| Current
Neurovascular Research
ISSN: 1567-2026
Current Neurovascular Research
Volume 7, Number 4, November 2010
Contents
ORIGINAL ARTICLES
Environmental Enrichment Influences BDNF and NR1 Levels in
the Hippocampus and Restores Cognitive Impairment in Chronic
Cerebral Hypoperfused Rats Pp. 268-280
Huimin Sun, Junjian Zhang, Lei Zhang, Hui Liu, Hong Zhu
and Ying Yang
[Abstract] [Full
text article]
Hsp20 Protects Neuroblastoma Cells from Ischemia/Reperfusion
Injury by Inhibition of Apoptosis via a Mechanism that Involves
the Mitochondrial Pathways Pp. 281-287
Liuwang Zeng, Jieqiong Tan, Zhiping Hu, Wei Lu and
Binbin Yang
[Abstract] [Full
text article]
Chronic Hypoxia Potentiates Age-Related Oxidative
Imbalance in Brain Vessels and Synaptosomes Pp. 288-300
Cristina Carvalho, Maria S. Santos, Inês Baldeiras,
Catarina R. Oliveira, Raquel Seiça and Paula
I. Moreira
[Abstract] [Full
text article]
Traumatic Spinal Cord Injury Alters Angiogenic Factors
and TGF-Beta1 that may Affect Vascular Recovery Pp.
301-310
Marie-Françoise Ritz, Ursula Graumann, Bertha Gutierrez
and Oliver Hausmann
[Abstract] [Full
text article]
Human Platelets Express Authentic CB1
and CB2 Receptors
Pp. 311-318
Maria V. Catani, Valeria Gasperi, Giuseppina Catanzaro,
Samantha Baldassarri, Alessandra Bertoni, Fabiola Sinigaglia,
Luciana Avigliano and Mauro Maccarrone
[Abstract] [Full
text article]
Free Radical Scavenger Edaravone Administration Protects
against Tissue Plasminogen Activator Induced Oxidative Stress
and Blood Brain Barrier Damage Pp. 319-329
Violeta Lukic-Panin, Kentaro Deguchi, Toru Yamashita,
Jingwei Shang, Xumei Zhang, Fengfeng Tian, Ning Liu, Hiromi
Kawai, Tohru Matsuura and Koji Abe
[Abstract] [Full
text article]
Interleukin-1 Drives Cerebrovascular Inflammation
via MAP Kinase-Independent Pathways Pp. 330-340
Peter Thornton, Barry W. McColl, Laura Cooper, Nancy J.
Rothwell and Stuart M. Allan
[Abstract] [Full
text article]
Protein-Energy Malnutrition Alters Hippocampal Plasticity-Associated
Protein Expression following Global Ischemia in the Gerbil
Pp. 341-360
Erin J. Prosser-Loose, Valerie M.K. Verge, Francisco S.
Cayabyab and Phyllis G. Paterson
[Abstract] [Full
text article]
Abstracts
[Back to top] [Full
text article]
Environmental Enrichment Influences BDNF
and NR1 Levels in the Hippocampus and Restores Cognitive Impairment
in Chronic Cerebral Hypoperfused Rats
Huimin Sun, Junjian Zhang, Lei Zhang, Hui Liu, Hong Zhu
and Ying Yang
An enriched environment (EE) is beneficial in modifying behaviors,
particularly in tasks involving complex cognitive functions.
However, the impact of EE on cognitive impairment induced
by chronic cerebral hypoperfusion (CCH) has not been studied.
We investigated the effects of EE on cognitive impairment
caused by CCH and examined whether CCH altered the protein
levels of brain-derived neurotrophic factor (BDNF) and N-methyl-D-aspartate
(NMDA) receptor subunit 1 (NR1) and subunit 2B (NR2B) in the
hippocampus of rats and whether EE exposure attenuated the
effects. Rats were divided into four groups that received
either permanent bilateral ligation of the common carotid
arteries (2-vessel occlusion) surgery or sham surgery followed
by either EE housing or standard environment housing for 4
weeks. We examined non-spatial recognition memory in the novel
object recognition task, spatial learning, and memory ability
in the Morris water maze as well as the protein levels of
BDNF, NR1, and NR2B in the hippocampus. CCH impaired both
spatial and non-spatial cognitive functions, and EE exposure
reversed the spatial cognitive performance and improved non-spatial
memory performance. CCH resulted in decreased levels of BDNF
and NR1 protein in the hippocampus, and EE exposure restored
the decreased expression. Our results demonstrate for the
first time that EE exposure restores cognitive impairment
induced by CCH and up-regulates the decreased protein levels
of BDNF and NR1. Inversely, BDNF and NR1 may contribute to
the beneficial effects of EE on CCH in rats.
