endothelin-1 and Cognition-Disorders

The exact pathogenesis of multiple sclerosis (MS) is incompletely understood. Although auto-immune responses have an important role in the development of hallmark focal demyelinating lesions, the underlying mechanism of axonal degeneration, the other key player in MS pathology and main determinant of long-term disability, remains unclear and corresponds poorly with inflammatory disease activity. Perfusion-weighted imaging studies have demonstrated that there is a widespread cerebral hypoperfusion in patients with MS, which is present from the early beginning to more advanced disease stages. This reduced cerebral blood flow (CBF) does not seems to be secondary to loss of axonal integrity with decreased metabolic demands but appears to be mediated by elevated levels of the potent vasospastic peptide endothelin-1 in the cerebral circulation. Evidence is evolving that cerebral hypoperfusion in MS is associated with chronic hypoxia, focal lesion formation, diffuse axonal degeneration, cognitive dysfunction, and fatigue. Restoring CBF may therefore emerge as a new therapeutic target in MS.

Topics: Blood Flow Velocity; Brain Ischemia; Cerebrovascular Circulation; Cognition Disorders; Diffuse Axonal Injury; Endothelin-1; Humans; Inflammation; Multiple Sclerosis

Neonatal arterial ischemic stroke is one of the more severe birth complications. The injury can result in extensive neurological damage and is robustly associated with later diagnoses of cerebral palsy (CP). An important part of efforts to develop new therapies include the on-going refinement and understanding of animal models that capture relevant clinical features of neonatal brain injury leading to CP. The potent vasoconstrictor peptide, Endothelin-1 (ET-1), has previously been utilised in animal models to reduce local blood flow to levels that mimic ischemic stroke. Our previous work in this area has shown that it is an effective and technically simple approach for modelling ischemic injury at very early neonatal ages, resulting in stable deficits in motor function. Here, we aimed to extend this model to also examine the impact on cognitive function. We show that focal delivery of ET-1 to the cortex of Sprague Dawley rats on postnatal day 0 (P0) resulted in impaired learning in a touchscreen-based test of visual discrimination and correlated with important clinical features of CP including damage to large white matter structures.

Topics: Animals; Animals, Newborn; Association Learning; Atrophy; Brain Ischemia; Cell Count; Cerebral Cortex; Cerebral Palsy; Cognition Disorders; Corpus Striatum; Disease Models, Animal; Endothelin-1; Inflammation; Injections; Microglia; Movement Disorders; Neurons; Perceptual Disorders; Rats; Rats, Sprague-Dawley; Rotarod Performance Test; Vasoconstrictor Agents; White Matter

Plasmodium falciparum infection causes a wide spectrum of diseases, including cerebral malaria, a potentially life-threatening encephalopathy. Vasculopathy is thought to contribute to cerebral malaria pathogenesis. The vasoactive compound endothelin-1, a key participant in many inflammatory processes, likely mediates vascular and cognitive dysfunctions in cerebral malaria. We previously demonstrated that C57BL6 mice infected with P. berghei ANKA, our fatal experimental cerebral malaria model, sustained memory loss. Herein, we demonstrate that an endothelin type A receptor (ETA) antagonist prevented experimental cerebral malaria-induced neurocognitive impairments and improved survival. ETA antagonism prevented blood-brain barrier disruption and cerebral vasoconstriction during experimental cerebral malaria, and reduced brain endothelial activation, diminishing brain microvascular congestion. Furthermore, exogenous endothelin-1 administration to P. berghei NK65-infected mice, a model generally regarded as a non-cerebral malaria negative control for P. berghei ANKA infection, led to experimental cerebral malaria-like memory deficits. Our data indicate that endothelin-1 is critical in the development of cerebrovascular and cognitive impairments with experimental cerebral malaria. This vasoactive peptide may thus serve as a potential target for adjunctive therapy in the management of cerebral malaria.

