Cereb Blood Flow Metab Research Articles

Venous Outflow and Parenchymal Hemorrhage: A Clogged Drain Problem?

Venous Outflow and Parenchymal Hemorrhage: A Clogged Drain Problem?

Anatomy embroiders function in Purkinje cells

The anatomy of the human cerebellar Purkinje cell, as captured by Ramón y Cajal in a drawing, inspired the spectacular cover embroidery by Lisa Stoneman (Roanoke College, Roanoke, VA, USA) in the October issue of The Lancet Neurology. 1 Mehta AR Abbott CM Chandran S Haley JE The Cajal Embroidery Project: celebrating neuroscience. Lancet Neurol. 2020; 19: 979 Summary Full Text Full Text PDF Scopus (6) Google Scholar Like contemporary confocal microscopy images do, this anatomical representation also raises fascinating questions about the function served by the complex array of dendrites in this cell type. Each Purkinje cell, in rodents, receives about 174 000 synaptic inputs from the parallel fibre axons of the far tinier cerebellar granule cells, along with a single powerful input from the climbing fibre arising from the inferior olivary nucleus. 2 Howarth C Gleeson P Attwell D Updated energy budgets for neural computation in the neocortex and cerebellum. J Cereb Blood Flow Metab. 2012; 32: 1222-1232 Crossref PubMed Scopus (337) Google Scholar Even though a large fraction of those synapses can become inactive with learning, 3 Isope P Barbour B Properties of unitary granule cell→Purkinje cell synapses in adult rat cerebellar slices. J Neurosci. 2002; 22: 9668-9678 Crossref PubMed Google Scholar it is remarkable that the information processed from such a large number of inputs, which are even more numerous in human beings, is ultimately channelled down a single inhibitory axon to the deep cerebellar nuclei, as denoted by the label a in Cajal's original 1894 drawing (appendix).

COVID-19 in a Hemorrhagic Neurovascular Disease, Cerebral Cavernous Malformation

COVID-19 in a Hemorrhagic Neurovascular Disease, Cerebral Cavernous Malformation

Temperature Management in Neurological and Neurosurgical Intensive Care Unit.

Temperature Management in Neurological and Neurosurgical Intensive Care Unit.

Interleukin 1 alpha administration is neuroprotective and neuro-restorative following experimental ischemic stroke

BackgroundStroke remains a leading cause of death and disability worldwide despite recent treatment breakthroughs. A primary event in stroke pathogenesis is the development of a potent and deleterious local and peripheral inflammatory response regulated by the pro-inflammatory cytokine interleukin-1 (IL-1). While the role of IL-1β (main released isoform) has been well studied in stroke, the role of the IL-1α isoform remains largely unknown. With increasing utilization of intravenous tissue plasminogen activator (t-PA) or thrombectomy to pharmacologically or mechanically remove ischemic stroke causing blood clots, respectively, there is interest in pairing successful cerebrovascular recanalization with neurotherapeutic pharmacological interventions (Fraser et al., J Cereb Blood Flow Metab 37:3531–3543, 2017; Hill et al., Lancet Neurol 11:942–950, 2012; Amaro et al., Stroke 47:2874–2876, 2016).MethodsTransient stroke was induced in mice via one of two methods. One group of mice were subjected to tandem ipsilateral common carotid artery and middle cerebral artery occlusion, while another group underwent the filament-based middle cerebral artery occlusion. We have recently developed an animal model of intra-arterial (IA) drug administration after recanalization (Maniskas et al., J Neurosci Met 240:22–27, 2015). Sub groups of the mice were treated with either saline or Il-1α, wherein the drug was administered either acutely (immediately after surgery) or subacutely (on the third day after stroke). This was followed by behavioral and histological analyses.ResultsWe now show in the above-mentioned mouse stroke models (transient tandem ipsilateral common carotid artery (CCA) and middle cerebral artery occlusion (MCA) occlusion, MCA suture occlusion) that IL-1α is neuroprotective when acutely given either intravenously (IV) or IA at low sub-pathologic doses. Furthermore, while IV administration induces transient hemodynamic side effects without affecting systemic markers of inflammation, IA delivery further improves overall outcomes while eliminating these side effects. Additionally, we show that delayed/subacute IV IL-1α administration ameliorates functional deficit and promotes neurorepair.ConclusionsTaken together, our present study suggests for the first time that IL-1α could, unexpectedly, be an effective ischemic stroke therapy with a broad therapeutic window.

Neurodegenerative Dementias: Improving Brain Health to Decrease Risk.