[Back to top] [Full
text article]
Hsp20 Protects Neuroblastoma Cells from Ischemia/Reperfusion
Injury by Inhibition of Apoptosis via a Mechanism that Involves
the Mitochondrial Pathways
Liuwang Zeng, Jieqiong Tan, Zhiping Hu, Wei Lu and
Binbin Yang
Hsp20 is a chaperone protein that is highly and constitutively
expressed in the brain, cardiac tissue and many other organs.
Recently, it is well established that Hsp20 can enhance cardiac
function and render cardioprotection. However, the potential
benefits of Hsp20 and its phosphorylation form action on ischemic
stroke and the underlying mechanism(s) are largely unknown.
To investigate whether Hsp20 exerts protective effects on
in vitro ischemia/ reperfusion (I/R) injury, mouse neuroblastoma
cells were subjected to oxygen-glucose deprivation (OGD) and
reoxygenation. Expressions of Hsp20 were strongly downregulated
in mouse N2A cells at the 0-hour and 6-hour recovery time
points following 4 hours of OGD, and returned to basal level
12 and 24 hours after OGD treatment, both at mRNA and protein
levels. The ratio of phosphorylated to total Hsp20 protein
was not significantly affected at the 0-hour and 6-hour recovery
time points following 4 hours of OGD. However, markedly higher
serine phosphorylation of Hsp20 was observed 12 and 24 hours
after OGD treatment. Furthermore, overexpression of Hsp20
reduced OGD-induced apoptosis by reducing the release of cytochrome
c from mitochondria to cytosol. However, blockade of Hsp20
phosphorylation at Ser16 abrogated this anti-apoptotic effect.
In conclusion, our data demonstrated that increased Hsp20
expression in mouse N2A neuroblastoma cells protected against
I/R injury, resulting in reduced apoptosis with the decrease
of the release of cytochrome c from mitochondria to cytosol.
Phosphorylation of Ser16 played an important role in the neuroprotective
effect of Hsp20. Thus, Hsp20 may constitute a new therapeutic
target for cerebral ischemic diseases.
[Back to top] [Full
text article]
Chronic Hypoxia Potentiates Age-Related Oxidative
Imbalance in Brain Vessels and Synaptosomes
Cristina Carvalho, Maria S. Santos, Inês Baldeiras,
Catarina R. Oliveira, Raquel Seiça and Paula
I. Moreira
This study was aimed to evaluate and compare the effect of
chronic hypoxia and aging in the oxidative status of brain
vessels and synaptosomes. For this purpose we isolated brain
vessels and synaptosomes from 3- and 12-month-old rats subjected
to chronic hypoxia (10% O2
for 7 days) or normoxia (21% O2).
Several parameters were evaluated: mitochondrial aconitase
activity, hydrogen peroxide (H2O2)
and malondialdehyde (MDA) levels and enzymatic [superoxide
dismutase (SOD), catalase, glutathione peroxidase (GPx) and
glutathione reductase (GR)] and non-enzymatic [glutathione
(GSH), glutathione disulfide (GSSG) and vitamin E] antioxidant
defences. Concerning brain vessels, we observed an age-dependent
increase in MDA levels and SOD, catalase, GR and GPx activities.
In vessels isolated from young animals, chronic hypoxia induced
an increase in H2O2,
GSSG and vitamin E levels and CuZnSOD and catalase activities
and a decrease in GSH levels. In mature animals, hypoxia induced
a decrease in GSH/GSSG ratio, vitamin E levels and mitochondrial
aconitase, MnSOD and GR activities and an increase in H2O2
levels and CuZnSOD and catalase activities. Concerning synaptosomes
we observed an age-dependent increase in MDA levels, CuZnSOD
and GPx activities and a decrease in MnSOD activity. In synaptosomes
from young animals, chronic hypoxia induced a decrease in
mitochondrial aconitase activity and GSH levels and an increase
in CuZnSOD activity and GSSG levels. In synaptosomes from
mature animals, hypoxia induced a decrease in mitochondrial
aconitase activity, GSH/GSSG ratio, GSH and vitamin E levels
and an increase in GSSG levels. Our results show that chronic
hypoxia promotes and potentiates age-dependent oxidative imbalance
predisposing to neurodegeneration. Further, synaptosomes and
brain vessels are differently affected by aging and chronic
hypoxia supporting the idea of the existence of tissue-specific
susceptibilities.