Topics: Animals; Blood-Brain Barrier; Brain; Cognition Disorders; Disease Models, Animal; Endothelin-1; Malaria, Cerebral; Mice, Inbred C57BL; Plasmodium berghei; Time

Stroke is the third leading cause of death and permanent disability in the United States, often producing long-term cognitive impairments, which are not easily recapitulated in animal models. The goals of this study were to assess whether: (1) the endothelin-1 (ET-1) model of chronic stroke produced discernable cognitive deficits; (2) a spatial operant reversal task (SORT) would accurately measure memory deficits in this model; and (3) bone-marrow-derived mesenchymal stem cells (BMMSCs) could reduce any observed deficits.. Rats were given unilateral intracerebral injections of vehicle or ET-1, a stroke-inducing agent, near the middle cerebral artery. Seven days later, they were given intrastriatal injections of BMMSCs or vehicle, near the ischemic penumbra. The cognitive abilities of the rats were assessed on a novel SORT, which was designed to efficiently distinguish cognitive deficits from potential motoric confounds.. Rats given ET-1 had significantly more cognitive errors at six weeks post-stroke on the SORT, and that these deficits were attenuated by BMMSC transplants.. These findings indicate that: (1) the ET-1 model produces chronic cognitive deficits; (2) the SORT efficiently measures cognitive deficits that are not confounded by motoric impairment; and (3) BMMSCs may be a viable treatment for stroke-induced cognitive dysfunction.

Topics: Animals; Body Weight; Brain; Chronic Disease; Cognition Disorders; Conditioning, Operant; Disease Models, Animal; Endothelin-1; Female; Male; Mesenchymal Stem Cell Transplantation; Psychological Tests; Rats, Sprague-Dawley; Stroke; Treatment Outcome

Ischemic stroke is one of the leading causes of neurological disability worldwide, and it has been estimated that about one quarter of stroke survivors experience some measurable long-term cognitive impairments. Many higher order cognitive deficits occur because of damage to the prefrontal cortex (PFC), which is one of the main areas of the brain responsible for executive functioning in mammals. Currently, there are few animal models that examine the effects of stroke on executive function. In this study we used bilateral micro-injections (1μl) of the vasoconstricting peptide endothelin-1 (ET-1) into the medial PFC in male Sprague-Dawley rats (or vehicle control, N=17-18 per group) in order to model ischemic lesions in the medial PFC. The effects of these lesions on executive function were assessed using tests of set-shifting and temporal object recognition. ET-1 injections in the medial PFC resulted in replicable and specific lesions within the PFC with an average infarct volume of 16.63±2.71mm(3). The ischemic lesions resulted in specific contextual set-shifting deficits within the maze, including an increased number of trials to criterion and a significant difference in learning curves. However, no deficits in temporal order memory processing were noted between sham and stroke animals. We conclude that ischemic lesions localized to the mPFC result in selective but not generalized deficits in executive function in rats.

Topics: Analysis of Variance; Animals; Attention; Brain Infarction; Brain Ischemia; Cognition Disorders; Endothelin-1; Executive Function; Male; Maze Learning; Neuropsychological Tests; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Recognition, Psychology; Set, Psychology; Time Factors

Cognitive impairments are prevalent following clinical stroke; however, preclinical research has focused almost exclusively on motor deficits. In order to conduct systematic evaluations into the nature of post-stroke cognitive dysfunction and recovery, it is crucial to develop focal stroke models that predominantly affect cognition while leaving motor function intact. Herein, we evaluated a range of cognitive functions 1-4 months following focal medial prefrontal cortex (mPFC) stroke using a battery of tests. Male Sprague-Dawley rats underwent focal ischemia induced in the mPFC using bilateral intracerebral injections of endothelin-1, or sham surgery. Cognitive function was assessed using an open field, several object recognition tests, attentional set-shifting, light-dark box, spontaneous alternation, Barnes maze, and win-shift/win-stay tests. Prefrontal cortex damage resulted in significant changes in object recognition function, behavioural flexibility, and anxiety-like behaviour, while spontaneous alternation and locomotor function remained intact. These deficits are similar to the cognitive deficits following stroke in humans. Our results suggest that this model may be useful for identifying and developing potential therapies for improving post-stroke cognitive dysfunction.

