Angiotensin II Type 2 Receptor Agonism Alleviates Progressive Post-stroke Cognitive Impairment in Aged Spontaneously Hypertensive Rats.

Hypertension and aging are leading risk factors for stroke and vascular contributions to cognitive impairment and dementia (VCID). Most animal models fail to capture the complex interplay between these pathophysiological processes. In the current study, we examined the development of cognitive impairment in 18-month-old spontaneously hypertensive rats (SHR) before and following ischemic stroke.

Stimulation of Angiotensin II Type 2 Receptor Modulates Pro-Inflammatory Response in Microglia and Macrophages: Therapeutic Implications for the Treatment of Stroke.

Background: Sustained microglial activation contributes to the development of post-stroke cognitive impairment (PSCI). Compound (C21), an angiotensin II type 2 receptor agonist, has shown some neurovascular protection after stroke. This study aimed to investigate the direct anti-inflammatory effects of C21 on macrophages, as well as brain innate immune cells.

Deferoxamine prevents poststroke memory impairment in female diabetic rats: potential links to hemorrhagic transformation and ferroptosis.

Diabetes increases the risk of poststroke 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.

Contralesional angiotensin type 2 receptor activation contributes to recovery in experimental stroke.

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 contralesional AT2R in recovery after stroke through a specific knockdown of the AT2R in this hemisphere only.

Neuroprotective Effects of Fingolimod in a Cellular Model of Optic Neuritis.

Visual dysfunction resulting from optic neuritis (ON) is one of the most common clinical manifestations of multiple sclerosis (MS), characterized by loss of retinal ganglion cells, thinning of the nerve fiber layer, and inflammation to the optic nerve. Current treatments available for ON or MS are only partially effective, specifically target the inflammatory phase, and have limited effects on long-term disability. Fingolimod (FTY) is an FDA-approved immunomodulatory agent for MS therapy.

Stimulation of angiotensin II receptor 2 preserves cognitive function and is associated with an enhanced cerebral vascular density after stroke.

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.

Overview and Update on Methods for Cargo Loading into Extracellular Vesicles.

The enormous library of pharmaceutical compounds presents endless research avenues. However, several factors limit the therapeutic potential of these drugs, such as drug resistance, stability, off-target toxicity, and inadequate delivery to the site of action. Extracellular vesicles (EVs) are lipid bilayer-delimited particles and are naturally released from cells.

Delayed Administration of Angiotensin Receptor (AT2R) Agonist C21 Improves Survival and Preserves Sensorimotor Outcomes in Female Diabetic Rats Post-Stroke through Modulation of Microglial Activation.

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 receptor agonist, at day 3 post-stroke improved sensorimotor outcomes by lowering neuroinflammation in diabetic male animals.

Stroke promotes the development of brain atrophy and delayed cell death in hypertensive rats.

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 neurodegenerative condition is unknown.

Deferoxamine Treatment Prevents Post-Stroke Vasoregression and Neurovascular Unit Remodeling Leading to Improved Functional Outcomes in Type 2 Male Diabetic Rats: Role of Endothelial Ferroptosis.

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 cognitive outcomes after ischemic stroke.

Three-dimensional printing for assessment of paravalvular leak in transcatheter aortic valve implantation.

Background: Three-dimensional (3D) models have the unique ability to replicate individualized cardiac anatomy and may therefore provide clinical benefit. Transcatheter aortic valve implantation (TAVI) currently relies on preoperative imaging for accurate valve sizing, type of valve used, and avoidance of complications. Three-dimensional (3D) modelling may provide benefit for optimal preoperative TAVI planning.

Microglia knockdown reduces inflammation and preserves cognition in diabetic animals after experimental stroke.

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 impairment, also known as post-stroke cognitive impairment (PSCI). Although we have shown that the development of PSCI in diabetes is associated with the upregulation and the activation of pro-inflammatory microglia, we have not established direct causation between the two.

Clinical Pulp Fiction: First Multimodality Imaging of Needle Migration From Distal Esophagus Into Ventricular Septum.

A 21-year-old woman self-ingested an 18-gauge needle that perforated the distal esophagus into the left inferior ventricular myocardium, with migration into the septum. Radiography, computed tomography, and echocardiography imaging characterized the needle's location. Following an initial endoscopy and pericardial tamponade drainage, complete needle removal occurred via median sternotomy and cardiopulmonary bypass.

Delayed Administration of Angiotensin II Type 2 Receptor (AT2R) Agonist Compound 21 Prevents the Development of Post-stroke Cognitive Impairment in Diabetes Through the Modulation of Microglia Polarization.

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 disease models in preclinical research further contributes to this lack of progress.

Inflammation within the neurovascular unit: Focus on microglia for stroke injury and recovery.

Neuroinflammation underlies the etiology of multiple neurodegenerative diseases and stroke. Our understanding of neuroinflammation has evolved in the last few years and major players have been identified. Microglia, the brain resident macrophages, are considered sentinels at the forefront of the neuroinflammatory response to different brain insults.

Neuropsychiatric Symptoms in Dementia: Considerations for Pharmacotherapy in the USA.

Dementia affects all domains of cognition. The relentless progression of the disease after diagnosis is associated with a 98% incidence of neuropsychiatric symptoms (NPS) at some point in the disease, including depression, psychosis, agitation, aggression, apathy, sleep disturbances, and disinhibition. These symptoms can be severe and lead to excess morbidity and mortality.

Angiotensin II type 2 receptor stimulation with compound 21 improves neurological function after stroke in female rats: a pilot study.

The angiotensin II type 2 receptor (ATR) 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, 2 h, and 1 h) using a silicone-coated monofilament, treated at reperfusion with 0.

NLRP3 inflammasome inhibition with MCC950 improves diabetes-mediated cognitive impairment and vasoneuronal remodeling after ischemia.

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 should target the conceptual neurovascular unit (NVU) rather than neurons alone.

Brain Vasculature and Cognition.

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 almost all forms of cognitive impairment, from mild to Alzheimer disease, there are changes in cerebrovascular function and structure leading to decreased cerebral blood flow, which may initiate or worsen cognitive impairment.

Angiotensin receptor (AT2R) agonist C21 prevents cognitive decline after permanent stroke in aged animals-A randomized double- blind pre-clinical study.

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.

Post-stroke neovascularization and functional outcomes differ in diabetes depending on severity of injury and sex: Potential link to hemorrhagic transformation.

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 protected from stroke until reaching the menopause age, but young females with diabetes have a higher risk of stroke and women account for the majority of stroke mortality.

Poststroke cognitive impairment and hippocampal neurovascular remodeling: the impact of diabetes and sex.

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 domain critical to memory and learning.

RAS modulation prevents progressive cognitive impairment after experimental stroke: a randomized, blinded preclinical trial.

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 cognitive decline in older adults, whether ARBs have a similar effect on VCID after stroke is unknown.