Neurodegenerative Dementias: Improving Brain Health to Decrease Risk.

DISTINCT ULTRASTRUCTURAL CHARACTERISTICS OF CAPILLARY BASAL LAMINA IN HUMAN AND MOUSE BRAINS: RELEVANCE TO MURINE MODELS OF NEUROVASCULAR DISEASE

Recent studies suggest that capillary dysfunction may be a source of neurodegeneration, stroke and cognitive decline (J Cereb Blood Flow Metab, 2016, 36:302; Neurobiol Aging, 2017, 50:107). Most neurovascular studies used mice to model human diseases. The morphologic changes in the capillary wall are less-well characterized in humans, especially in early or presymptomatic phases and in early onset diseases. Here we describe major differences in ultrastructure of capillary basal lamina (CBL) in humans (normal and diseased, <50 years) compared with mouse (young to middle age). Human autopsy brains without or with neurodegeneration, including Parkinson's disease, frontotemporal degeneration and amyotrophic lateral sclerosis, and mouse models of tauopathy were evaluated. Brain tissues were fixed in formaldehyde and/or glutaraldehyde and processed for electron microscopy (EM) or post-embedding immunogold EM. Antibodies to types I, III and IV collagen and to fibronectin were used. Mouse CBL is a thin and uniformly amorphous structure that is labeled with anti-type IV collagen in both normal mice and models of neurodegenerative disease at all ages. In contrast, the CBL in normal and diseased human brains has the amorphous BL, but also banded collagens. In addition, the BL frequently shows segmental splitting between endothelial and astrocytic sides of the BL. The split creates an expanded space that contains banded fibrils of type I and III collagen, but not type IV collagen. The expansion and splitting of BL increase with age and in diseased brains. The CBL in diseased human brains often extends into the pericapillary space. Anti-fibronectin co-localizes with collagens. These ultrastructural features are rarely observed in mice, but are detected in the youngest human brains studied. Human CBL has age- and disease-related alternations including split BL and accumulation of banded type I and III collagen fibrils associated with fibronectin. This BL “fibrosis” is rarely observed in mice brains. If these structural BL alterations are associated with capillary dysfunction, the lack of these changes in mice warrants caution about use of mouse models for neurovascular studies.

Isn't functional neuroimaging all about Ca2+ signaling in astrocytes?

Extensive research over the past decades about the multifaceted roles of brain astrocytes led to the suggestion that the signals observed with functional neuroimaging might primarily reflect astrocytic rather than neuronal activity. The basis for this paradigm-shifting concept was the evidence for an involvement of astrocytes in the control of local cerebral blood flow through intracellular Ca(2+) signaling. In this Neuro Forum, I discuss new important experimental findings obtained by Jego et al. (Jego P, Pacheco-Torres J, Araque A, Canals S. J Cereb Blood Flow Metab 34: 1599-1603, 2014) as well as other closely related studies published recently, prompting a dismissal of substantial astrocytic contribution in functional neuroimaging.

Lipopolysaccharide-induced cross-tolerance against renal ischemia–reperfusion injury is mediated by hypoxia-inducible factor-2α-regulated nitric oxide production

Although the protective effect of lipopolysaccharide (LPS) pretreatment on renal ischemia/reperfusion injury is known, a link to hypoxia-inducible factors (HIFs) has not been established. Here we show that LPS treatment led to HIF-2α accumulation in mouse kidneys and endothelial cells, a result of nuclear factor-κB activation. Inactivation of HIF-2α, rather than HIF-1α, completely negated LPS-mediated protection against renal ischemia/reperfusion injury. LPS-stimulated renoprotection was related to inducible/endothelial nitric oxide synthase (iNOS/eNOS) expression, increased production of nitric oxide, and enhanced postischemic microcirculatory recovery. All these effects were lost in HIF-2α knockout mice. Preischemic administration of a nitric oxide donor, rather than erythropoietin, restored the lost preconditioning effect of LPS in HIF-2α knockout mice. In vitro and in vivo studies demonstrated that HIF-2α in endothelial cells, rather than myeloid cells or hepatocytes, was responsible for the LPS-mediated effects. Thus, our results demonstrated that LPS preconditioning protected against renal ischemia/reperfusion injury by HIF-2α activation in endothelial cells that subsequently improved renal microvascular perfusion and reduced ischemic tubular damage.

