| Current
Neurovascular Research
ISSN: 1567-2026
Current Neurovascular Research
Volume 6, Number 1, February 2009
Contents
ORIGINAL ARTICLES
Secondary Brain Injuries in Thalamus and Hippocampus after
Focal Ischemia Caused by Mild, Transient Extradural Compression
of the Somatosensori Cortex in the Rat Pp.
1-11
Per Holmberg, Sture Liljequist and
Anna Wägner
[Abstract] [Purchase
Article] [PMID:
19355921 PubMed - indexed for MEDLINE]
RNase Therapy Assessed by Magnetic Resonance Imaging
Reduces Cerebral Edema and Infarction Size in Acute Stroke
Pp. 12-19
Maureen Walberer, Marlene Tschernatsch,
Silvia Fischer, Nouha Ritschel, Kai Volk, Carolin Friedrich,
Georg Bachmann, Clemens Mueller, Manfred Kaps, Max Nedelmann,
Franz Blaes, Klaus T. Preissner and Tibo Gerriets
[Abstract] [Purchase
Article] [PMID:
19355922 PubMed - indexed for MEDLINE]
The Forkhead Transcription Factor FOXO3a Controls
Microglial Inflammatory Activation and Eventual Apoptotic
Injury through Caspase 3 Pp. 20-31
Yan Chen Shang, Zhao Zhong Chong, Jinling
Hou and Kenneth Maiese
[Abstract][Purchase
Article] [PMID:
19355923 PubMed - indexed for MEDLINE]
Haptoglobin Phenotype May Alter Endothelial Progenitor
Cell Cluster Formation in Cerebral Small Vessel Disease
Pp. 32-41
Rob P.W. Rouhl, R.J. van Oostenbrugge, J.G.M.C.
Damoiseaux, L.L. Debrus-Palmans, R.O.M.F.I.H. Theunissen,
I.L.H. Knottnerus, J.E.A. Staals, J.R. Delanghe, J.W. Cohen
Tervaert and J. Lodder
[Abstract] [Purchase
Article] [PMID:
19355924 PubMed - indexed for MEDLINE]
Brain-Derived Neurotrophic Factor (BDNF) has Proliferative
Effects on Neural Stem Cells through the Truncated TRK-B Receptor,
MAP Kinase, AKT, and STAT-3 Signaling Pathways Pp.
42-53
Omedul Islam, Tze X. Loo and Klaus
Heese
[Abstract] [Purchase
Article] [PMID:
19355925 PubMed - indexed for MEDLINE]
Fluorogold Induces Persistent Neurological Deficits
and Circling Behavior in Mice Over-Expressing Human Mutant
Tau Pp. 54-61
Zhen He
[Abstract] [Purchase
Article] [PMID:
19355926 PubMed - indexed for MEDLINE]
Use of Telemetry Blood Pressure Transmitters to Measure
Intracranial Pressure (ICP) in Freely Moving Rats Pp.
62-69
Gergely Silasi, Crystal L. MacLellan and
Frederick Colbourne
[Abstract] [Purchase
Article] [PMID:
19355927 PubMed - indexed for MEDLINE]
REVIEW ARTICLE
Resveratrol and Neurodegenerative Diseases:
Activation of SIRT1 as the Potential Pathway towards Neuroprotection
Pp. 70-81
Mercè Pallàs, Gemma Casadesús,
Mark A. Smith, Ana Coto-Montes, Carme Pelegri, Jordi Vilaplana
and Antoni Camins
[Abstract] [Purchase
Article] [PMID:
19355928 PubMed - indexed for MEDLINE]
Abstracts
[Back to top]
[Purchase
Article] [PMID:
19355921 PubMed - indexed for MEDLINE]
Secondary Brain Injuries in Thalamus and Hippocampus
after Focal Ischemia Caused by Mild, Transient Extradural
Compression of the Somatosensori Cortex in the Rat
Per Holmberg, Sture Liljequist and
Anna Wägner
The development and distribution of secondary brain lesions,
subsequent to ischemic stroke, are of considerable clinical
interest but so far only a limited number of studies have
investigated the distribution and development of these secondary
lesions in detail. In this study, we used an animal model
of focal ischemia caused by extradural compression of the
sensorimotor cortex. This paradigm of focal ischemia was shown
to produce a consistent pattern of secondary lesions located
distally from the primary lesion. Functionally the primary
brain lesion produced a transient neurological deficit, which
was evaluated by daily beam walking tests. Morphological changes
were assessed in parallel after the ischemic event using Fluoro-Jade
(FJ) staining as a marker of neuronal cell death. Secondary
brain lesions were observed in the thalamus as well as in
the hippocampus. The first sign of the slowly developing secondary
brain lesions was present on day 3 with subsequent lesions
being identified until day 16 after the primary ischemia.
