| Current
Neurovascular Research
ISSN: 1567-2026
Current Neurovascular Research
Volume 3, Number 2, May 2006
Contents
Compromise and Care of the Brain's Compartments: The Quintessence
of the Neurovascular Unit Pp. 79-80
K. Maiese
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ORIGINAL ARTICLE
Endothelin-1 Impairs Retrograde Axonal Transport and
Leads to Axonal Injury in Rat Optic Nerve Pp. 81-88
T. Taniguchi, M. Shimazawa, M. Sasaoka, A. Shimazaki,
and H. Hara
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Article]
Sigma Receptor Activation Reduces Infarct
Size at 24 hours after Permanent Middle Cerebral Artery Occlusion
in Rats Pp. 89-98
C.T. Ajmo Jr., D.O.L. Vernon, L. Collier, K.R.
Pennypacker and J. Cuevas
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Endothelial Colony Forming Capacity is Related to
C-reactive Protein Levels in Healthy Subjects Pp.
99-106
M.M. Ciulla, A. Giorgetti, I. Silvestris, M.
Cortiana, E. Montelatici, R. Paliotti, G.A. Annoni, A.V. Fiore,
R. Giordano, F. De Marco, F. Magrini, P. Rebulla, A. Cortelezzi
and L. Lazzari
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Group I Metabotropic Receptor Neuroprotection Requires
Akt and its Substrates that Govern FOXO3a, Bim, and β-catenin
During Oxidative Stress Pp. 107-117
Z.Z. Chong, F. Li and K. Maiese
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REVIEW ARTICLES
Cerebral Ischemia and Angiogenesis Pp. 119-129
T. Hayashi, K. Deguchi, S. Nagotani, H. Zhang, Y. Sehara,
A. Tsuchiya and K. Abe
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Article]
Neurovascular Mechanisms of Hypertension in Pregnancy
Pp. 131-148
A.K. Stennett and R.A. Khalil
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Article]
Autoantibodies Associated with Psychiatric Disorders
Pp. 149-157
P. Margutti, F. Delunardo and E. Ortona
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Article]
Vascular Changes of the Retina and Choroid in Systemic
Lupus Erythematosus: Pathology and Pathogenesis Pp.
159-168
T.C. Nag and S. Wadhwa
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Abstracts
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Compromise and Care of the Brain's Compartments:
The Quintessence of the Neurovascular Unit
K. Maiese
During the 17th century, the human body began to be viewed
as a system of subunits and independent compartments. This
eventually led to the first human anatomical descriptions
that mapped the body into different organs and tissues. As
a result of this "subunit" or "compartment"
theory, the Latin term herniation was employed to
describe the protrusion of a portion of an organ or tissue
through an abnormal passage.
In respect to the central nervous system, brain herniation
can result from either supratentorial or subtentorial lesions.
Supratentorial masses, such as those that result from lobar
hemorrhage, subsequently yield shifts in the brain architecture
that can be described as either cingulate, central, or uncal
in nature. Cingulate herniation refers to the displacement
of the cingulate gyrus under the falx cerebri with subsequent
compression of the internal cerebral vein. Downward displacement
of the hemisphere with compression of the diencephalon and
midbrain through the tentorial notch results in central herniation.
Lesions of the frontal, parietal, and occipital lobes can
initially precipitate cingulate herniation that progresses
to central herniation. The third possibility for brain herniation,
known as uncal herniation, involves shift of the temporal
lobe, uncus, and hippocampal gyrus toward the midline with
compression of the adjacent midbrain. During this process,
the ipsilateral third cranial nerve and the posterior cerebral
artery are compressed by the uncus and edge of the tentorium.
This scenario can result in the well described "blown
pupil" that is unilateral, dilated, and fixed, suggesting
damage to parasympathetic fibers of the external portion of
the third cranial nerve.
