Cerebrovascular Effects Research Articles

The Cardiovascular and Cerebrovascular Effects on Cognition in Persons with Parkinson’s Disease: A Systematic Review of the Literature

Purpose: The purpose of this systematic review of the literature is to examine the cerebrovascular and cardiovascular effects on cognition in persons with Parkinson’s disease. Relevance: Physical therapy treatment of persons with Parkinson’s disease (PD) has traditionally focused on lessening the impact of disease severity by improving quality of life and functional capacity. Research has shown that quality of life in persons with PD is not only significantly affected by motor symptoms, but also by the presence of defined non-motor symptoms such as cerebrovascular perfusion, cardiovascular dysfunction, and cognitive impairment. This study seeks to determine a causative effect among these non-motor symptoms with the intention to better manage cognitive impairment in persons with PD. Methods: A literature search was conducted utilizing the following databases: Scopus, PubMed, and CINAHL. After evaluating and grading studies using the Downs and Black Checklist, a total of seven studies remained for the final review. Results: Five common domains of cognition emerged throughout the seven studies: executive function, attention, verbal memory and fluency, visual memory, and working memory. Considering the articles reviewed, a relationship between cerebrovascular and cardiovascular deficiency and cognitive impairment in persons with PD was established. Conclusions: Persons with PD and certain cerebrovascular and cardiovascular risk factors, including orthostatic hypotension and systemic hypertension, should be referred to appropriate professionals for comprehensive neuropsychological testing secondary to an increased risk for more severe cognitive deficit.

Fucoxanthin: A Promising Medicinal and Nutritional Ingredient.

Fucoxanthin, an allenic carotenoid, can be isolated from edible brown seaweeds. Recent studies have reported that fucoxanthin has many physiological functions and biological properties, such as antiobesity, antitumor, antidiabetes, antioxidant, anti-inflammatory, and hepatoprotective activities, as well as cardiovascular and cerebrovascular protective effects. Therefore, fucoxanthin can be used as both medicinal and nutritional ingredient to prevent and treat chronic diseases. Although fucoxanthin possesses many medicinal ingredient and nutritional qualities, studies indicated that its structure was unstable. In this paper, we consulted the current documents and reviewed structural properties and factors affecting the stability of fucoxanthin. We also reported the metabolism, safety, pharmacological activities, and the methods of improving the bioavailability of fucoxanthin. Based on these studies providing essential background knowledge, fucoxanthin can be developed into marine drugs and nutritional products.

Anti-Neuroinflammatory Effects of Uncaria sinensis in LPS-Stimulated BV2 Microglia Cells and Focal Cerebral Ischemic Mice

Uncaria sinensis (US) has long been used as a traditional Korean medicine to treat cardiovascular and central nervous system diseases, including hypertension and cerebral ischemia. Several recent studies have indicated that US has neuroprotective and cerebrovascular protective effects in ischemic brain injury; however, little is known about the anti-inflammatory effects of US. Therefore, the present study was designed to validate the anti-inflammatory effects of US. The anti-neuroinflammatory properties of US on pro-inflammatory mediators were investigated in lipopolysaccharide (LPS)-stimulated murine BV2 microglia and injured brains induced by photothrombotic cortical ischemia. Hexane extracts of US (HEUS) significantly suppressed the production of nitric oxide (NO) and prostaglandin E2 (PGE2) in LPS-stimulated BV2 microglia and inhibited LPS-induced expression of iNOS and COX-2 in a dose-dependent manner without causing cytotoxicity in BV2 cells. In addition, HEUS significantly reduced the generation of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6. Moreover, HEUS treatment inhibited the transcriptional activity and nuclear translocation of NF-κB in LPS-stimulated BV2 cells. In an in vivo study, treatment of HEUS resulted in significantly reduced infarct volume and improved neurological function 48 h after ischemic brain injury, possibly through the inhibition of the production of pro-inflammatory cytokines. HEUS inhibits LPS-stimulated production of pro-inflammatory mediators and prevents cerebral ischemic damage, suggesting that US may have therapeutic potential for the prevention and treatment of ischemic stroke accompanied by microglia activation.