Single-cell analysis of K562 cells: An imatinib-resistant subpopulation is adherent and has upregulated expression of BCR-ABL mRNA and protein

In chronic myeloid leukemia (CML) cells from different stages of maturation may have differential expression of BCR-ABL at both messenger RNA (mRNA) and protein level. However, the significance of such differential expression to clinical disease behavior is unknown. Using the CML-derived, BCR-ABL expressing cell line, K562, distinct plastic-adherent (K562/Adh) and nonadherent (K562/NonAdh) subpopulations were established and then analyzed both as single cells and as bulk cell populations. BCR-ABL mRNA was upregulated in K562/Adh compared with K562/NonAdh cells in both single cell and bulk population analyses (p < 0.0001). Similarly, phosphorylation of BCR protein was upregulated in K562/Adh, compared with K562/NonAdh cells (63.42% vs. 23.1%; p = 0.007), and these two K562 subpopulations were found to express significantly different microRNA species. Furthermore, treatment with the BCR-ABL tyrosine kinase inhibitor, imatinib, reduced cell viability more rapidly in K562/NonAdh compared with K562/Adh cells (p < 0.005) both at single and bulk cell levels. This discovery of an adherent subpopulation of K562 cells with increased BCR-ABL mRNA, increased phosphorylated BCR protein expression, differential microRNA expression, and increased imatinib resistance suggests that a similar subpopulation of cells can also mediate clinical resistance to imatinib during treatment of patients with CML.

In Support of EHP ’s Proposal to Adopt the ARRIVE Guidelines

In Support of <i>EHP</i> ’s Proposal to Adopt the ARRIVE Guidelines

Intermediate filaments are important for astrocyte response to oxidative stress induced by oxygen–glucose deprivation and reperfusion

As a response to central nervous system injury, astrocytes become reactive. Two cellular hallmarks of reactive gliosis are hypertrophy of astrocyte processes and upregulation of intermediate filament (nanofilament) proteins glial fibrillary acidic protein (GFAP), vimentin, nestin, and synemin. Astrocytes in mice devoid of GFAP and vimentin (GFAP (-/-) Vim (-/-)) do not form cytoplasmic intermediate filaments. GFAP (-/-) Vim (-/-) mice develop larger infarcts after ischemic stroke (Li et al. in J Cereb Blood Flow Metab 28(3):468-481, 2008). Here, we attempted to analyze the underlying mechanisms using oxygen-glucose deprivation (OGD), an in vitro ischemia model, examining a potential link between astrocyte intermediate filaments and reactive oxygen species (ROS). We observed a reorganization of the intermediate filament network in astrocytes exposed to OGD. ROS accumulation was higher in GFAP (-/-) Vim (-/-) than wild-type astrocytes when exposed to OGD followed by reperfusion or when exposed to hydrogen peroxide. These results indicate that the elimination of ROS is impaired in the absence of the intermediate filament system. Compared to wild-type astrocytes, GFAP (-/-) Vim (-/-) astrocytes exposed to OGD and reperfusion exhibited increased cell death and conferred lower degree of protection to cocultured neurons. We conclude that the astrocyte intermediate filament system is important for the cell response to oxidative stress induced by OGD followed by reperfusion.

Neuropsychiatric Symptoms as a Putative Crescendo Warning of a Striatocapsular Infarct?

Neuropsychiatric Symptoms as a Putative Crescendo Warning of a Striatocapsular Infarct?

Temperature Affects Thrombolytic Efficacy Using rt-PA and Eptifibatide, an In Vitro Study: Editorial Commentary on Meunier et al., 2012

Therapeutic Hypothermia and Temperature ManagementVol. 2, No. 4 Invited Editorial CommentTemperature Affects Thrombolytic Efficacy Using rt-PA and Eptifibatide, an In Vitro Study: Editorial Commentary on Meunier et al., 2012Midori A. YenariMidori A. YenariSearch for more papers by this authorPublished Online:16 Dec 2012https://doi.org/10.1089/ther.2012.0020AboutSectionsView articleView Full TextPDF/EPUB ToolsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View article"Temperature Affects Thrombolytic Efficacy Using rt-PA and Eptifibatide, an In Vitro Study: Editorial Commentary on Meunier et al., 2012." , 2(4), p. 166FiguresReferencesRelatedDetailsCited byThrombolytic Therapy During ex-vivo Normothermic Machine Perfusion of Human Livers Reduces Peribiliary Vascular Plexus Injury17 June 2021 | Frontiers in Surgery, Vol. 8 Volume 2Issue 4Dec 2012 InformationCopyright 2012, Mary Ann Liebert, Inc.To cite this article:Midori A. Yenari.Temperature Affects Thrombolytic Efficacy Using rt-PA and Eptifibatide, an In Vitro Study: Editorial Commentary on Meunier et al., 2012.Therapeutic Hypothermia and Temperature Management.Dec 2012.166-166.http://doi.org/10.1089/ther.2012.0020Published in Volume: 2 Issue 4: December 16, 2012Online Ahead of Print:December 5, 2012PDF download