Topics: Animals; Chronic Disease; Cognition; Cognition Disorders; Disease Models, Animal; Endothelin-1; Male; Motor Activity; Neuropsychological Tests; Prefrontal Cortex; Rats, Sprague-Dawley; Severity of Illness Index; Stroke

Adequate hydration is essential for normal brain function and dehydration induces cognitive deterioration. In addition, dehydration has emerged as a stroke risk factor. However, it is unknown whether alterations in cerebrovascular regulation are responsible for these effects. To address this issue, C57Bl/6 mice were water deprived for 24 or 48 hours and somatosensory cortex blood flow was assessed by laser-Doppler flowmetry in a cranial window. Dehydration increased plasma osmolality and vasopressin levels, and suppressed the increase in blood flow induced by neural activity, by the endothelium-dependent vasodilator acetylcholine and the smooth muscle relaxant adenosine. The cerebrovascular dysfunction was associated with oxidative stress and cognitive deficits, assessed using the Y maze. The vasopressin 1a receptor antagonist SR49059 improved the dehydration-induced oxidative stress and vasomotor dysfunction. Dehydration upregulated endothelin-1 in cerebral blood vessels, an effect blocked by SR49059. Furthermore, the endothelin A receptor antagonist BQ123 ameliorated cerebrovascular function. These findings show for the first time that dehydration alters critical mechanisms regulating the cerebral circulation through vasopressin and oxidative stress. The ensuing cerebrovascular dysregulation may alter cognitive function and increase the brain's susceptibility to cerebral ischemia.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Brain; Cerebrovascular Circulation; Cognition Disorders; Dehydration; Endothelin-1; Male; Mice; Mice, Inbred C57BL; Osmolar Concentration; Oxidative Stress; Vasopressins; Water Deprivation

Angiotensin II (AngII) receptor blockers that bind selectively AngII type 1 (AT1) receptors may protect from Alzheimer's disease (AD). We studied the ability of the AT1 receptor antagonist losartan to cure or prevent AD hallmarks in aged (~18months at endpoint, 3months treatment) or adult (~12months at endpoint, 10months treatment) human amyloid precursor protein (APP) transgenic mice. We tested learning and memory with the Morris water maze, and evaluated neurometabolic and neurovascular coupling using [(18)F]fluoro-2-deoxy-D-glucose-PET and laser Doppler flowmetry responses to whisker stimulation. Cerebrovascular reactivity was assessed with on-line videomicroscopy. We measured protein levels of oxidative stress enzymes (superoxide dismutases SOD1, SOD2 and NADPH oxidase subunit p67phox), and quantified soluble and deposited amyloid-β (Aβ) peptide, glial fibrillary acidic protein (GFAP), AngII receptors AT1 and AT2, angiotensin IV receptor AT4, and cortical cholinergic innervation. In aged APP mice, losartan did not improve learning but it consolidated memory acquisition and recall, and rescued neurovascular and neurometabolic coupling and cerebrovascular dilatory capacity. Losartan normalized cerebrovascular p67phox and SOD2 protein levels and up-regulated those of SOD1. Losartan attenuated astrogliosis, normalized AT1 and AT4 receptor levels, but failed to rescue the cholinergic deficit and the Aβ pathology. Given preventively, losartan protected cognitive function, cerebrovascular reactivity, and AT4 receptor levels. Like in aged APP mice, these benefits occurred without a decrease in soluble Aβ species or plaque load. We conclude that losartan exerts potent preventive and restorative effects on AD hallmarks, possibly by mitigating AT1-initiated oxidative stress and normalizing memory-related AT4 receptors.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Angiotensin II Type 1 Receptor Blockers; Animals; Arginine; Blood Pressure; Brain; Cerebrovascular Circulation; Cognition Disorders; Disease Models, Animal; Endothelin-1; Enzyme Inhibitors; Female; Gene Expression Regulation; Humans; Losartan; Male; Mice; Mice, Transgenic; Mutation

Increased level of endothelin-1 (ET-1), a potent vasoconstrictor, has been found in the cerebral spinal fluid (CSF) of patients with multi-infarction dementia, suggesting a possible role of ET-1 in cognitive deficit associated with stroke. Previously, we have reported that synthesis of ET-1 is induced in endothelial cells in hypoxic/ischemic conditions. Transgenic mice over-expressing endothelin-1 in endothelial cells (TET-1) developed systemic hypertension and showed more severe brain damage after transient ischemia. To further understand the significance of endothelial ET-1 in cognitive deficit, we subjected adult TET-1 mice to 30 min middle cerebral artery occlusion (MCAO) with 7 days reperfusion. At baseline, TET-1 mice showed similar locomotor activity, emotion and cognitive function compared to non-transgenic (NTg) mice. However, after 30 min MCAO and 7 days reperfusion, although the sensorimotor function measured by neurological scores was recovered in both genotypes, TET-1 mice showed increased anxiety-like behavior in the open field test and impaired spatial learning and reference memory in the Morris water maze. Parallel with these behavioral changes, TET-1 mice showed more severe brain damage with blood-brain-barrier breakdown (BBB), reactive astrogliosis, increased caspase-3, and increased peroxiredoxin 6 (Prx6) expressions around blood vessels in the ipsilateral hippocampus, compared to that of NTg mice, suggesting that ET-1 over-expression in the endothelial cells leads to more severe BBB breakdown and increased oxidative stress which may resulted in neuronal apoptosis and glial reactivity, which might contribute to the emotional changes and cognitive deficits after short-term ischemia with long-term reperfusion.