Cardiovascular and Cerebrovascular Effects in Response to Red Bull Consumption Combined With Mental Stress

The sale of energy drinks is often accompanied by a comprehensive and intense marketing with claims of benefits during periods of mental stress. As it has been shown that Red Bull negatively impacts human hemodynamics at rest, we investigated the cardiovascular and cerebrovascular consequences when Red Bull is combined with mental stress. In a randomized cross-over study, 20 young healthy humans ingested either 355 ml of a can Red Bull or water and underwent 80 minutes after the respective drink a mental arithmetic test for 5 minutes. Continuous cardiovascular and cerebrovascular recordings were performed for 20 minutes before and up to 90 minutes after drink ingestion. Measurements included beat-to-beat blood pressure (BP), heart rate, stroke volume, and cerebral blood flow velocity. Red Bull increased systolic BP (+7 mm Hg), diastolic BP (+4 mm Hg), and heart rate (+7 beats/min), whereas water drinking had no significant effects. Cerebral blood flow velocity decreased more in response to Red Bull than to water (-9 vs -3 cm/s, p <0.005). Additional mental stress further increased both systolic BP and diastolic BP (+3 mm Hg, p <0.05) and heart rate (+13 beats/min, p <0.005) in response to Red Bull; similar increases were also observed after water ingestion. In combination, Red Bull and mental stress increased systolic BP by about 10 mm Hg, diastolic BP by 7 mm Hg, and heart rate by 20 beats/min and decreased cerebral blood flow velocity by -7 cm/s. In conclusion, the combination of Red Bull and mental stress impose a cumulative cardiovascular load and reduces cerebral blood flow even under a mental challenge.

The key role of transient receptor potential melastatin-2 channels in amyloid-β-induced neurovascular dysfunction

Alzheimer's dementia is a devastating and incurable disease afflicting over 35 million people worldwide. Amyloid-β (Aβ), a key pathogenic factor in this disease, has potent cerebrovascular effects that contribute to brain dysfunction underlying dementia by limiting the delivery of oxygen and glucose to the working brain. However, the downstream pathways responsible for the vascular alterations remain unclear. Here we report that the cerebrovascular dysfunction induced by Aβ is mediated by DNA damage caused by vascular oxidative-nitrosative stress in cerebral endothelial cells, which, in turn, activates the DNA repair enzyme poly(ADP)-ribose polymerase. The resulting increase in ADP ribose opens transient receptor potential melastatin-2 (TRPM2) channels in endothelial cells leading to intracellular Ca(2+) overload and endothelial dysfunction. The findings provide evidence for a previously unrecognized mechanism by which Aβ impairs neurovascular regulation and suggest that TRPM2 channels are a potential therapeutic target to counteract cerebrovascular dysfunction in Alzheimer's dementia and related pathologies.

Targeting thrombin: an inflammatory neurotoxin in Alzheimer's disease.

The Alzheimer's disease (AD) epidemic proceeds unabated. Estimates suggest 5.4 million Americans and 36 million people worldwide have AD. No single mechanism or pathologic mediator can account for AD progression. Currently no disease modifying therapies are available. There is a large literature documenting an association among cardiovascular risk factors (CVRFs), especially diabetes and hypoxia, with increased AD incidence. CVRFs directly impair vascular function and could mediate cerebrovascular dysfunction in AD. This is important as cerebrovascular dysfunction precedes cognitive decline and onset of neurodegenerative changes in AD and AD animal models. In this review we present evidence that thrombin may be a heretofore unexplored target for AD therapy. This idea is based on the following observations. Thrombin is elevated in the brain and cerebral microvasculature in AD, is directly neurotoxic, and causes pro-inflammatory effects in endothelial cells, microglia, and astrocytes. Diabetes- and hypoxia-induced cerebrovascular effects are mediated by thrombin. Thrombin inhibitors block the effects of hypoxia on brain endothelial cells and reduce vascular inflammation in transgenic AD mice. Based on reports that reducing cerebrovascular expression of inflammatory proteins in AD mice is associated with improved cognition, we propose thrombin inhibitors could prove useful for improving cognition in AD patients. The next generation of AD therapeutics should not focus on single target drugs but rather employ a multi-component cocktail approach. We propose thrombin inhibitors be considered as potential contributors to the dementia therapy pharmacopeia. The urgent need for disease-modifying drugs in AD demands new thinking about disease pathogenesis and exploration of novel drug targets.

Endothelial nitric oxide synthase mediates the cerebrovascular effects of erythropoietin in traumatic brain injury.