No change in [11C]CUMI‐101 binding to 5‐HT1A receptors after intravenous citalopram in human

The main objective of this study was to determine the sensitivity of [¹¹C]CUMI-101 to citalopram challenge aiming at increasing extracellular 5-HT. CUMI-101 has agonistic properties in human embryonic kidney 293 cells transfected with human recombinant 5-HT(1A) receptors (Hendry et al. [2011] Nucl Med Biol 38:273-277; Kumar et al. [2006] J Med Chem 49:125-134) and has previously been demonstrated to be sensitive to bolus citalopram in monkeys (Milak et al. [2011] J Cereb Blood Flow Metab 31:243-249). We studied six healthy individuals. Two PET-scans were performed on the same day in each individual before and after constant infusion of citalopram (0.15 mg/kg). The imaging data were analyzed using two tissue compartment kinetic modeling with metabolite corrected arterial input and Simplified Reference Tissue Modeling using cerebellum as a reference region. There was no significant difference in regional distribution volume or non-displaceable binding potential values before and after citalopram infusion. The mean receptor occupancy was 0.03 (range -0.14 to 0.17). Our data imply that [¹¹C]CUMI-101 binding is not sensitive to citalopram infusion in humans.

Shuttling glucose across brain microvessels, with a little help from GLUT1 and AMP kinase. Focus on “AMP kinase regulation of sugar transport in brain capillary endothelial cells during acute metabolic stress”

The Blood-Brain Barrier: a Gatekeeper of Brain “Individuality” The blood-brain barrier (BBB) maintains the individuality of brain fluid, while allowing it to selectively import nutrients and process toxic products. Its major constituent is a single layer of continuous, nonfenestrated endothelium lining the microvessels, whose unique features account in large part for the integrity of the barrier. The endothelial cell monolayer is the major determinant, but other cells in the central nervous system (e.g., pericytes and astrocytes) contribute to the integrity of the BBB. The interendothelial tight junctions of the BBB are one of its signature elements that greatly restrict paracellular permeability to solutes, fluid, and transmigrating cells. This is markedly distinct from the leakier, discontinuous, and fenestrated endothelium of liver microvessels (sinusoids). For example, the tight junctions of the cerebral endothelium (pial vessels) confer an electrical resistance (1,300 ·cm 2 ) far higher than other endothelia (6). Therefore, communication between blood and the brain interstitial fluid requires individually tailored molecular mechanisms. Transcytosis is the movement of molecules through a cellular barrier. Whereas proteins can traverse through vesicular carrier processes that could carry solutes through fluid phase endocytosis, the brain microvasculature is uniquely poor in plasmalemmal and cytoplasmic caveolae (1). Instead, bidirectional passage of small molecules across the BBB is stringently regulated by numerous transporters and receptors. These typically work in tandem across the luminal and abluminal membranes of the endothelial cell.

Sphingolipids signal rapid loss of P‐glycoprotein transport activity at the blood‐brain barrier

Blood‐brain barrier P‐glycoprotein is a major obstacle to CNS pharmacotherapy. We previously showed that TNF‐α signals through TNFR1, ET‐BR, iNOS and PKCβ1 to rapidly reduce P‐glycoprotein transport activity in rat brain capillaries (Hartz et al., Mol Pharmacol 69, 462, 2006; Rigor et al., J Cereb Blood Flow Metab 30, 1373, 2010). Here we investigate sphingolipid signaling downstream of PKCβ1. Exposing capillaries to sphingosine or sphingosine‐1‐phosphate (S1P) rapidly (minutes) and reversibly reduced P‐glycoprotein transport activity by a S1PR1‐dependent mechanism. Blocking sphingosine kinase activity or S1PR1 attenuated the ability of TNF‐α exposure or PKCβ1 activation to reduce P‐glycoprotein activity. Using in situ brain perfusion in rats, we found that infusing S1P into the cerebral vasculature increased brain accumulation of 14C‐verapamil, indicating loss of P‐glycoprotein activity; this effect was blocked by S1PR1 antagonists. S1P did not alter 3H‐sucrose accumulation, indicating no change in paracelllular permeability. We are currently testing S1PR1 agonists for possible use in improving delivery to the brain of CNS‐acting drugs that are P‐glycoprotein substrates.

