| Current
Neurovascular Research
ISSN: 1567-2026
Current Neurovascular Research
Volume 7, Number 2, May 2010
Contents
Experimental Diabetes Mellitus Down-Regulates Large-Conductance
Ca2+-Activated K+
Channels in Cerebral Artery Smooth Muscle and Alters Functional
Conductance Pp. 75-84
Yan Wang, Hong-Tao Zhang, Xing-Li Su, Xiu-Ling Deng, Bing-Xiang
Yuan, Wei Zhang, Xin-Feng Wang and Yu-Bai Yang
[Abstract] [Purchase
Article] [PMID:
20334613 PubMed - indexed for MEDLINE]
Ginsenoside RB1 Reduces Neurologic Damage, is Anti-Apoptotic,
and Down-Regulates p53 and BAX in Subarachnoid Hemorrhage
Pp. 84-94
Yingbo Li, Jiping Tang, Nikan H. Khatibi, Mei Zhu, Di
Chen, Weiping Zheng and Shali Wang
[Abstract] [Purchase
Article] [PMID:
20353383 PubMed - indexed for MEDLINE]
Early Apoptotic Vascular Signaling is Determined by
Sirt1 Through Nuclear Shuttling, Forkhead Trafficking, Bad,
and Mitochondrial Caspase Activation Pp. 95-112
Jinling Hou, Zhao Zhong Chong, Yan Chen Shang and
Kenneth Maiese
[Abstract] [Purchase
Article] [PMID:
20370652 PubMed - indexed for MEDLINE]
Contribution of Mast Cells to Cerebral Aneurysm Formation
Pp. 113-124
Ryota Ishibashi, Tomohiro Aoki, Masaki Nishimura, Nobuo
Hashimoto and Susumu Miyamoto
[Abstract] [Purchase
Article] [PMID:
20334612 PubMed - indexed for MEDLINE]
Sublethal Total Body Irradiation Leads to Early Cerebellar
Damage and Oxidative Stress Pp. 125-135
Li Cui, Dwight Pierce, Kim E. Light, Russell B. Melchert,
Qiang Fu, K. Sree Kumar and Martin Hauer-Jensen
[Abstract] [Purchase
Article] [PMID:
20334614 PubMed - indexed for MEDLINE]
Leptin Reduces Infarct Size in Association with Enhanced
Expression of CB2, TRPV1, SIRT-1 and Leptin Receptor
Pp. 136-143
Yosefa Avraham, Neta Davidi, Moran Porat, David Chernoguz,
Iddo Magen, Lia Vorobeiv, Elliot M. Berry and Ronen
R. Leker
[Abstract] [Purchase
Article] [PMID:
20374198 PubMed - indexed for MEDLINE]
CD133 Expressing Pericytes and Relationship to SDF-1
and CXCR4 in Spinal Cord Injury Pp. 144-154
Ursula Graumann, Marie-Françoise Ritz, Bertha Gutierrez
Rivero and Oliver Hausmann
[Abstract] [Purchase
Article] [PMID:
20374199 PubMed - indexed for MEDLINE]
REVIEW ARTICLE
Small Heat Shock Proteins: Recent Advances in Neuropathy
Pp. 155-166
Liuwang Zeng, Zhiping Hu, Wei Lu, Xiangqi Tang, Jie Zhang,
Ting Li and Binbin Yang
[Abstract] [Purchase
Article] [PMID:
20438447 PubMed - indexed for MEDLINE]
Abstracts
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[Purchase
Article] [PMID:
20334613 PubMed - indexed for MEDLINE]
Experimental Diabetes Mellitus Down-Regulates Large-Conductance
Ca2+-Activated K+
Channels in Cerebral Artery Smooth Muscle and Alters Functional
Conductance
Yan Wang, Hong-Tao Zhang, Xing-Li Su, Xiu-Ling Deng, Bing-Xiang
Yuan, Wei Zhang, Xin-Feng Wang and Yu-Bai Yang
Cerebral vascular dysfunction and associated vascular complications
often develop over time in type-2 diabetes, but the underlying
mechanisms are not wholly understood. The aim of the present
study was to investigate whether large-conductance Ca2+-activated
K+ (BKCa)
channels in cerebral artery smooth muscle cells (CASMCs) were
impaired in experimental model of type-2 diabetes, and the
changes could account for cerebral vascular complication in
type-2 diabetes. Sprague-Dawley rats were fed with high fat
and glucose diet for 8 weeks and then injected with streptozotocin
(STZ/30 mg/kg i.p.). Three months after injection
of STZ, the alterations of BKCa
channels were assessed by using multi-myograph system, patch-clamp,
RT-PCR and Western blot. Our results show that the model is
characterized by insulin resistance, hyperglycaemia, hyperlipidemia
and moderate hypertension, which resembles the clinical manifestation
of patients with type-2 diabetes. Inhibition of BKCa
channels with 1 mM tetraethylammonium (TEA) or 1 µM
paxilline (PAX) causes smaller constriction in type-2 diabetic
cerebral basilar arteries than control arteries. The contractile
efficacy of 5-Hydroxytryptamine (5-HT) is substantially reduced
by TEA or PAX pretreatment in control >
diabetic basilar artery rings. The response to 5-HT in diabetic
basilar artery rings is higher than that of control artery
rings after activation of BKCa
channels with NS1619. The whole-cell K+
currents are significantly decreased in type-2 diabetic CASMCs
compared to control, and the sensitivity of BKCa
channels to voltage, the specific inhibitor and opener are
all diminished in diabetic CASMCs. The expression of BKCa
channel β1,
but not a-subunits is markedly reduced at both of mRNA and
protein levels in endothelial-denudated cerebral arteries.