Background: Erythropoietin (Epo) improves post-traumatic cerebral blood flow (CBF), pressure autoregulation, and vascular reactivity to l-arginine. This study examines the dependence of these cerebral hemodynamic effects of Epo on nitric oxide generated by endothelial nitric oxide synthase (eNOS).Methods: Using laser Doppler flow imaging, CBF was monitored in wild-type (WT) and eNOS-deficient mice undergoing controlled cortical impact followed by administration of Epo (5000 U/kg) or normal saline.Results: Cerebral blood flow decreased in all groups post-injury with the greatest reductions occurring at the impact site. Epo administration resulted in significantly higher CBF in the peri-contusional sites in the WT mice [70.2 ± 3.35% in Epo-treated compared to 53 ± 3.3% of baseline in saline-treated mice (p < 0.0001)], but no effect was seen in the eNOS-deficient mice. No CBF differences were found at the core impact site where CBF dropped to 20–25% of baseline in all groups.Conclusion: These differences between eNOS-deficient and WT mice indicate that the Epo mediated improvement in CBF in traumatic brain injury is eNOS dependent.

Advances in the management of low-grade gliomas.

Low-grade gliomas (LGGs) represent the most common childhood brain tumors and are a histologically heterogenous group of tumors. Most LGGs are surgically resectable with excellent 10-year overall survival outcomes of more than 90 % with surgery alone. Tumors not amenable to surgical resection and those with an aggressive biology are more challenging to treat. Conventional radiotherapy is a more efficacious method of long-term tumor control than chemotherapy. However, radiation is associated with significant cognitive, endocrine, and cerebrovascular late effects, making chemotherapy an often-preferred modality over radiotherapy, especially in younger children. Multiple chemotherapy regimens have been evaluated over the past few decades with comparable survival outcomes and differing toxicity profiles. Newer regimens containing antiangiogenic agents also show promise. Recent molecular studies have implicated the BRAF oncogene, a key regulator of the MAPK pathway, and the AKT/mTOR pathway in pediatric LGG tumorigenesis. This has opened up promising new avenues for targeted therapy, with many agents currently under investigation.

Aging exacerbates obesity-induced cerebromicrovascular rarefaction, neurovascular uncoupling, and cognitive decline in mice.

Epidemiological studies show that obesity has deleterious effects on the brain and cognitive function in the elderly population. However, the specific mechanisms through which aging and obesity interact to promote cognitive decline remain unclear. To test the hypothesis that aging exacerbates obesity-induced cerebromicrovascular impairment, we compared young (7 months) and aged (24 months) high-fat diet-fed obese C57BL/6 mice. We found that aging exacerbates the obesity-induced decline in microvascular density both in the hippocampus and in the cortex. The extent of hippocampal microvascular rarefaction and the extent of impairment of hippocampal-dependent cognitive function positively correlate. Aging exacerbates obesity-induced loss of pericyte coverage on cerebral microvessels and alters hippocampal angiogenic gene expression signature, which likely contributes to microvascular rarefaction. Aging also exacerbates obesity-induced oxidative stress and induction of NADPH oxidase and impairs cerebral blood flow responses to whisker stimulation. Collectively, obesity exerts deleterious cerebrovascular effects in aged mice, promoting cerebromicrovascular rarefaction and neurovascular uncoupling. The morphological and functional impairment of the cerebral microvasculature in association with increased blood-brain barrier disruption and neuroinflammation (Tucsek Z, Toth P, Sosnowsk D, et al. Obesity in aging exacerbates blood-brain barrier disruption, neuroinflammation and oxidative stress in the mouse hippocampus: effects on expression of genes involved in beta-amyloid generation and Alzheimer's disease. J Gerontol Biol Med Sci. 2013. In press, PMID: 24269929) likely contribute to obesity-induced cognitive decline in aging.

ApoE-deficient promotes blood-brain barrier disruption in experimental autoimmune encephalomyelitis via alteration of MMP-9.

Disruption of the blood-brain barrier (BBB) is a surrogate marker of acute inflammatory lesions in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Data from experiments suggest that apolipoprotein E (ApoE) plays an important role in the antiinflammatory and immunological process in MS/EAE. Recent researches have shown that lack of ApoE leads to loss of cerebrovascular integrity and BBB breakdown causing neuronal injury. Cerebrovascular effects of ApoE might be another important element resulting to more susceptibility to MS/EAE. However, there is no direct evidence that ApoE dependently contributes to maintaining BBB integrity in EAE. In this study, we induced EAE in ApoE-/- mice and wild-type mice. During EAE, our results show that lack of ApoE increased the Evan's blue (EB) permeability of BBB. Furthermore, deficiency of ApoE upregulated MMP-9 expression activity but decreased the expression of endothelial cell tight junction integral proteins claudin-5 and occludin. Our result also suggests that the protective role of ApoE in EAE by maintaining BBB integrity could be another interesting therapeutic target at MS/EAE.