In addition to the identification of neuronal cell death by
the FJ assays, immunostaining for parvalbumin (PA), a marker
of GABAergic interneurons, revealed a loss of PA-staining
in the pyramidal layer of CA1 on day 3, thus showing a similar
time pattern for loss of PA-staining as for the loss of FJ
stained cells. Based upon our present results, we suggest
that the current animal model of focal ischemia represents
a valuable tool for studies concerning the development of
secondary remote brain lesions and their association to impaired
motor and cognitive functions.
[Back to top] [Purchase
Article] [PMID:
19355922 PubMed - indexed for MEDLINE]
RNase Therapy Assessed by Magnetic Resonance Imaging Reduces
Cerebral Edema and Infarction Size in Acute Stroke
Maureen Walberer, Marlene Tschernatsch,
Silvia Fischer, Nouha Ritschel, Kai Volk, Carolin Friedrich,
Georg Bachmann, Clemens Mueller, Manfred Kaps, Max Nedelmann,
Franz Blaes, Klaus T. Preissner and Tibo Gerriets
Ischemic stroke causes cell necrosis with the exposure
of extracellular ribonucleic acid (RNA) and other intracellular
material. As shown recently, extracellular RNA impaired the
blood-brain-barrier and contributed to vasogenic edema-formation.
Application of ribonuclease 1 (RNase 1) diminished edema-formation
and also reduced lesion volume in experimental stroke. Here
we investigate whether reduction of lesion volume is due to
the reduction of edema or of other neuroprotective means.
Neuroprotective and edema protective effects of RNase 1 pretreatment
were assessed using a temporary middle cerebral artery occlusion
(MCAO) model in rats. Lesion volume was assessed on magnetic
resonance imaging (MRI). T2-relaxation-time and midline-shift
as well as brain water content (wet-dry-method) were measured
to quantify edema formation. The impact of edema formation
on infarct volume was evaluated in craniectomized animals.
Exogenous RNase 1 was well tolerated and reduced edema-formation
and infarct size (26.7% ±
10.7% vs. 41.0% ±
10.3%; p<0.01)
at an optimal dose of 42 μg/kg
as compared to placebo. Craniectomized animals displayed a
comparable edema reduction but no reduction in infarct size.
The present study introduces a hitherto unrecognized mechanism
of ischemic brain damage and a novel neuroprotective approach
towards acute stroke treatment.
[Back to top] [Purchase
Article] [PMID:
19355923 PubMed - indexed for MEDLINE]
The Forkhead Transcription Factor FOXO3a Controls Microglial
Inflammatory Activation and Eventual Apoptotic Injury through
Caspase 3
Yan Chen Shang, Zhao Zhong Chong, Jinling
Hou and Kenneth Maiese
Memory loss and cognitive failure are increasingly being
identified as potential risks with the recognized increase
in life expectancy of the general population. As a result,
the development of novel therapeutic strategies for disorders
such as Alzheimer’s disease have garnered increased
attention. The etiologies that can lead to Alzheimer’s
disease are extremely varied, but a number of therapeutic
options are directed against amyloid-β
peptide and inflammatory cell regulation to prevent or halt
progressive cognitive loss. In particular, inflammatory microglial
cells may have disparate functions that in some scenarios
lead to disability through the removal of functional neurovascular
cells and in other circumstances foster tissue repair. Given
the significance microglial cells hold for neurodegenerative
disorders, we therefore examined the function that amyloid
(Aβ1-42)
has upon the microglial cell line EOC 2 and identified a novel
role for the forkhead transcription factor FoxO3a and caspase
3. Here we show that Aβ1-42
leads to progressive injury and apoptotic cell loss in microglial
cells that involves both early phosphatidylserine (PS) externalization
and late genomic DNA fragmentation over a 24 hour course.
Prior to these injury programs, Aβ1-42
results in the activation and proliferation of microglia as
demonstrated by increased proliferating cell nuclear antigen
(PCNA) expression and bromodeoxyuridine (BrdU) uptake. Both
apoptotic injury as well as the prior activation and proliferation
of microglial cells relies upon the presence of FoxO3a, since
specific gene silencing of FoxO3a promotes microglial cell
protection and prevents the early activation and proliferation
of these cells. Furthermore, Aβ1-42
exposure maintained FoxO3a in an unphosphorylated “active”
state and facilitated the cellular trafficking of FoxO3a from
the cytoplasm to the cell nucleus to potentially lead to “pro-apoptotic”
programs by this transcription factor. One apoptotic program
in particular appears to involve the activation of caspase
3, since loss of FoxO3a through gene silencing prevents the
induction of caspase 3 activity by Aβ1-42.