Topics: Animals; Anxiety; Behavior, Animal; Blood-Brain Barrier; Brain Ischemia; Caspase 3; Cognition Disorders; Endothelin-1; Hippocampus; Infarction, Middle Cerebral Artery; Memory Disorders; Mice; Mice, Transgenic; Oxidative Stress; Peroxiredoxin VI; Reperfusion Injury

Autopsy evidence suggests that the presence of both Alzheimer(')s disease (AD) and cerebral infarction pathology is associated with more severe cognitive impairment than that produced by AD pathology alone. This study aims to investigate the effect of cerebral ischemia on cognitive function in rats with AD constructed by hippocampal injection and to determine its underlying mechanism, which is proposed to be of significance to the treatment of AD.. AD was modeled by injection of aggregated Aβ(1-40), either alone or followed by hippocampal endothelin-1 injection to mimic cerebral ischemia in hippocampus, into the right dentate gyrus (DG) of rats. The Morris water maze was used to evaluate cognitive function. Aβ deposition, neuronal loss and phosphorylated tau expression in hippocampus were examined by Congo red staining, Nissl's staining and immunohistochemistry, respectively. Reactive astrocytes, IL-1β and TNF-α expressions were measured by immunohistochemistry, in situ hybridization and reverse transcription-polymerase chain reaction.. Compared with rats treated with either Aβ or endothelin alone, rats treated with both Aβ and endothelin showed more aggravated cognitive impairment and more Aβ deposits, neuron loss, phosphorylated tau expression, reactive astrocytes, IL-1β and TNF-α expressions in hippocampus.. Hippocampal ischemia aggravates cognitive impairment of AD rats by increasing Aβ deposits, neuron loss and tau phosphorylation in hippocampus. The enhanced inflammatory response may be responsible for cerebral ischemia-induced aggravation of cognitive impairment in AD rats. Based on these findings, prevention and treatment of cerebral ischemia may improve clinical symptoms of AD and suppress the progression of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Astrocytes; Brain Ischemia; Cognition Disorders; Disease Models, Animal; Drug Therapy, Combination; Endothelin-1; Hippocampus; Interleukin-1beta; Male; Maze Learning; Memory; Neurons; NF-kappa B; Peptide Fragments; Phosphorylation; Rats; Rats, Sprague-Dawley; tau Proteins; Tumor Necrosis Factor-alpha

This series of experiments represents a test of a theory concerning the etiology of age-related cognitive decline, including Alzheimer's disease (AD). The theory suggests that multiple combinations of cofactors produce variants of these disorders. Two factors that have been linked to the etiology of AD, that are of interest to our laboratories, are stress and vascular strokes. The current experiments tested the cofactors theory by evaluating the neuronal and functional effects of localized subthreshold strokes in the hippocampus of different groups of rats. One group experienced episodes of stress prior to stroke induction while the other did not. The results showed that a low dose of endothelin-1 (ET-1) injected into the hippocampus of groups of rats that had previously experienced stressful episodes showed enhanced hippocampal cell death and neurodegeneration that did not occur in the rats that did not experience stress prior to stroke induction. The results also showed that the stressed rats given subthreshold ET-1 injections into the hippocampus showed hippocampal-based learning and memory deficits that were not present in the non-stressed group given the same injections. This pattern of results suggests that individuals that are under stress are more vulnerable to insults to the hippocampus that have little effect on an individual that is not stressed. This vulnerability might be due to the actions of stress hormones, like the glucocorticoids, that have been previously shown to endanger hippocampal neurons.

Topics: Animals; Behavior, Animal; Cell Death; Cognition Disorders; Corticosterone; Endothelin-1; Hippocampus; Immunohistochemistry; Male; Nerve Degeneration; Rats; Rats, Long-Evans; Stress, Psychological; Stroke