| Current
Neurovascular Research
ISSN: 1567-2026
Current Neurovascular Research
Volume 6, Number 4, November 2009
Contents
ORIGINAL ARTICLES
Oxidative Stress-Induced Necrotic Cell Death via
Mitochondira-Dependent Burst of Reactive Oxygen Species
Pp. 213-222
Kyungsun Choi, Jinho Kim, Gyung W. Kim and Chulhee
Choi
[Abstract] [Full
Text Article] [PMID:
19534723 PubMed - indexed for MEDLINE]
FoxO3a Governs Early Microglial Proliferation and
Employs Mitochondrial Depolarization with Caspase 3, 8, and
9 Cleavage During Oxidant Induced Apoptosis Pp. 223-238
Yan Chen Shang, Zhao Zhong Chong, Jinling Hou
and Kenneth Maiese
[Abstract] [Full
Text Article] [PMID:
19534723 PubMed - indexed for MEDLINE]
Spatial Correlations between the Vacuolation, Prion Protein
(PrPsc) Deposits and the
Cerebral Blood Vessels in Sporadic Creutzfeldt-Jakob Disease
Pp. 239-245
Richard A. Armstrong
[Abstract] [Full
Text Article][PMID:
19534723 PubMed - indexed for MEDLINE]
Role of Endogenous Granulocyte-Macrophage Colony Stimulating
Factor Following Stroke and Relationship to Neurological Outcome
Pp. 246-251
Miriam Navarro-Sobrino, Anna Rosell, Anna Penalba,
Marc Ribó, José Alvarez-Sabín, Israel
Fernández-Cadenas and Joan Montaner
[Abstract] [Full
Text Article] [PMID:
19534723 PubMed - indexed for MEDLINE]
The Immunosuppressive Agent FK506 Prevents Subperineurial
Degeneration and Demyelination on Ultrastructural and Functional
Analysis† Pp.
252-258
Arzu Utuk, Levent Sarikcioglu, Bahadir M. Demirel
and Necdet Demir
[Abstract] [Full
Text Article] [PMID:
19534723 PubMed - indexed for MEDLINE]
Chronic Methylphenidate-Effects Over
Circadian Cycle of Young and Adult Rats Submitted to Open-Field
and Object Recognition Tests Pp. 259-266
Karin M. Gomes, Renan P. Souza, Samira S. Valvassori,
Gislaine Z. Réus, Cecília G. Inácio,
Márcio R. Martins, Clarissa M. Comim and João
Quevedo
[Abstract] [Full
Text Article] [PMID:
19534723 PubMed - indexed for MEDLINE]
Preservation of Cellular Glutathione Status and Mitochondrial
Membrane Potential by N-Acetylcysteine and Insulin
Sensitizers Prevent Carbonyl Stress-Induced Human Brain Endothelial
Cell Apoptosis Pp. 267-278
Masahiro Okouchi, Naotsuka Okayama and Tak
Yee Aw
[Abstract] [Full
Text Article] [PMID:
19534723 PubMed - indexed for MEDLINE]
Cortical and Putamen Age-Related Changes in the Microvessel
Density and Astrocyte Deficiency in Spontaneously Hypertensive
and Stroke-Prone Spontaneously Hypertensive Rats Pp.
279-287
Marie-Françoise Ritz, Felix Fluri, Stefan
T. Engelter, Nicole Schaeren-Wiemers and Philippe
A. Lyrer
[Abstract] [Full
Text Article] [PMID:
19534723 PubMed - indexed for MEDLINE]
Abstracts
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[Full
Text Article] [PMID:
19534723 PubMed - indexed for MEDLINE]
Oxidative Stress-Induced Necrotic Cell Death via
Mitochondira-Dependent Burst of Reactive Oxygen Species
Kyungsun Choi, Jinho Kim, Gyung W. Kim and Chulhee
Choi
Oxidative stress is deeply involved in various brain
diseases, including neurodegenerative diseases, stroke, and
ischemia/reperfusion injury. Mitochondria are thought to be
the target and source of oxidative stress. We investigated
the role of mitochondria in oxidative stress-induced necrotic
neuronal cell death in a neuroblastoma cell line and a mouse
model of middle cerebral artery occlusion. The exogenous administration
of hydrogen peroxide was used to study the role of oxidative
stress on neuronal cell survival and mitochondrial function
in vitro. Hydrogen peroxide induced non-apoptotic neuronal
cell death in a c-Jun N-terminal kinase- and poly(ADP-ribosyl)
polymerase-dependent manner. Unexpectedly, hydrogen peroxide
treatment induced transient hyperpolarization of the mitochondrial
membrane potential and a subsequent delayed burst of endogenous
reactive oxygen species (ROS). The inhibition of mitochondrial
hyperpolarization by diphenylene iodonium or rotenone, potent
inhibitors of mitochondrial respiratory chain complex I, resulted
in reduced ROS production and subsequent neuronal cell death
in vitro and in vivo. The inhibition of
mitochondrial hyperpolarization can protect neuronal cells
from oxidative stress-induced necrotic cell death, suggesting
a novel method of therapeutic intervention in oxidative stress-induced
neurological disease.