[Back to top] [Purchase
Article] [PMID:
19355924 PubMed - indexed for MEDLINE]
Haptoglobin Phenotype May Alter Endothelial Progenitor Cell
Cluster Formation in Cerebral Small Vessel Disease
Rob P.W. Rouhl, R.J. van Oostenbrugge, J.G.M.C.
Damoiseaux, L.L. Debrus-Palmans, R.O.M.F.I.H. Theunissen,
I.L.H. Knottnerus, J.E.A. Staals, J.R. Delanghe, J.W. Cohen
Tervaert and J. Lodder
Cerebral small vessel disease results in silent ischemic
lesions (SIL) among which is leukoaraiosis. In this process,
endothelial damage is probably involved. Endothelial progenitor
cells (EPC), are involved in endothelial repair. By restoring
the damaged endothelium, EPC could mitigate SIL and cerebral
small vessel disease. Haptoglobin 1-1, one of three phenotypes
of haptoglobin, relates to SIL and may therefore attenuate
the endothelial repair by EPC. Our aim was to quantify EPC
number and function and to assess haptoglobin phenotype and
its effect on EPC function in patients with a high prevalence
of SIL: lacunar stroke patients. We assessed EPC In 42 lacunar
stroke patients and 18 controls by flow cytometry and culture
with fetal calf serum, patient and control serum. We determined
haptoglobin phenotype and cultured EPC with the three different
haptoglobin phenotypes. We found that EPC cluster counts were
lower in patients (96.9 clusters/well ±
83.4 (mean ±
SD)), especially in those with SIL (85.0 ±
64.3), than in controls (174.4 ±
112.2). Cluster formation was inhibited by patient serum,
especially by SIL patient serum, but not by control serum.
Patients with haptoglobin 1-1 had less clusters in culture,
and when haptoglobin 1-1 was added to EPC cultures, cluster
numbers were lower than with the other haptoglobin phenotypes.
We conclude that lacunar stroke patients, especially those
with SIL, have impaired EPC cluster formation, which may point
at decreased endothelial repair potential. The haptoglobin
1-1 phenotype is likely a causative factor in this impairment.
[Back to top] [Purchase
Article] [PMID:
19355925 PubMed - indexed for MEDLINE]
Brain-Derived Neurotrophic Factor (BDNF) has Proliferative
Effects on Neural Stem Cells through the Truncated TRK-B Receptor,
MAP Kinase, AKT, and STAT-3 Signaling Pathways
Omedul Islam, Tze X. Loo and Klaus
Heese
Neurospheres can be generated from the mouse fetal forebrain
by exposing multipotent neural stem cells (NSCs) to epidermal
growth factor (EGF). In the presence of EGF, NSCs can proliferate
continuously while retaining the potential to differentiate
into neurons, astrocytes and oligodendrocytes. We examined
the expression pattern of the neurotrophin (NT) receptors
tropomysin-related kinase (TRK)-A, TRK-B, TRK-C and p75 neurotrophin
receptor (p75NTR) in NSCs
and the corresponding lineage cells. Furthermore, we analyzed
the action of the NT Brain-Derived Neurotrophic Factor (BDNF)
on NSCs’ behavior. The effects of BDNF on NSC proliferation
and differentiation were examined together with the signaling
pathways by which BDNF receptors transduce signaling effects.
We found that all the known NT receptors, including the truncated
isoforms of TRK-B (t-TRK-B) and TRK-C (t-TRK-C), were expressed
by Nestin-positive cells within the neurosphere. Proliferation
was enhanced in Nestin-positive and BrdU-positive cells in
the presence of BDNF. In particular, we show that t-TRK-B
was abundantly expressed in NSCs and the corresponding differentiated
glia cells while full length TRK-B (fl-TRK-B) was expressed
in fully differentiated post-mitotic neurons such as the neuronal
cells of the newborn mouse cortex, suggesting that BDNF may
exert its proliferative effects on NSCs through the t-TRK-B
receptor. Finally, we analyzed the cell fates of NSCs differentiated
with BDNF in the absence of EGF and we demonstrate that BDNF
stimulated the formation of differentiated cell types in different
proportions through the MAP kinase, AKT and STAT-3 signaling
pathways. Thus, the in-vivo regulation of neurogenesis
may be mediated by the summation of signals from the BDNF
receptors, in particular the t-TRK-B receptor, regulating
physiological fates as diverse as normal neural replacement,
excessive neural loss, or tumor development.