Effects of acute hypoxia on cerebrovascular responses to carbon dioxide

In normoxic conditions, a reduction in arterial carbon dioxide tension causes cerebral vasoconstriction, thereby reducing cerebral blood flow and modifying dynamic cerebral autoregulation (dCA). It is unclear to what extent these effects are altered by acute hypoxia and the associated hypoxic ventilatory response (respiratory chemoreflex). This study tested the hypothesis that acute hypoxia attenuates arterial CO2 tension-mediated regulation of cerebral blood flow to help maintain cerebral O2 homeostasis. Eight subjects performed three randomly assigned respiratory interventions following a resting baseline period, as follows: (1) normoxia (21% O2); (2) hypoxia (12% O2); and (3) hypoxia with wilful restraint of the respiratory chemoreflex. During each intervention, 0, 2.0, 3.5 or 5.0% CO2 was sequentially added (8 min stages) to inspired gas mixtures to assess changes in steady-state cerebrovascular CO2 reactivity and dCA. During normoxia, the addition of CO2 increased internal carotid artery blood flow and middle cerebral artery mean blood velocity (MCA Vmean), while reducing dCA (change in phase = -0.73 ± 0.22 rad, P = 0.005). During acute hypoxia, internal carotid artery blood flow and MCA Vmean remained unchanged, but cerebrovascular CO2 reactivity (internal carotid artery, P = 0.003; MCA Vmean, P = 0.031) and CO2-mediated effects on dCA (P = 0.008) were attenuated. The effects of hypoxia were not further altered when the respiratory chemoreflex was restrained. These findings support the hypothesis that arterial CO2 tension-mediated effects on the cerebral vasculature are reduced during acute hypoxia. These effects could limit the degree of hypocapnic vasoconstriction and may help to regulate cerebral blood flow and cerebral O2 homeostasis during acute periods of hypoxia.

Relation of Plasma Tissue Kallikrein Levels to Presence and Severity of Coronary Artery Disease in a Chinese Population

ObjectivesTissue kallikrein (TK) has been shown to provide cardiovascular and cerebrovascular protective effects in animal models. The aim of this study was to investigate the relationship of plasma TK levels with the presence and severity of coronary artery disease (CAD) in the Chinese.MethodsThe study involved 898 consecutive CAD patients and 905 ethnically and geographically matched controls. CAD was angiographically confirmed in all the patients, and the severity of CAD was expressed by the number of affected vessel and coronary artery stenosis scores. Plasma TK levels were measured using an enzyme-linked immunosorbent assay.ResultsPlasma TK levels were significantly higher in CAD patients than controls (0.347±.082 vs. 0.256±0.087 mg/L, P<0.001), and elevated plasma TK levels were directly associated with a higher risk of CAD (OR = 3.49, 95% CI 2.90–4.19). One-way ANOVA and multivariable stepwise linear regression analysis demonstrated that TK levels were negatively associated with the severity of CAD according to vessel scores (P<0.001) and stenosis scores (r = −0.211, p<0.001).ConclusionsOur findings suggest that higher levels of TK in plasma are associated with the presence of CAD and are a predictor of mild coronary arteriosclerosis.

Hexane extracts of Polygonum multiflorum improve tissue and functional outcome following focal cerebral ischemia in mice