Obviously, patients with elevated intracranial pressure resulting
in cerebral herniation require rapid care to prevent permanent
damage to the critical "compartments" of the brain's
neurovascular unit that consists of neuronal, vascular, and
inflammatory cells. The approach is multidisciplinary that
begins with a detailed examination of the patient and culminates
with several treatment modalities that can involve hyperventilation,
fluid restriction, blood pressure control, surgery, and drug
therapy that may require osmotic agents, steroids, or barbiturates
as indicated. Yet, the availability of true neuroprotective
agents to preserve both neuronal and vascular cell integrity
is severely limited and successful future development for
effective therapies relies directly upon the knowledge of
the cellular pathways that impact upon the brain's neurovascular
unit.
In this issue of Current Neurovascular Research,
both original and review articles delve into novel cellular
pathways that can integrate the function and survival of the
neuronal, vascular, and inflammatory components of the neurovascular
unit. With our initial article, Taniguchi et al.
examine the hypothesis that loss of retinal ganglion cells
that can occur during open angle glaucoma may be the result
of disturbances in blood flow rather than raised intraocular
pressure alone. The authors employ the vasoactive peptide
endothelin-1 that is a product of vascular endothelial cells
and elegantly demonstrate that intravitreous injection of
endothelin-1 in progressive concentrations can lead to the
significant constriction of retinal vessels, decrease the
retrograde axonal transport in retinal ganglion cells, and
lead to histological optic nerve damage. Given that endothelin-1
and its receptors are present in the retina and optic nerve
pathways, their work provides fresh evidence for the intricate
relationship between neuronal and vascular cells that can
impact both normal physiology and disease processes in the
nervous system.
However, it appears that the neurovascular unit requires the
integrity of each of its components, or "sub-compartments",
that involve neuronal, vascular, and inflammatory cells to
effectively prevent the injury of an organism. For example,
Ajmo et al. investigate the neurovascular unit in
an experimental model of focal cerebral ischemia. The authors
inhibit both sigma-1 and sigma-2 receptor activation following
the onset of middle cerebral artery occlusion and show that
modulation of sigma receptor activation increases neuronal
survival twenty-four hours after the initial insult. These
results suggest high clinical relevance for the treatment
of patients with stroke. Another aspect of this work that
is equally important is the recognition that protection with
sigma receptor activation relies strongly upon the complete
integrity of the neurovascular unit to protect neuronal cells,
since these investigators observed that neuronal protection
with blockade of sigma receptors necessitates modulation of
a post-stroke inflammatory response by decreasing the presence
of reactive astrocytes and activated microglia. Our next article
further supports the premise that more than one component
of the neurovascular unit, namely vascular endothelial cells,
plays a role in the reparative processes of the brain. In
a clinical study that examines peripheral blood endothelial
progenitor cells (EPCs) in healthy subjects, Ciulla et
al. illustrate the presence of circulating EPCs that
are associated with serum levels of high sensitivity C-reactive
protein and vascular endothelial growth factor. Although the
study focused on healthy subjects and additional work is required
to exclude potential underlying inflammatory disease processes,
EPCs have been reported to be essential for tissue repair
and angiogenesis during vascular injury and they can serve
as a marker for these processes. The clinical implications
of the work suggest that the presence of high sensitivity
C-reactive protein, vascular endothelial growth factor, and
EPCs in normal subjects are necessary for disease prevention
throughout the body to actively generate and maintain vascular
endothelial cell integrity. On the flip side of these studies
is the ability of neuronal cells in the neurovascular unit
to oversee protection within their own subcellular environment.
To this end, Chong et al. provide insight into some of these
potential mechanisms in their work that examines the protective
capacity of the metabotropic glutamate system. They show that
during activation of group I metabotropic glutamate receptors,
central "anti-apoptotic" pathways involving the
protein kinase B family member Akt1 orchestrate the activity
of a series of cellular mechanisms that require inhibition
of the Forkhead transcription factor FOXO3a, down-regulation
of Bim expression, and the intracellular trafficking of β-catenin
from the neuronal cytoplasm to the nucleus to provide robust
neuroprotection against oxidative stress within the sole boundaries
of the neuronal cell.