[Back to top] [Full
Text Article] [PMID:
19534723 PubMed - indexed for MEDLINE]
FoxO3a Governs Early Microglial Proliferation and Employs
Mitochondrial Depolarization with Caspase 3, 8, and 9 Cleavage
During Oxidant Induced Apoptosis
Yan Chen Shang, Zhao Zhong Chong, Jinling Hou
and Kenneth Maiese
Microglia of the central nervous system have a dual role
in the ability to influence the survival of neighboring cells.
During inflammatory cell activation, microglia can lead to
the disposal of toxic cellular products and permit tissue
regeneration, but microglia also may lead to cellular destruction
with phagocytic removal. For these reasons, it is essential
to elucidate not only the underlying pathways that control
microglial activation and proliferation, but also the factors
that determine microglial survival. In this regard, we investigated
in the EOC 2 microglial cell line with an oxygen-glucose deprivation
(OGD) injury model of oxidative stress the role of the “O”
class forkhead transcription factor FoxO3a that in some scenarios
is closely linked to immune system function. We demonstrate
that FoxO3a is a necessary element in the control of early
and late apoptotic injury programs that involve membrane phosphatidylserine
externalization and nuclear DNA degradation, since transient
knockdown of FoxO3a in microglia preserves cellular
survival 24 hours following OGD exposure. However, prior to
the onset of apoptotic injury, FoxO3a facilitates the activation
and proliferation of microglia as early as 3 hours following
OGD exposure that occurs in conjunction with the trafficking
of the unphosphorylated and active post-translational form
of FoxO3a from the cytoplasm to the cell nucleus. FoxO3a also
can modulate apoptotic mitochondrial signal transduction pathways
in microglia, since transient knockdown of FoxO3a
prevents mitochondrial membrane depolarization as well as
the release of cytochrome c during OGD. Control of this apoptotic
cascade also extends to progressive caspase activation as
early as 1 hour following OGD exposure. The presence of FoxO3a
is necessary for the expression of cleaved (active) caspase
3, 8, and 9, since loss of FoxO3a abrogates the induction
of caspase activity. Interestingly, elimination of FoxO3a
reduced caspase 9 activity to a lesser extent than that noted
with caspase 3 and 8 activities, suggesting that FoxO3a in
relation to caspase 9 may be more reliant upon other signal
transduction pathways potentially independent from caspase
3 and 8.
[Back to top] [Full
Text Article] [PMID:
19534723 PubMed - indexed for MEDLINE]
Spatial Correlations between the Vacuolation, Prion Protein
(PrPsc) Deposits and the
Cerebral Blood Vessels in Sporadic Creutzfeldt-Jakob Disease
Richard A. Armstrong
In the variant form of Creutzfeldt-Jakob disease (vCJD),
‘florid’ deposits of the protease resistant form
of prion protein (PrPsc)
were aggregated around the cerebral blood vessels suggesting
the possibility that prions may spread into the brain via
the cerebral micro circulation. The objective of the present
study was to determine whether the pathology was spatially
related to blood vessels in cases of sporadic CJD (sCJD),
a disease without an iatrogenic etiology, and therefore, less
likely to be caused by hematogenous spread. Hence, the spatial
correlations between the vacuolation (‘spongiform change’),
PrPsc deposits, and the blood
vessels were studied in immunolabeled sections of the cerebral
cortex and cerebellum in eleven cases of the common M/M1 subtype
of sCJD. Both the vacuolation and the PrPsc
deposits were spatially correlated with the blood vessels;
the PrPsc deposits being
more focally distributed around the vessels than the vacuoles.
The frequency of positive spatial correlations was similar
in the different gyri of the cerebral cortex, in the upper
and lower cortical laminae, and in the molecular layer of
the cerebellum. It is hypothesised that the spatial correlation
is attributable to factors associated with the blood vessels
which promote the aggregation of PrPsc
to form deposits rather than representing the hematogenous
spread of the disease. The aggregated form of PrPsc
then enhances cell death and may encourages the development
of vacuolation in the vicinity of the blood vessels.