Polygonum multiflorum is a traditional Korean medicine that has been utilized widely in East Asian countries as a longevity agent. Clinical studies have demonstrated that Polygonum multiflorum improves hypercholesterolemia, coronary heart disease, neurosis and other diseases commonly associated with aging. However, scientific evidence defining the protective effects and mechanisms of Polygonum multiflorum against ischemic stroke is incomplete. In the present study, we investigated the cerebrovascular protective effects of Polygonum multiflorum against ischemic brain injury using an in vivo photothrombotic mouse model. To examine the underlying mechanism of action, we utilized an in vitro human brain microvascular endothelial cell (HBMEC) culture system. Hexane extracts (HEPM), ethyl acetate extracts (EAEPM) and methanol extracts (MEPM) of Polygonum multiflorum (100 mg/kg) were administered intraperitoneally 30 min prior to ischemic insult. Focal cerebral ischemia was induced in C57BL/6J mice and endothelial nitric oxide synthase knockout (eNOS KO) mice by photothrombotic cortical occlusion. We evaluated the infarct volume, as well as neurological and motor function, 24 h after ischemic brain injury. Following ischemic insult, HEPM induced a significant reduction in infarct volume and subsequent neurological deficits, compared with EAEPM and MEPM. HEPM significantly decreased infarct size and improved neurological and motor function, which was not observed in eNOS KO mice, suggesting that this cerebroprotective effect is primarily an eNOS-dependent mechanism. In vitro, HEPM effectively promoted NO production, however these effects were inhibited by the NOS inhibitor, L-NAME and the PI3K/Akt inhibitor, LY-294002. Furthermore, HEPM treatment resulted in increased phosphorylation-dependent activation of Akt and eNOS in HBMEC, suggesting that HEPM increased NO production via phosphorylation-dependent activation of Akt and eNOS. In conclusion, HEPM prevents cerebral ischemic damage through an eNOS-dependent mechanism, and thus may have clinical applications as a protective agent against neurological injury in stroke.

Abstract W MP84: Erythropoietin Inhibits Oxidation of Tetrahydrobiopterin and Restores Bioavailability of Endothelial Nitric Oxide in Cerebral Microvessels of Hph-1 Mice

Background: While reported neuroprotective effects of erythropoietin (EPO) make it an appealing candidate for its evaluation in protection of neurovascular unit during cerebrovascular or neurodegenerative disorders, effects of EPO on cerebral microvessels, the vascular component of neurovascular unit, have not been studied to date. The present study was designed to determine the effects of EPO in cerebral microvessels derived from wild-type mice and also from hph-1 mice, a genetic mouse model of BH4 deficiency. Methods: Hph-1 mice and wild-type littermates (C57BL/6 background) were administered recombinant human EPO (1000 U/kg/day) intraperitoneally for 3 days. Following treatment, mice were killed by injection of an overdose of pentobarbital, brains were removed and cerebral microvessels were isolated. Results: Treatment of wild-type mice with EPO did not affect BH4 bioavailability, superoxide anion production or basal cGMP levels. We have reported that cerebral microvessels of hph-1 mice demonstrated reduced bioavailability of BH4, increased production of superoxide anions and impaired endothelial NO/cGMP signaling. Treatment of hph-1 mice with EPO attenuated the levels of 7,8-dihydrobiopterin (7,8-BH2; P&lt;0.05, n=5), oxidized product of BH4, and significantly increased the ratio of BH4 to 7,8-BH2 (P&lt;0.05, n=5), indicative of increased bioavailability of BH4 for eNOS activation. Increased superoxide anion production in cerebral microvessels of hph-1 mice were attenuated by EPO treatment (P&lt;0.05, n=5). While eNOS expression remained unchanged, levels of cGMP were significantly increased on EPO treatment in hph-1 mice (P&lt; 0.05, n=6). Furthermore, EPO treatment selectively increased expression of manganese superoxide dismutase. Conclusion: The ability of EPO to attenuate oxidative stress and restore bioavailability of endothelial NO in cerebral microvessels may help to explain mechanisms responsible for cerebrovascular protective effects of EPO.

Cerebrovascular and neuroprotective effects of adamantane derivative.

Objectives. The influence of 5-hydroxyadamantane-2-on was studied on the rats' brain blood flow and on morphological state of brain tissue under the condition of brain ischemia. The interaction of the substance with NMDA receptors was also studied. Methods. Study has been implemented using the methods of local blood flow registration by laser flowmeter, [3H]-MK-801binding, and morphological examination of the brain tissue. We used the models of global transient ischemia of the brain, occlusion of middle cerebral artery, and hypergravity ischemia of the brain. Results. Unlike memantine, antagonist of glutamatergic receptors, the 5-hydroxyadamantane-2-on does not block NMDA receptors but enhances the cerebral blood flow of rats with brain ischemia. This effect is eliminated by bicuculline. Under conditions of permanent occlusion of middle cerebral artery, 5-hydroxyadamantane-2-on has recovered compensatory regeneration in neural cells, axons, and glial cells, and the number of microcirculatory vessels was increased. 5-Hydroxyadamantane-2-on was increasing the survival rate of animals with hypergravity ischemia. Conclusions. 5-Hydroxyadamantane-2-on, an adamantane derivative, which is not NMDA receptors antagonist, demonstrates significant cerebrovascular and neuroprotective activity in conditions of brain ischemia. Presumably, the GABA-ergic system of brain vessels is involved in mechanisms of cerebrovascular and neuroprotective activity of 5-hydroxyadamantane-2-on.