[Back to top] [Full
text article]
Traumatic Spinal Cord Injury Alters Angiogenic Factors
and TGF-Beta1 that may Affect Vascular Recovery
Marie-Françoise Ritz, Ursula Graumann, Bertha Gutierrez
and Oliver Hausmann
Traumatic spinal cord injury (SCI) disrupts the blood-spinal
cord barrier and reduces the blood supply caused by microvascular
changes. Vessel regression and neovascularization have been
observed in the course of secondary injury contributing to
microvascular remodeling after trauma. Spatio-temporal distribution
of blood vessels and modulation of gene expression of several
angiogenic factors have been investigated in rats after spinal
cord compression injury.
Rarefaction of vessels was detectable at the injury site 2
days after SCI before they disappeared in the developing cavity
after 2 and 4 weeks, whereas no changes were observed in the
penumbra. Investigation of the temporal expression of angiogenic
genes using quantitative RT-PCR disclosed a constant down-regulation
of the vascular endothelial growth factor (VEGF), and transient
decreases of angiopoietin-1 (Ang-1), platelet-derived growth
factor-BB (PDGF-BB), as well as placental growth factor (PlGF),
with the lowest values obtained 3 days after injury, when
compared to the expression levels obtained in sham-operated
rats. Hepatocyte growth factor (HGF) was the only angiogenic
factor with a constant increased gene expression when compared
with controls, starting at day 3 post-SCI. mRNA levels of
transforming growth factor-beta 1 (TGF-β1) were elevated
at every time point following SCI, whereas those encoding
for the cysteine-rich protein CCN1/CYR61 were upregulated
after 2 h, 6 h, and 1 week only. Our data provide an overview
of the temporal modulated expression of the major angiogenic
factors, hampering revascularization in the lesion during
the phase of secondary injury. These findings should be considered
in order to improve therapeutic interventions.
[Back to top] [Full
text article]
Human Platelets Express Authentic CB1
and CB2 Receptors
Maria V. Catani, Valeria Gasperi, Giuseppina Catanzaro,
Samantha Baldassarri, Alessandra Bertoni, Fabiola Sinigaglia,
Luciana Avigliano and Mauro Maccarrone
In the last decade, the neurovascular effects exerted by endocannabinoids
(eCBs) have attracted growing interest, because they hold
the promise to open new avenues of therapeutic intervention
against major causes of death in Western society. Several
actions of eCBs are mediated by type-1 (CB1)
or type-2 (CB2) cannabinoid
receptors, yet there is no clear evidence of the presence
of these proteins in platelets.
To demonstrate that CB1 and
CB2 are expressed in human
platelets, we analyzed their protein level by Western blotting
and ELISA, visualized their cellular localization by confocal
microscopy, and ascertained their functionality by binding
assays. We found that CB1,
and to a lesser extent CB2, are expressed
in highly purified human platelets. Both receptor subtypes
were predominantly localized inside the cell, thus explaining
why they might remain undetected in preparations of plasma
membranes.
The identification of authentic CB1
and CB2 in human platelets supports
the potential exploitation of selective agonists or antagonists
of these receptors as novel therapeutics to combat neurovascular
disorders. It seems remarkable that some of these substances
have been already used in humans to treat disease states.
[Back to top] [Full
text article]
Free Radical Scavenger Edaravone Administration Protects
against Tissue Plasminogen Activator Induced Oxidative Stress
and Blood Brain Barrier Damage
Violeta Lukic-Panin, Kentaro Deguchi, Toru Yamashita,
Jingwei Shang, Xumei Zhang, Fengfeng Tian, Ning Liu, Hiromi
Kawai, Tohru Matsuura and Koji Abe
One of the therapeutics for acute cerebral ischemia is tissue
plasminogen activator (t-PA). Using t-PA after 3 hour time
window increases the chances of hemorrhage, involving multiple
mechanisms. In order to show possible mechanisms of t-PA toxicity
and the effect of the free radical scavenger edaravone, we
administered vehicle, plasmin, and t-PA into intact rat cortex,
and edaravone intravenously. Plasmin and t-PA damaged rat
brain with the most prominent injury in t-PA group on 4-HNE,
HEL, and 8-OHdG immunostainings. Such brain damage was strongly
decreased in t-PA plus edaravone group. For the neurovascular
unit immunostainings, occludin and collagen IV expression
was decreased in single plasmin or t-PA group, which was recovered
in t-PA plus edaravone group. In contrast, matrix metalloproteinase-9
intensity was the strongest in t-PA group, less in plasmin,
and was the least prominent in t-PA plus edaravone group.