[Back to top] [Full
Text Article] [PMID:
19534723 PubMed - indexed for MEDLINE]
Role of Endogenous Granulocyte-Macrophage Colony Stimulating
Factor Following Stroke and Relationship to Neurological Outcome
Miriam Navarro-Sobrino, Anna Rosell, Anna Penalba,
Marc Ribó, José Alvarez-Sabín, Israel
Fernández-Cadenas and Joan Montaner
Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF)
is a proinflammatory cytokine with neuroprotective and angiogenic
properties demonstrated in animal models of cerebral ischemia
but its role in human ischemic stroke is still unknown. Thus,
our aim is to determine human GM-CSF plasma level in control
subjects and stroke patients and its relationship to clinical
outcome. Forty-three patients with middle cerebral artery
occlusion who received thrombolytic therapy within the first
three hours of stroke onset and nineteen healthy controls
were included. Blood samples were drawn before tissue plasminogen
activator (t-PA) treatment. In a group of thirteen strokes
blood samples were also obtained one hour after t-PA treatment,
at 24 hours of symptoms onset, at discharge and at three months.
GM-CSF levels were determined by enzyme-linked immunosorbent
assay (ELISA). Stroke severity and neurological outcome were
assessed by National Institute of Health Stroke Scale (NIHSS)
and functional outcome was scored by modified Rankin Scale
(mRS) at 3 months. Baseline GM-CSF level was significantly
higher in stroke patients than in healthy controls (17.8 pg/ml
vs. 12.8 pg/ml); p<0.0001 and was positively correlated
with NIHSS score at 12 hours (R=0.3, p=0.03). No association
was detected with functional status at three months measured
by mRS. Temporary profile of GM-CSF level in stroke patients
gradually decreases from admission to three months. Higher
plasma endogenous GM-CSF level is found in stroke patients
compared to controls. However, no relation was found with
a better outcome. Further research is necessary for elucidating
the role of GM-CSF in ischemic stroke.
[Back to top] [Full
Text Article] [PMID:
19534723 PubMed - indexed for MEDLINE]
The Immunosuppressive Agent FK506 Prevents Subperineurial
Degeneration and Demyelination on Ultrastructural and Functional
Analysis†
Arzu Utuk, Levent Sarikcioglu, Bahadir M. Demirel
and Necdet Demir
Several kinds of injury models, such as crush, transection
and graft repair have been well studied in terms of neuroprotective
effect of FK506. However, definitive experimental studies
are lacking on focal degeneration or ischemia. In the present
study, our goal was to investigate the effect of FK506 on
functional recovery of the sciatic nerve after focal ischemia,
produced by stripping of the epineurial vessels. A total number
of 48 Wistar rats were used for this purpose and divided into
four groups (control, sham-operated, FK506-treated, and Vehicle-treated).
Sciatic nerves were approached by femoral and gluteal muscle
splitting. Then, epineurial vessels around the sciatic nerve
were stripped in the FK506-treated and Vehicle-treated groups.
After operation, 5mg/kg/day FK506 administration was initiated
by subcutaneous injection until animal sacrifice. The same
volume of saline was administrated to the vehicle-treated
group. The functional and sensory recoveries were tested by
walking pattern analysis and pinch test in every postoperative
week. The animals were sacrificed in the end of the fourth
postoperative week and sciatic nerve samples were harvested
and processed for electron microscopic evaluation. Our data
revealed that FK506 administration showed beneficial effect
on subperineurial degeneration/demyelinization from functional,
sensorial, and ultrastructural points of view. The sciatic
nerve samples in the FK506-treated group had several remyelinated
fibers compared to the vehicle-treated group. Our literature
searches revealed that FK506 administration has not, to our
knowledge, been studied in focal ischemic degeneration produced
by stripping of the epineurial vessels.
[Back to top] [Full
Text Article] [PMID:
19534723 PubMed - indexed for MEDLINE]
Chronic Methylphenidate-Effects Over Circadian Cycle of Young
and Adult Rats Submitted to Open-Field and Object Recognition
Tests
Karin M. Gomes, Renan P. Souza, Samira S. Valvassori,
Gislaine Z. Réus, Cecília G. Inácio,
Márcio R. Martins, Clarissa M. Comim and João
Quevedo
In this study age-, circadian rhythm- and methylphenidate
administration- effect on open field habituation and object
recognition were analyzed. Young and adult male Wistar rats
were treated with saline or methylphenidate 2.0mg/kg for 28
days. Experiments were performed during the light and the
dark cycle. Locomotor activity was significantly altered by
circadian cycle and methylphenidate treatment during the training
session and by drug treatment during the testing session.