Hyperventilation, cerebral perfusion, and syncope

This review summarizes evidence in humans for an association between hyperventilation (HV)-induced hypocapnia and a reduction in cerebral perfusion leading to syncope defined as transient loss of consciousness (TLOC). The cerebral vasculature is sensitive to changes in both the arterial carbon dioxide (PaCO2) and oxygen (PaO2) partial pressures so that hypercapnia/hypoxia increases and hypocapnia/hyperoxia reduces global cerebral blood flow. Cerebral hypoperfusion and TLOC have been associated with hypocapnia related to HV. Notwithstanding pronounced cerebrovascular effects of PaCO2 the contribution of a low PaCO2 to the early postural reduction in middle cerebral artery blood velocity is transient. HV together with postural stress does not reduce cerebral perfusion to such an extent that TLOC develops. However when HV is combined with cardiovascular stressors like cold immersion or reduced cardiac output brain perfusion becomes jeopardized. Whether, in patients with cardiovascular disease and/or defect, cerebral blood flow cerebral control HV-induced hypocapnia elicits cerebral hypoperfusion, leading to TLOC, remains to be established.

Circulating Endothelin-1 Alters Critical Mechanisms Regulating Cerebral Microcirculation

Endothelin-1 (ET1) is a potent vasoconstrictor peptide implicated in the cerebrovascular alterations occurring in stroke, subarachnoid hemorrhage, and brain trauma. Brain or circulating levels of ET1 are elevated in these conditions and in risk factors for cerebrovascular diseases. Most studies on the cerebrovascular effects of ET1 have focused on vascular smooth muscle constriction, and little is known about the effect of the peptide on cerebrovascular regulation. We tested the hypothesis that ET1 increases cerebrovascular risk by disrupting critical mechanisms regulating cerebral blood flow. Male C57Bl6/J mice equipped with a cranial window were infused intravenously with vehicle or ET1, and somatosensory cortex blood flow was assessed by laser Doppler flowmetry. ET1 infusion increased mean arterial pressure and attenuated the blood flow increase produced by neural activity (whisker stimulation) or neocortical application of the endothelium-dependent vasodilator acetylcholine but not A23187. The cerebrovascular effects of ET1 were abrogated by the ET(A) receptor antagonist BQ123 and were not related to vascular oxidative stress. Rather, the dysfunction was dependent on Rho-associated protein kinase activity. Furthermore, in vitro studies demonstrated that ET1 suppresses endothelial nitric oxide (NO) production, assessed by its metabolite nitrite, an effect associated with Rho-associated protein kinase-dependent changes in the phosphorylation state of endothelial NO synthase. Collectively, these novel observations demonstrate that increased ET1 plasma levels alter key regulatory mechanisms of the cerebral circulation by modulating endothelial NO synthase phosphorylation and NO production through Rho-associated protein kinase. The ET1-induced cerebrovascular dysfunction may increase cerebrovascular risk by lowering cerebrovascular reserves and increasing the vulnerability of the brain to cerebral ischemia.

Pioglitazone Improves Reversal Learning and Exerts Mixed Cerebrovascular Effects in a Mouse Model of Alzheimer’s Disease with Combined Amyloid-β and Cerebrovascular Pathology