In conclusion, type-2 diabetes downregulates BKCa
channel β1-subunits
in CASMCs, resulting in reduced activity of BKCa
channel, increased vascular tone and blood pressure, thereby
contributing to cerebral vascular complication in type-2 diabetes.
[Back to top] [Purchase
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20353383 PubMed - indexed for MEDLINE]
Ginsenoside RB1 Reduces Neurologic Damage, is Anti-Apoptotic,
and Down-Regulates p53 and BAX in Subarachnoid Hemorrhage
Yingbo Li, Jiping Tang, Nikan H. Khatibi, Mei Zhu, Di
Chen, Weiping Zheng and Shali Wang
Stroke is the second leading cause of death worldwide and
the number one cause of adult disability in the United States
and Europe. A subtype of stroke, subarachnoid hemorrhage (SAH),
accounts for 7% of all strokes each year and claims one of
the highest mortalities and morbidities. Many therapeutic
interventions have been used to treat brain injury following
SAH but none have reached the level of effectiveness needed
to clinically reduce mortality. Ginsenoside Rb1 (GRb1), a
major component of the Chinese traditional medicine Panax
Ginseng, has been shown to reduce ischemic brain injury
and myocardial injury via anti-apoptotic pathways.
In the present study, we investigated the use of GRb1 on SAH
induced brain injury in rats. Four groups were used: sham,
vehicle (SAH), low dose treatment (SAH+ 5mg/kg GRb1), and
high dose treatment (SAH+ 20mg/kg GRb1). Post assessment included
wall thickness and mean cross-section area of basilar artery
were measured for evaluating cerebral vasospasm, Evans blue
extravasations to assess blood brain barrier (BBB) permeability,
immunohistochemistry and Western Blot analysis looking for
specific pro-apoptotic markers, and tunnel staining for cell
death assessment. In addition, mortality, neurological function
and brain edema were investigated. The results showed that
high dose GRb1 treatment significantly enlarged mean cross-sectional
area and decreased wall thickness of basilar artery, reduced
neurological deficits, brain edema, BBB disruption, and TUNEL
positive cell expression. Same time, we found that the proteins
expression of P53, Bax and Caspase-3 were significantly reduced,
whereas the expression of bcl-2 was up-regulated in Rb1 treatment.
The results of this study suggest that GRb1 could relieve
cerebral vasospasm and potentially provide neuroprotection
in SAH victims. The underlying mechanisms may be partly related
to inhibition of P53 and Bax dependent proapoptosis pathway.
More studies will be needed to confirm these results and determine
its potential as a long-term agent.
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20370652 PubMed - indexed for MEDLINE]
Early Apoptotic Vascular Signaling is Determined by
Sirt1 Through Nuclear Shuttling, Forkhead Trafficking, Bad,
and Mitochondrial Caspase Activation
Jinling Hou, Zhao Zhong Chong, Yan Chen Shang and
Kenneth Maiese
Complications of diabetes mellitus (DM) weigh heavily upon
the endothelium that ultimately affect multiple organ systems.