Our review articles in this issue of Current Neurovascular
Research offer a broader perspective on the neurovascular
unit for a range of disease processes involving the nervous
system during stroke, pregnancy, psychiatric illness, and
immune mediated disease. Given recent reports of the potential
of progenitor stem cells to alleviate clinical conditions
such as stroke that may require new vessel formation, Hayashi
et al. outline for us the molecular mediators of angiogenesis
during cerebral ischemic injury. The authors describe a number
of factors that become essential to maintain the function
of the neurovascular unit that involve preservation of endothelial
cell integrity, promotion of endothelial cell migration, and
protection of the vascular extracellular matrix. In our next
article, Stennett and Khalil provide an interesting perspective
on neuronal, vascular, and inflammatory cell compromise in
the neurovascular unit that can occur during the hypertensive
complications of pregnancy. The authors describe for us the
multifaceted processes that involve placental ischemia, circulating
cytokines, reactive oxygen species, and vasoactive substance
that can ultimately impair nervous system function. Margutti
et al. extend our knowledge of the neurovascular
unit into disease mechanisms associated with psychiatric disorders.
Their work initially points to the role of autoantibodies
during well documented conditions such as systemic lupus erythematosus
and autoimmune thyroid disease. The authors expand this work
with a fascinating discussion of autoantibodies that can affect
broad regions of the central nervous system and the potential
involvement of these autoantibodies in diseases such as schizophrenia,
autism, and substance abuse. Nag and Wadhwa further the discussion
of immune mediated disease processes in the nervous system
with the role of systemic lupus erythematosus during ocular
disease. The authors focus upon the vascular changes in the
retina and the choroid during systemic lupus erythematosus,
while outlining essential aspects of the neurovascular unit
that involve immune complex deposition. They argue for a multi-level
therapeutic approach that recognizes neuronal, vascular, and
inflammatory components of the disease.
In essence, these studies conclude nicely for us in this issue
of Current Neurovascular Research the significant
role the neurovascular unit wields during normal physiological
function of the nervous system as well as during the development
of neurodegenerative disorders. As we look back to the 17th
century, the observation that the human body can be considered
as an integrated group of functional, but independent compartments
has served us well as we seek to understand the complexities
of the human body and its nervous system. Yet, it is very
clear that these compartments, especially the components of
the neurovascular unit, do not function in isolation, but
work in a concerted process to maintain the function of the
nervous system. As a result, the fruitful development of any
therapeutic consideration for the brain must consistently
address the intricate relationship between neuronal, vascular,
and inflammatory cells if we are to closely consider the brain's
compartments during their compromise.
Kenneth Maiese
Editor-in-Chief
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Endothelin-1 Impairs Retrograde Axonal Transport and
Leads to Axonal Injury in Rat Optic Nerve
T. Taniguchi, M. Shimazawa, M. Sasaoka, A. Shimazaki,
and H. Hara
The purpose of this study was to examine the effects of
endothelin-1 (ET-1) on retrograde axonal transport in the
rat optic nerve. Vehicle or ET-1 (0.2, 1, or 5 pmol/eye) were
injected into the vitreous body in Sprague-Dawley rats. Retinal
vessels were observed, using a fundus camera, before, and
at 10 min, 3 days and 7 days after a single intravitreous
injection. Two days after the injection, a neuronal tracer,
fluoro gold, was administered via the superior colliculi to
retrogradely label active retinal ganglion cells (RGCs). Five
days after the tracer administration, retrogradely labeled
RGCs were evaluated in the flat-mounted retina, and cross
sections from each optic nerve were graded for injury by four
independent, masked observers. ET-1 at 5 pmol/eye caused a
significant constriction of retinal vessels (versus the vehicle-treated
group) at 10 min after the injection. Intravitreous injection
of ET-1 caused a dose-related decrease in the number of retrogradely
labeled RGCs. Injection of 5 pmol/eye ET-1 led to a statistically
significant decrease in the number of retrogradely labeled
RGCs (versus the vehicle-treated group). ET-1 at 1 and 5 pmol/eye
caused histological optic nerve damage (evaluated using a
graded scale). The histological optic nerve damage correlated
with the number of retrogradely labeled RGCs. In conclusion,
a single intravitreous injection of ET-1 impaired retrograde
axonal transport in the rat optic nerve and this impairment
correlated with the histological optic nerve damage.