Low-Dose-Rate, Low-Dose Irradiation Delays Neurodegeneration in a Model of Retinitis Pigmentosa

The existence of radiation hormesis is controversial. Several stimulatory effects of low-dose (LD) radiation have been reported to date; however, the effects on neural tissue or neurodegeneration remain unknown. Here, we show that LD radiation has a neuroprotective effect in mouse models of retinitis pigmentosa, a hereditary, progressive neurodegenerative disease that leads to blindness. Various LD radiation doses were administered to the eyes in a retinal degeneration mouse model, and their pathological and physiological effects were analyzed. LD gamma radiation in a low-dose-rate (LDR) condition rescues photoreceptor cell apoptosis both morphologically and functionally. The greatest effect was observed in a condition using 650 mGy irradiation and a 26 mGy/minute dose rate. Multiple rounds of irradiation strengthened this neuroprotective effect. A characteristic up-regulation (563%) of antioxidative gene peroxiredoxin-2 (Prdx2) in the LDR-LD-irradiated retina was observed compared to the sham-treated control retina. Silencing the Prdx2 using small-interfering RNA administration reduced the LDR-LD rescue effect on the photoreceptors. Our results demonstrate for the first time that LDR-LD irradiation has a biological effect in neural cells of living animals. The results support that radiation exhibits hormesis, and this effect may be applied as a novel therapeutic concept for retinitis pigmentosa and for other progressive neurodegenerative diseases regardless of the mechanism of degeneration involved.

Comments on Point:Counterpoint: High altitude is/is not for the birds!

TO THE EDITOR: The debate between Scott et al. (6) and Llanos et al. (4) highlights the remarkable ability of birds and mammals to adapt and survive at high altitudes and cope with reduced oxygen (O2) availability. Scott and colleagues (6) make a compelling argument that birds are far superior to mammals at adapting and thriving in hypoxic environments, both at rest and during exercise. While their argument is supported by comparisons between birds and terrestrial mammals, it ignores marine mammals. Marine mammals such as seals are routinely exposed to and tolerate long bouts of hypoxia during breath-hold diving. For example, elephant seals may dive to depths of nearly 1,600 m and occasionally remain submerged for 2 h (3). Moreover, marine mammals can be exposed to partial pressures of arterial oxygen (PaO2) as low as 12 mmHg during free dives (5), which is less than the 20 mmHg observed in the bar-headed goose (6). Interestingly, a PaO2 of 12 mmHg observed in elephant seals corresponds to arterial saturations and O2 content of only 8% and 2.7 ml O2/dl (5). Thus marine mammals such as the elephant seal demonstrate a remarkable hypoxia tolerance. The integration of several key physiological adaptations including 1) substantially greater myoglobin concentrations compared to other mammals, 2) reductions in metabolism, 3) a greater reliance on aerobic metabolism (i.e., less lactate production), 4) a host of dramatic acute cardiovascular adjustments; and 5) an increased intrinsic cerebral hypoxia tolerance allow marine mammals to thrive in hypoxic environments and enable long deep dives (1–3).

MiRNA Expression Profile after Status Epilepticus and Hippocampal Neuroprotection by Targeting miR-132

When an otherwise harmful insult to the brain is preceded by a brief, noninjurious stimulus, the brain becomes tolerant, and the resulting damage is reduced. Epileptic tolerance develops when brief seizures precede an episode of prolonged seizures (status epilepticus). MicroRNAs (miRNAs) are small, noncoding RNAs that function as post-transcriptional regulators of gene expression. We investigated how prior seizure preconditioning affects the miRNA response to status epilepticus evoked by intra-amygdalar kainic acid in mice. The miRNA was extracted from the ipsilateral CA3 subfield 24 hours after focal-onset status epilepticus in animals that had previously received either seizure preconditioning (tolerance) or no preconditioning (injury), and mature miRNA levels were measured using TaqMan low-density arrays. Expression of 21 miRNAs was increased, relative to control, after status epilepticus alone, and expression of 12 miRNAs was decreased. Increased miR-132 levels were matched with increased binding to Argonaute-2, a constituent of the RNA-induced silencing complex. In tolerant animals, expression responses of >40% of the injury-group-detected miRNAs differed, being either unchanged relative to control or down-regulated, and this included miR-132. In vivo microinjection of locked nucleic acid-modified oligonucleotides (antagomirs) against miR-132 depleted hippocampal miR-132 levels and reduced seizure-induced neuronal death. Thus, our data strongly suggest that miRNAs are important regulators of seizure-induced neuronal death.