These concerns call for innovative treatment strategies that
employ molecular pathways responsible for cell survival and
longevity. Here we show in a clinically relevant model of
DM with elevated D-glucose that endothelial cell (EC) SIRT1
is vital for the prevention of early membrane apoptotic phosphatidylserine
externalization and subsequent DNA degradation supported by
studies with modulation of SIRT1 activity and gene knockdown
of SIRT1. Furthermore, during elevated D-glucose
exposure, we show that SIRT1 is sequestered in the cytoplasm
of ECs, but specific activation of SIRT1 shuttles the protein
to the nucleus to allow for cytoprotection. The ability of
SIRT1 to avert apoptosis employs the activation of protein
kinase B (Akt1), the post-translational phosphorylation of
the forkhead member FoxO3a, the blocked trafficking of FoxO3a
to the nucleus, and the inhibition of FoxO3a to initiate a
“pro-apoptotic” program as shown by complimentary
gene knockdown studies of FoxO3a. Vascular apoptotic
oversight by SIRT1 extends to the direct modulation of mitochondrial
membrane permeability, cytochrome c release, Bad activation,
and caspase 1 and 3 activation, since inhibition of SIRT1
activity and gene knockdown of SIRT1 significantly
accentuate cascade progression while SIRT1 activation abrogates
these apoptotic elements. Our work identifies vascular SIRT1
and its control over early apoptotic membrane signaling, Akt1
activation, post-translational modification and trafficking
of FoxO3a, mitochondrial permeability, Bad activation, and
rapid caspase induction as new avenues for the treatment of
vascular complications during DM.
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20334612 PubMed - indexed for MEDLINE]
Contribution of Mast Cells to Cerebral Aneurysm Formation
Ryota Ishibashi, Tomohiro Aoki, Masaki Nishimura, Nobuo
Hashimoto and Susumu Miyamoto
Cerebral aneurysm (CA) has a high prevalence and causes a
fatal subarachnoid hemorrhage. Although CA is a socially important
disease, there are currently no medical treatments for CA,
except for surgical procedures, because the detailed mechanisms
of CA formation remain unclear. From recent studies, we propose
that CA is a chronic inflammatory disease of the arterial
walls and various inflammation-related factors participate
in its pathogenesis. Mast cells are well recognized as major
inflammatory cells related to allergic inflammation. Mast
cells have numerous cytoplasmic granules that contain various
cytokines. Recent studies have revealed that mast cells contribute
to various vascular diseases through degranulation and release
of cytokines. In the present study, we examined the role of
mast cells in the pathogenesis of CA using an experimental
rat model. The number of mast cells was significantly increased
in CA walls during CA formation. Inhibitors of mast cell degranulation
effectively inhibited the size and medial thinning of induced
CA through the inhibition of chronic inflammation, as evaluated
by nuclear factor-kappa B activation, macrophage infiltration,
and the expression of monocyte chemoattractant protein-1,
matrix metalloproteinases (MMPs), and interleukin-1β.
Furthermore, an in vitro study revealed that the
degranulation of mast cells induced the expression and activation
of MMP-2, -9, and inducible nitric oxide synthase in primary
cultured smooth muscle cells from rat intracranial arteries.
These results suggest that mast cells contribute to the pathogenesis
of CA through the induction of inflammation and that inhibitors
of mast cell degranulation can be therapeutic drugs for CA.
[Back to top] [Purchase
Article] [PMID:
20334614 PubMed - indexed for MEDLINE]
Sublethal Total Body Irradiation Leads to Early Cerebellar
Damage and Oxidative Stress
Li Cui, Dwight Pierce, Kim E. Light, Russell B. Melchert,
Qiang Fu, K. Sree Kumar and Martin Hauer-Jensen
The present study aimed at identifying early damage index
in the cerebellum following total body irradiation (TBI).
Adult male CD2F1 mice (n=18) with or without TBI challenge
(8.5 Gy irradiation) were assessed for histology and expression
of selected immunohistochemical markers including malondiadehyde
(MDA), 8-hydroxy-2'-deoxyguanosine (8-OHdG), protein 53 (p53),
vascular endothelial growth factor receptor 2 (VEGF-R2), CD45,
calbindin D-28k (CB-28) and vesicular glutamate transport-2
(VGLUT2) in cerebellar folia II to IV. Compared to sham-controls,
TBI significantly increased vacuolization of the molecular
layer. At high magnification, deformed fiber-like structures
were found along with the empty matrix space. Necrotic Purkinje
cells were identified on 3.5 days after TBI, but not on 1
day. Purkinje cell count was reduced significantly 3.5 days
after TBI. Compared with sham control, overall intensities
of MDA and 8-OHdG immunoreactivities were increased dramatically
on 1 and 3.5 days after TBI. Expression of VEGF-R2 was identified
to be co-localized with 8-OHdG after TBI. This validates microvessel
endothelial damage. The p53 immunoreactivities mainly deposited
in the granular layer and microvessels after TBI and co-localization
of the p53 with the CD45, both which were found within the
microvessels. After TBI, CB28 expression decreased whereas
the VGLUT2 expression increased significantly; Purkinje cells
exhibited a reduced body size and deformity of dendritic arbor,
delineated by CB28 immunoreactivity. Substantial damage to
the cerebellum can be detectable as early as 1- 3.5 days in
adult animals following sublethal TBI. Oxidative stress, inflammatory
response and calcium neurotoxicity-associated mechanisms are
involved in radiation-induced neuronal damage.