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Sigma Receptor Activation Reduces Infarct Size at
24 hours after Permanent Middle Cerebral Artery Occlusion
in Rats
C.T. Ajmo Jr., D.O.L. Vernon, L. Collier, K.R.
Pennypacker and J. Cuevas
The only available treatment for embolic stroke is recombinant
tissue plasminogen activator, which must be administered within
three hours of stroke onset. We examined the effects of 1,3-di-o-tolyguanidine
(DTG), a high affinity sigma receptor agonist, as a potential
treatment for decreasing infarct area at delayed time points.
Rats were subjected to permanent embolic middle cerebral artery
occlusion (MCAO) and allowed to recover before receiving subcutaneous
injec-tions of 15 mg/kg of DTG at 24, 48, and 72 hours. At
96 hours the rats were euthanized, and brains harvested and
sectioned. Infarct areas were quantified at the level of the
cortical/striatal and cortical/hippocampal regions in control
(MCAO-only) and DTG treated animals using a marker for neurodegeneration,
Fluoro–Jade. DTG treatment significantly reduced infarct
area in both cortical/striatal and cortical/hippocampal regions
by >80%, relative to control rats. These findings were
confirmed by immunohistochemical experiments using the neuronal
marker, mouse anti-neuronal nuclei monoclonal antibody (NeuN),
which showed that application of DTG significantly increased
the number of viable neurons in these regions. Furthermore,
DTG blocked the inflammatory response evoked by MCAO, as indicated
by decreases in the number of reactive astrocytes and activated
microglia/macrophages detected by immunostaining for glial
fibrillary acidic protein (GFAP) and binding of isolectin
IB4, respectively. Thus, our results demonstrate that the
sigma receptor-selective agonist, DTG, can enhance neuronal
survival when administered 24 hr after an ischemic stroke.
In addition, the efficacy of sigma receptors for stroke treatment
at delayed time points is likely the result of combined neuroprotective
and anti-inflammatory properties of these receptors.
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Endothelial Colony Forming Capacity is Related to
C-reactive Protein Levels in Healthy Subjects
M.M. Ciulla, A. Giorgetti, I. Silvestris, M.
Cortiana, E. Montelatici, R. Paliotti, G.A. Annoni, A.V. Fiore,
R. Giordano, F. De Marco, F. Magrini, P. Rebulla, A. Cortelezzi
and L. Lazzari
The majority of clinical studies on endothelial progenitor
cells (EPCs) focuses on the role of these cells in cardiovascular
diseases and no systematic studies exist regarding their variations
in healthy subjects. In order to define the burden of angiogenesis
in physiological conditions we assessed the frequency of peripheral
blood endothelial colonies (PB-ECs) and their relation with
other factors possibly involved in their function such as
high-sensitivity C-reactive protein (hs-CRP), endothelial
cell-specific mitogen factor (VEGF) and tissue inhibitor of
metalloproteinases-1 (TIMP-1) in a highly selected healthy
population. A PB sample was obtained from 37/47 healthy subjects
(age 40.2±15.0yrs; M/F 15/22) without known cardiovascular
risk factors. The serum level of hs-CRP, VEGF, TIMP-1, the
frequency of PB-ECs by clonogenic assay, and the number of
early EPCs and late EPCs by flow cytometry analysis were evaluated.