[Back to top] [Purchase
Article] [PMID:
19355926 PubMed - indexed for MEDLINE]
Fluorogold Induces Persistent Neurological Deficits and Circling
Behavior in Mice Over-Expressing Human Mutant Tau
Zhen He
An increasing number of applications use nanospecie-fluorescent
labeling technology; however, no established guidelines are
available to warrant their safety for potential clinical use.
Here, rTg4510 transgenic mice and their littermate controls
were injected with fluorogold, a nanospecie tracer, or phosphate
buffered saline (PBS) targeted to the right amygdala. No significant
abnormal behavior was detected in any mice injected with PBS.
After fluorogold injection, however, rTg4510 mice displayed
persistent left-sided neurological deficits and left circling
behavior for up to 14 days post-injection, while control mice
demonstrated a transient syndrome. Mortality occurred only
in rTg4510 mice and statistically significant differences
appeared independent of age. An immunofluorescent study revealed
TUNEL positive cells that were heavily and extensively distributed
in the periamygdalar region that overlapped with the fluorogold
deposit region in rTg4510 mice, whereas control mice showed
only sporadic distribution of TUNEL-positive cells. Colocalization
of TUNEL and caspase-3 active peptide immunoreactivity was
identified in a subset of the cells, indicating an involvement
of caspase-dependent apoptotic mechanisms. In conclusion,
fluorogold induces damage in the central nervous system most
noticeably in mice over-expressing human mutant tau.
[Back to top] [Purchase
Article] [PMID:
19355927 PubMed - indexed for MEDLINE]
Use of Telemetry Blood Pressure Transmitters to Measure
Intracranial Pressure (ICP) in Freely Moving Rats
Gergely Silasi, Crystal L. MacLellan and
Frederick Colbourne
Stroke and traumatic brain injuries often lead to cerebral
edema and persistent elevations in intracranial pressure (ICP)
that can be life threatening. Thus, rodent models would benefit
from a simple and reliable method to measure ICP in awake,
mobile animals. Up to now most techniques have been limited
to anesthetized or immobile animals, which is not practical
for following the prolonged elevations in ICP that follow
stroke and traumatic brain injury. With an initial set of
data, we describe a simple method that uses blood pressure
telemetry sensors, which are commercially available (Data
Sciences Int.) to measure ICP in freely moving rats for several
days following implantation. Basically, an epidural cannula
is secured to the skull and connected to the catheter of the
telemetry probe, which is then secured inside a protective
plastic shield on the skull. We confirm the sensitivity of
our measurements by experimentally modifying ICP by either
the Valsalva maneuver (abdominal compression) or a large ischemic
brain injury. The Valsalva maneuver caused a small brief spike
in ICP (lasting about 2-3 sec), whereas a transient middle
cerebral artery occlusion substantially increased ICP (up
to 50 mmHg) for approximately 3 days post-surgery. In summary,
the current method allows for ICP to be continuously monitored
in rats for several days, and thus is suitable for studies
investigating mechanisms of raised ICP and in testing experimental
treatments that mitigate it.
[Back to top] [Purchase
Article] [PMID: 19355928 PubMed - indexed for MEDLINE]
Resveratrol and Neurodegenerative Diseases: Activation of
SIRT1 as the Potential Pathway towards Neuroprotection
Mercè Pallàs, Gemma Casadesús,
Mark A. Smith, Ana Coto-Montes, Carme Pelegri, Jordi Vilaplana
and Antoni Camins
One of the current problems in medicine research is the
development of safe drugs for the treatment of neurological
disorders. Furthermore, there is a close relationship between
the process of aging and the appearance of neurological disorders,
particularly Parkinson’s disease and Alzheimer’s
disease. Therefore, an ideal compound would have two characteristics:
neuroprotective action and an anti-aging effect. The natural
compound resveratrol is a suitable candidate for this purpose
due to its low toxicity and antioxidant properties. In addition,
recent research has shown that it has an anti-aging effect
in rat, yeast, Caenorhabditis elegans, and Drosophila,
although the mechanism involved in this process remains to
be clarified. One hypothesis is that by activating Sirtuin
1, resveratrol modulates the activity of numerous proteins,
including peroxisome proliferator-activated receptor coactivator-1α
(PGC-1 alpha), the FOXO family, Akt (protein kinase B) and
nuclear factor-κβ
(NFκβ).
This review summarises recent research on the molecular mechanisms
through which resveratrol might exert its therapeutic effects
via the interaction with Sirtuin 1, as well as other
targets. In addition, we discuss the possibility of using
resveratrol in the treatment of neurodegenerative diseases.
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