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20374198 PubMed - indexed for MEDLINE]
Leptin Reduces Infarct Size in Association with Enhanced
Expression of CB2, TRPV1, SIRT-1 and Leptin Receptor
Yosefa Avraham, Neta Davidi, Moran Porat, David Chernoguz,
Iddo Magen, Lia Vorobeiv, Elliot M. Berry and Ronen
R. Leker
Brain ischemia is associated with detrimental changes in energy
production and utilization. Therefore, we hypothesized that
leptin, an adipokynin hormone protecting against severe energy
depletion, would reduce infarct volume and improve functional
outcome after stroke. Male Sabra mice underwent permanent
middle cerebral artery occlusion (PMCAO) by photothrombosis.
Following initial dose-response and time-window experiments
animals were treated with vehicle or leptin, were examined
daily by a neurological severity score (NSS) and were sacrificed
72 hours after stroke. Infarct volume was determined and the
expression of key genes involved in neuroprotection and survival
including the cannabinoid receptors CB1,
CB2 and TRPV1, SIRT-1, leptin
receptor and Bcl-2 was quantified in the cortex. A separate
group of mice were examined with the neurological severity
scale 1, 24 and 48 hours and 1, 2 and 3 weeks after stroke,
and were killed 3 weeks post stroke to examine metabolic status
in the peri-infarct area. Leptin given at a dose of 1mg/kg
intra-peritoneally 30 minutes after PMCAO significantly improved
neurological disability and reduced infarct volume. Leptin
treatment led to increased expression of CB2
receptor, TRPV1, SIRT-1 and leptin receptor and reduced expression
of CB1 receptor. There was
also a non-significant increase in Bcl-2 gene expression following
leptin administration. These results suggest that leptin may
be used for attenuating ischemic injury after stroke via
induction of an anti-apoptotic state.
[Back to top] [Purchase
Article] [PMID:
20374199 PubMed - indexed for MEDLINE]
CD133 Expressing Pericytes and Relationship to SDF-1
and CXCR4 in Spinal Cord Injury
Ursula Graumann, Marie-Françoise Ritz, Bertha Gutierrez
Rivero and Oliver Hausmann
Compression injury to the spinal cord (SC) results in vascular
changes affecting the severity of the primary damage of the
spinal cord. The recruitment of bone marrow (BM)-derived cells
contribute to revascularization and tissue regeneration in
a wide range of ischemic pathologies. Involvement of these
cells in the vascular repair process has been investigated
in an animal model of spinal cord injury (SCI).
Temporal gene and protein expression of the BM-derived stem
cell markers CD133 and CD34, of the mobilization factor SDF-1
and its receptor CXCR4 were determined following SC compression
injury in rats. CD133 was expressed in uninjured tissue by
cells surrounding arterioles identified as pericytes by co-expression
of α-SMA.
These cells mostly disappeared 2 days after injury but repopulated
the tissue after 2 weeks. CD34 was expressed by endothelial
cells and CD11b+ macrophages/microglia invading the injured
tissue as observed 2 weeks following injury. SDF-1 was induced
in reactive astrocytes and endothelial cells not until 2 weeks
post-SCI.
Comparison of the variation between CD34, CD133, CXCR4, and
SDF-1 revealed a corresponding trend of CD133 with the SDF-1
expression. This study showed that resident microvascular
CD133+ pericytes with presumptive stem cell potential are
sensitive to SCI. Their decline following SCI and the delayed
induction of SDF-1 may contribute to vessel destabilisation
and inefficient revascularization. In addition, none of the
analyzed markers could be assigned clearly to BM-derived cells.
Together, our findings suggest that effective recruitment
of pericytes may serve as a therapeutic option to improve
microcirculation after SCI.
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Article] [PMID:
20438447 PubMed - indexed for MEDLINE]
Small Heat Shock Proteins: Recent Advances in Neuropathy
Liuwang Zeng, Zhiping Hu, Wei Lu, Xiangqi Tang, Jie Zhang,
Ting Li and Binbin Yang
Small heat shock proteins(sHSPs), with a small molecular mass
of 12-43 kDa, are molecular chaperones that protect cells
against stress by assisting them in the correct folding of
denatured proteins and thus prevent aggregation of misfolded
proteins. During the past several years, there has been an
increasing interest in the relationship between sHSPs and
neuropathy. sHSPs have emerged as a particularly potent neuroprotectant
in diverse neurological disorders. Therefor, in this review,
we will focus on the expression of sHSPs in different neurological
disorders, and discuss the recent findings of the biological
implications of sHSPs in physiological and pathological processes
in these diseases. Novel therapeutic strategies aiming at
restoring sHSPs in neuropathy will also be presented.
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