PB-ECs were formed by 40.5% of studied subjects with a mean
of 0.40±0.82 colonies/106 cells.
The differences in the frequency of colony formation between
genders were not statistically significant. The subjects with
PB-ECs were characterized by higher values of hs-CRP, when
compared with those not forming colonies, 0.276±0.230
vs 0.095±0.077 mg/l (p=0.003) respectively, and of
VEGF, 328.3±162.9 vs 202.68±118.53 pg/ml (p=0.02).
No significant differences were found in TIMP-1 values. The
EPC clonogenic potential seems to be related to hs-CRP and
VEGF levels even in healthy population supporting the concept
that these mediators are involved in physiological ECs function.
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Group I Metabotropic Receptor Neuroprotection Requires
Akt and its Substrates that Govern FOXO3a, Bim, and β-catenin
During Oxidative Stress
Z.Z. Chong, F. Li and K. Maiese
Metabotropic glutamate receptors are expressed throughout
the nervous system, but their function as well as their ability
to promote neuronal survival rests heavily upon the intracellular
mechanisms governed by this family of G-proteins. In this
regard, we examined one of the primary pathways that can oversee
cell survival, namely protein kinase B (Akt1), and its functional
integration with some of its substrates that may work in concert
with group I metabotropic glutamate receptor (mGluRI) activation
to protect primary hippocampal neurons during oxidative stress.
We demonstrate that neuroprotection against free radical injury
through mGluRI activation with DHPG requires the activation
of Akt1, since loss of Akt1 activity assessed through its
GSK-3α/β
substrate by pharmacological blockade of the phosphatidylinositide-3-kinase
pathway or the gene silencing of Akt1 expression prevents
neuronal protection during mGluRI activation. Closely coupled
to the robust neuroprotection by mGluRI activation are the
inhibitory phosphorylation and prevention of caspase 3 cleavage
of the Forkhead transcription factor FOXO3a, the down-regulation
of Bim expression, and the protection of β-catenin
by Akt1 against phosphorylation and degradation to promote
its translocation from the cytoplasm to the nucleus and allow
it to assist with a "pro-survival" cellular program.
Further insight into the cellular mechanisms that determine
neuronal protection by the metabotropic glutamate system will
foster the successful therapeutic development of mGluRs for
neurodegenerative disorders.
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Cerebral Ischemia and Angiogenesis
T. Hayashi, K. Deguchi, S. Nagotani, H. Zhang, Y. Sehara,
A. Tsuchiya and K. Abe
Angiogenesis occurs in a wide range of conditions. As ischemic
tissue usually depends on collateral blood flow from newly
produced vessels, acceleration of angiogenesis should be of
therapeutic value to ischemic disorders. Indeed, therapeutic
angiogenesis reduced tissue injury in myocardial or limb ischemia.
In ischemic stroke, on the other hand, angiogenic factors
often increase vascular permeability and thus may deteriorate
tissue damage. In order to apply safely the therapeutic angiogenesis
for ischemic stroke treatment, elucidating precise mechanism
of brain angiogenesis is mandatory. In the present article,
we review previous reports which investigated molecular mechanisms
of angiogenesis. Endothelial cell mitogens, enzymes that degrade
surrounding extracellular matrix, and molecules implicated
in endothelial cells migration are induced rapidly in the
ischemic brain. Their possible neuroprotective or injury exacerbating
effects are discussed. Because therapeutic potential of angiogenic
factors application had gained much attention, we here extensively
reviewed relevant previous reports. In the future however,
there is a need to consider angiogenesis in relation with
regenerative medicine, as angiogenic factors sometimes possess
neuron producing property.