Animal models of Alzheimer’s disease (AD) are invaluable in dissecting the pathogenic mechanisms and assessing the efficacy of potential new therapies. Here, we used the peroxisome proliferator-activated receptor gamma agonist pioglitazone in an attempt to rescue the pathogenic phenotype in adult (12 months) and aged (>18 months) bitransgenic A/T mice that overexpress a mutated human amyloid precursor protein (APPSwe,Ind) and a constitutively active form of transforming growth factor-β1 (TGF-β1). A/T mice recapitulate the AD-related cognitive deficits, amyloid beta (Aβ) and cerebrovascular pathologies, as well as the altered metabolic and vascular coupling responses to increased neuronal activity. Pioglitazone normalized neurometabolic and neurovascular coupling responses to sensory stimulation, and reduced cortical astroglial and hippocampal microglial activation in both age groups. Spatial learning and memory deficits in the Morris water maze were not rescued by pioglitazone, but reversal learning was improved in the adult cohort notwithstanding a progressing Aβ pathology. While pioglitazone preserved the constitutive nitric oxide synthesis in the vessel wall, it unexpectedly failed to restore cerebrovascular reactivity in A/T mice and even exacerbated the dilatory deficits. These data demonstrate pioglitazone’s efficacy on selective AD hallmarks in a complex AD mouse model of comorbid amyloidosis and cerebrovascular pathology. They further suggest a potential benefit of pioglitazone in managing neuroinflammation, cerebral perfusion and glucose metabolism in AD patients devoid of cerebrovascular pathology.

Cerebral Effects of Commonly Used Vasopressor-Inotropes: A Study in Newborn Piglets

BackgroundDespite widespread use in sick infants, it is still debated whether vasopressor-inotropes have direct cerebral effects that might affect neurological outcome. We aimed to test direct cerebrovascular effects of three commonly used vasopressor-inotropes (adrenaline, dopamine and noradrenaline) by comparing the responses to those of nonpharmacologically induced increases in blood pressure. We also searched for reasons for a mismatch between the response in perfusion and oxygenation.MethodsTwenty-four piglets had long and short infusions of the three vasopressor-inotropes titrated to raise mean arterial blood pressure (MAP) 10 mmHg in random order. Nonpharmacological increases in MAP were induced by inflation of a balloon in the descending aorta. We measured cerebral oxygenation (near-infrared spectroscopy), perfusion (laser-Doppler), oxygen consumption (co-oximetry of arterial and superior sagittal sinus blood), and microvascular heterogeneity (side stream dark field video microscopy).ResultsVasopressor-inotropes increased cerebral oxygenation significantly less (p≤0.01) compared to non-pharmacological MAP increases, whereas perfusion was similar. Furthermore, cerebral total hemoglobin concentration increased significantly less during vasopressor-inotrope infusions (p = 0.001). These physiologic responses were identical between the three vasopressor-inotropes (p>0.05). Furthermore, they induced a mild, although insignificant increase in cerebral metabolism and microvascular heterogeneity (p>0.05). Removal of the scalp tissue did not influence the mismatch (p>0.05).ConclusionWe demonstrated a moderate vasopressor-inotrope induced mismatch between cerebral perfusion and oxygenation. Scalp removal did not affect this mismatch, why vasopressor-inotropes appear to have direct cerebral actions. The statistically nonsignificant increases in cerebral metabolism and/or microvascular heterogeneity may explain the mismatch. Alternatively, it may simply reflect a vasopressor-inotrope-induced decrease in the arterial-to-venous volume ratio as detected by near-infrared spectroscopy.

Oral l-Citrulline administration improves memory deficits following transient brain ischemia through cerebrovascular protection

l-citrulline (l-Cit) is known to increase nitric oxide (NO) production via the increase of l-arginine (l-Arg) concentration in the blood and improve endothelial dysfunction in cardiovascular diseases. However, little is known about the effects of l-Cit on cerebrovascular dysfunction. Here we showed that oral l-Cit administration prevents cerebrovascular injury following cerebral ischemia using a 20-min bilateral common carotid artery occlusion (BCCAO) mouse model. After BCCAO ischemia, mice were treated with l-Cit (50, 75, or 100mg/kg p.o.) for 10 days once a day. l-Cit administration not only prevented neuronal cell death but also prevented capillary loss in the hippocampal region following brain ischemia. The cerebrovascular protective effect of l-Cit was associated with the restoration of endothelial nitric oxide synthase (eNOS) expression in the hippocampus. In addition, we devised a novel protocol to analyze NOx− (NO2− and NO3−) productions following l-Arg infusion using in vivo microdialysis and revealed that decreased l-Arg-induced NOx− levels were improved in the hippocampus of BCCAO mice following repeated l-Cit administration. Finally, memory deficits following brain ischemia were improved by oral administration of l-Cit. In summary, l-Cit is a potential therapeutic agent that protects cerebrovascular injury and in turn prevents neuronal cell death. Thereby, oral l-Cit administration improves cognitive deficits following brain ischemia.