Exploratory activity was significantly modulated by age during
the training session and by age and drug treatment during
the testing session. Object recognition memory was altered
by cycle at the training session; by age 1.5 h later and by
cycle and age 24 h after the training session. These results
show that methylphenidate treatment was the major modulator
factor on open-field test while cycle and age had an important
effect on object recognition experiment.
[Back to top] [Full
Text Article] [PMID:
19534723 PubMed - indexed for MEDLINE]
Preservation of Cellular Glutathione
Status and Mitochondrial Membrane Potential by N-Acetylcysteine
and Insulin Sensitizers Prevent Carbonyl Stress-Induced Human
Brain Endothelial Cell Apoptosis
Masahiro Okouchi, Naotsuka Okayama and Tak
Yee Aw
Oxidative stress-induced cerebral endothelial cell dysfunction
is associated with cerebral microvascular complication of
primary diabetic encephaolopathy, a neurodegenerative disorder
of long-standing diabetes, but the injury mechanisms are poorly
understood. This study sought to determine the contribution
of carbonyl (methylglyoxal, MG) stress to human brain endothelial
cell (IHEC) apoptosis, the relationship to cellular redox
status and mitochondrial membrane potential, and the protection
by thiol antioxidant and insulin sensitizers. MG exposure
induced IHEC apoptosis in association with perturbed cellular
glutathione (GSH) redox status, decreased mitochondrial membrane
potential (ΔΨm),
activation of caspase-9 and -3, and cleavage of polyADP-ribose
polymerase. Insulin sensitizers such as biguanides or AMP-activated
protein kinase activator, but not glitazones, afforded cytoprotection
through preventing ΔΨm
collapse and activation of caspase-9 that was independent
of cellular GSH. Similarly, cyclosporine A prevented ΔΨm
collapse, while N-acetylcysteine (NAC) mediated the
recovery of cellular GSH redox balance that secondarily preserved
ΔΨm.
Collectively, these results provide mechanistic insights into
the role of GSH redox status and mitochondrial potential in
carbonyl stress-induced apoptosis of brain endothelial cells,
with implications for cerebral microvascular complications
associated with primary diabetic encephalopathy. The findings
that thiol antioxidant and insulin sensitizers afforded cytoprotection
suggest potential therapeutic approaches.
[Back to top] [Full
Text Article] [PMID:
19534723 PubMed - indexed for MEDLINE]
Cortical and Putamen Age-Related Changes in the Microvessel
Density and Astrocyte Deficiency in Spontaneously Hypertensive
and Stroke-Prone Spontaneously Hypertensive Rats
Marie-Françoise Ritz, Felix Fluri, Stefan
T. Engelter, Nicole Schaeren-Wiemers and Philippe
A. Lyrer
Cerebral small vessel disease (SVD) is a major contributor
to dementia in the elderly, and hypertension represents a
major cause for developing the disease. However, little is
known about its development and progression. Modifications
of large cerebral arteries due hypertension are thought to
participate to the development of small ischemic infarcts,
but the status of the small vessels before the establishment
of hypertension is not well defined. Using spontaneously hypertensive
rats (SHR) and stroke-prone SHR (SP-SHR) as a models for SVD,
we analysed the effect of hypertension on the microvasculature
in the cortex and putamen, and on its relationship with astrocytes
in animals aged 2 to 9 months. Compared with the normotensive
Wistar-Kyoto rats (WKY), the densities of the collagen type
IV-positive capillaries were significantly higher in both
brain areas of young SHR and SP-SHR. In contrast, the expression
of the astrocytic marker GFAP was significantly lower in these
animals, whereas astrogliosis was observed after 6 months
in their cortex only. To investigate if chronic hypoxia occurs
due to the lower number of astrocytes in young SHR and SP-SHR,
we evaluated the levels of HIF-1α
in both brain regions. The accumulation of HIF-1α
was not observed at the youngest ages, but was apparent
in neurons of 9-month-old SHR and SP-SHR. Our results indicate
that the brains of young SHR and SP-SHR rats show evidence
of cellular imbalance between microvessels and astrocytes
at the neurovascular unit that may lead to their higher vulnerability
to hypoxic events at older ages.
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