In vitro data showed a strong damage to tight junctions
for occludin and claudin 5 in both administration groups,
while there were no changes for endothelial (NAGO) and perivascular
(GFAP) stainings. Such damage to tight junctions was recovered
in t-PA plus edaravone group with similar recovery in Sodium-Fluorescein
permeability assay. Administration of t-PA caused oxidative
stress damage to lipids, proteins and DNA, and led to disruption
of outer parts of neurovascular unit, greater than the effect
in plasmin administration. Additive edaravone ameliorated
such an oxidative damage by t-PA with protecting outer layers
of blood-brain barrier (in vivo) and tight junctions
(in vitro).
[Back to top] [Full
text article]
Interleukin-1 Drives Cerebrovascular Inflammation
via MAP Kinase-Independent Pathways
Peter Thornton, Barry W. McColl, Laura Cooper, Nancy J.
Rothwell and Stuart M. Allan
Cerebrovascular inflammation is triggered by diverse central
nervous system (CNS) insults and contributes to disease pathogenesis.
The pro-inflammatory cytokine interleukin (IL)-1 is central
to this cerebrovascular inflammatory response and understanding
the underlying signalling mechanisms of IL-1 actions in brain
endothelium may provide therapeutic targets for disease intervention.
For the first time, we compare the contributions of p38, JNK
and ERK mitogen-activated protein (MAP) kinase and NF-κB
pathways to IL-1-induced brain endothelial activation. In
cultures of primary mouse brain endothelium and the rat brain
endothelial GPNT cell line, interleukin-1β
(IL-1β)
induced a rapid (within 5 minutes) and transient activation
of p38 and JNK (but not ERK) MAP kinases. IL-1β also
induced nuclear recruitment of nuclear factor (NF)-κB
p65. IL-1β-induced
brain endothelial expression of intercellular adhesion molecule
(ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 was
insensitive to MAP kinase inhibitors. IL-1β-induced
brain endothelial expression of ICAM-1 and VCAM-1 was inhibited
(80-88 %) by the proteasome inhibitor MG132 or the antioxidant
caffeic acid phenethyl ester (CAPE), effects suggested to
be NF-κB-dependent.
IL-1β-induced brain endothelial CXCL1 expression was
partially inhibited by JNK MAP kinase or MG132 (62 or 56 %,
respectively). However, CXCL1 secretion from brain
endothelium was reduced (65 %) only by MG132, and not MAP
kinase inhibitors. Similarly, IL-1β-induced
neutrophil transendothelial migration was reduced (77-89 %)
by MG132, but not MAP kinase inhibitors. In summary, we show
that several key components of IL-1β-induced
brain endothelial activation (CAM, CXCL1 expression or release
and neutrophil transmigration) are largely independent of
MAP kinase activity but are reduced by proteasome inhibition,
possibly reflecting a requirement for NF-κB
activity. Similar mechanisms may contribute to cerebrovascular
inflammation in response to CNS injury.
[Back to top] [Full
text article]
Protein-Energy Malnutrition Alters Hippocampal Plasticity-Associated
Protein Expression following Global Ischemia in the Gerbil
Erin J. Prosser-Loose, Valerie M.K. Verge, Francisco S.
Cayabyab and Phyllis G. Paterson
Previously it has been demonstrated that protein-energy malnutrition
(PEM) impairs habituation in the open field test following
global ischemia. The present study examined the hypothesis
that PEM exerts some of its deleterious effects on functional
outcome by altering the post-ischemic expression of the plasticity-associated
genes brain-derived neurotrophic factor (BDNF), its receptor
tropomyosin-related kinase B (trkB), and growth-associated
protein-43 (GAP- 43). Male, Mongolian gerbils (11-12wk) were
randomized to either control diet (12.5% protein) or PEM (2%
protein) for 4wk, and then underwent 5min bilateral common
carotid artery occlusion or sham surgery. Tympanic temperature
was maintained at 36.5 ±
0.5°C during surgery. Brains collected at 1, 3 and 7d
post-surgery were processed by in situ hybridization
or immunofluorescence. BDNF and trkB mRNA expression was increased
in hippocampal CA1 neurons after ischemia at all time points
and was not significantly influenced by diet. However, increased
trkB protein expression after ischemia was exacerbated by
PEM at 7d in the CA1 region. Post-ischemic GAP-43 protein
increased at 3 and 7d in the CA1 region, and PEM intensified
this response and extended it to the CA3 and hilar regions.
PEM exerted these effects without exacerbating CA1 neuron
loss caused by global ischemia. The findings suggest that
PEM increases the stress response and/or hyper-excitability
in the hippocampus after global ischemia. Nutritional care
appears to have robust effects on plasticity mechanisms important
to recovery after brain ischemia.
|