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Neurovascular Mechanisms of Hypertension in Pregnancy
A.K. Stennett and R.A. Khalil
Normal pregnancy is associated with significant changes
in the neuronal and vascular control mechanisms of blood pressure
(BP). Preeclampsia (PE) is a major complication of pregnancy
characterized by proteinuria, and increased vascular resistance
and BP. If untreated, PE leads to eclampsia with serious seizures
and severe hypertension. However, the neurovascular mechanisms
of hypertension in pregnancy and PE are unclear. Studies in
animal models of hypertension in pregnancy suggest that inadequate
cytotrophoblast invasion of uterine spiral arteries causes
reduction in uteropla-cental perfusion pressure leading to
placental ischemia/hypoxia. Placental ischemia may promote
the release of biologically active factors such as cytokines
and reactive oxygen species. These circulating factors may
increase the vascular permeability, cross the blood-brain
barrier, and affect the sympathetic tone and the neuronal
control mechanisms of BP. Placental factors could also cause
endothelial cell dysfunction and inhibit nitric oxide (NO)-cyclic
guanosine monophosphate (cGMP), prostacyclin (PGI2)-cyclic
adenosine monophosphate (cAMP), and hyperpolarizing factor
vascular relaxation pathways. Additionally, placental factors
may induce endothelium-derived contracting factors such as
endothelin, thromboxane and angiotensin II, which stimulate
Ca2+-dependent vascular smooth muscle (VSM) contraction
or increase protein kinase C activity and enhance myofilament
sensitivity to intracellular free calcium concentration ([Ca2+]i).
The increased sympathetic tone combined with systemic decrease
in endothelium-dependent vascular relaxation and enhanced
VSM contraction may contribute to the increased vascular resistance
and BP associated with PE. The hypertensive state in severe
PE may weaken the blood-brain barrier and precipitate convulsions
and cerebral hemorrhage. Careful monitoring of maternal neuronal,
endothelial, and VSM function during pregnancy should circumvent
the life-threatening neurovascular complications of PE-eclampsia.
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Autoantibodies Associated with Psychiatric Disorders
P. Margutti, F. Delunardo and E. Ortona
Growing evidence suggests that autoantibodies to neuronal
or endothelial targets in psychiatric disorders exist and
may be pathogenic. This review describes and discusses the
possible role of autoantibodies related to the psychiatric
manifestations in autoimmune diseases, autoantibodies related
to the psychiatric disorders present in post-streptococcal
diseases, celiac disease, chronic fatigue syndrome and substance
abuse, and autoantibodies related to schizophrenia and autism,
disorders now considered of autoimmune origin.
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Vascular Changes of the Retina and Choroid in Systemic
Lupus Erythematosus: Pathology and Pathogenesis
T.C. Nag and S. Wadhwa
Systemic lupus erythematosus (SLE) is a chronic autoimmune
disorder that affects multiple organ systems. When eyes are
involved, the principle manifestations are hemorrhage, retinal
cotton wool spots, microangiopathy and vaso-occlusion. Research
in the past two decades has significantly contributed to our
understanding about this disease in general and its therapeutic
management, although knowledge about the mechanism of ocular
involvement and pathogenesis in SLE is limited. This is an
important issue, because the ocular symptoms in this disease
could be potentially sight threatening in acute cases. Here,
we present an overview of the clinical and histopathologic
features of retinal and choroidal vascular changes, as seen
in patients with SLE. We discuss the role of immune complex
deposition in vascular pathogenesis in the eye. Reports indicated
an involvement of antiphospholipid antibodies (APAs) in the
retinal and choroidal vasculopathy in SLE, although their
precise role in this process is uncertain. It is important
to look for mechanisms of immune complex-mediated vasculopathy
and role of inflammatory mediators in this process in SLE.
For this, established animal models can be utilized in research
to learn about the precise role of various autoantibodies
and complements involved in disease pathogenesis. A clear
knowledge about the immunopathogenesis is warranted, and the
rationale for the future therapy should be based on reducing
vascular inflammation as well as ameliorating autoimmunity
in this disease.
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