhagic transformation (HT), profound loss of cerebral vasculature, and poor behavioral outcomes after ischemic stroke induced by suture or embolic middle cerebral artery occlusion (MCAO). Females are protect...

Diabetes increases the risk and severity of cognitive impairment, especially after ischemic stroke. Pathological remodeling of the cerebrovasculature has been postulated to contribute to poor neuronal repair and worsened cognitive deficits in diabetes. However, little is known about the effect of diabetes on the vascularization of hippocampus, a do...

Background: With the aging population, the prevalence and incidence of cerebrovascular disease will continue to rise, as well as the number of individuals with vascular cognitive impairment/dementia (VCID). No specific FDA-approved treatments for VCID exist. Although clinical evidence supports that angiotensin receptor blockers (ARBs) prevent cogn...

Metabolic diseases including obesity, insulin resistance, and diabetes have profound effects on cerebral circulation. These diseases not only affect the architecture of cerebral blood arteries causing adverse remodeling, pathological neovascularization, and vasoregression but also alter the physiology of blood vessels resulting in compromised myoge...

For many years, modulators of the renin angiotensin system (RAS) have been trusted by clinicians for the control of essential hypertension. It was recently demonstrated that these modulators have other pleiotropic properties independent of their hypotensive effects, such as enhancement of cognition. Within the brain, different components of the RAS...

The aim of this translational, randomized, controlled, blinded preclinical trial was to determine the effect of compound 21 (C21) in embolic stroke. Rats were subjected to embolic-middle cerebral artery occlusion (eMCAO). They received C21 (0.01, 0.03 and 0.06 mg/kg/d) or saline (orally) for five days, with the first-dose given IV at 3 h post-eMCAO...

Matrix metalloprotease-3 (MMP3) activation mediates the tissue plasminogen activator (tPA)-induced hemorrhagic transformation after stroke. Hyperglycemia (HG) further exacerbates this outcome. We have recently shown that HG increases MMP3 activity in the brain after stroke. However, the combined HG-tPA effect on MMP3 activation, and the mechanisms...

Diabetes increases the risk of hemorrhagic transformation (HT) in ischemic stroke, especially with the use of tissue plasminogen activator (tPA). We showed that iron chelation therapy with deferoxamine (DFX) improves functional outcome in male diabetic animals after embolic stroke but its interaction with tPA remained unknown. We also reported that...

Background and objectives: Post stroke cognitive impairment (PSCI) is an understudied, long-term complication of stroke, impacting nearly 30-40% of all stroke survivors. No cure is available once the cognitive deterioration manifests. Compound 21 (C21), a novel selective non-peptide angiotensin receptor (AT2R) agonist, has also shown therapeutic ef...

We have previously shown that diabetes causes dysfunctional cerebral neovascularization that increases the risk for cerebrovascular disorders such as stroke and cognitive impairment. Pericytes (PC) play a pivotal role in the angiogenic process through interaction with endothelial cells (EC). Yet, the role of PCs in dysfunctional cerebral neovascula...

Diabetes not only increases the risk of stroke, it also worsens recovery after stroke. We previously showed that ischemic stroke causes cerebral vasoregression that is associated with poor outcomes in a lean model of diabetes. Current experiments were designed to 1) study the effect of ischemic stroke on cerebral vasculature in male and female rats...

Premenopausal women have lower stroke risk and mortality than age-matched men, a finding replicated in preclinical models. However, we recently reported that female diabetic rats developed greater hemorrhagic transformation (HT) after embolic stroke and thrombolysis with tPA, leading to poor short term outcomes, despite no change in infarct size. G...

Diabetes increases the risk and severity of cognitive impairment, especially after ischemic stroke. We showed pathological rearrangement of cerebrovascular networks in the cortex and striatum is associated with poor neuronal restoration leading to worsened cognitive deficits in diabetes. However, little is known about the effect of diabetes on vasc...

Introduction: The angiotensin type 2 receptor (AT2R) agonist, compound 21 (C21), has been shown to be neuro-protective, pro-angiogenic and anti-inflammatory after stroke in male rats. Here we aimed to study the effect of C21 treatment on ovary-intact female rats after stroke. Methods: Female Wistar rats were subjected to 3 h middle cerebral artery...

Background: With the aging population, the prevalence and incidence of cerebrovascular disease will continue to rise, as will the number of individuals with post-stroke cognitive impairment (PSCI). Unfortunately, no specific FDA approved treatments for PSCI exist. Although clinical trial evidence supports that renin angiotensin system (RAS) modulat...