| Current
Neurovascular Research
ISSN: 1567-2026
Current Neurovascular Research
Volume 4, Number 3, August 2007
Contents
Editorial Pp. 152
Exciting News from the Messenger
K. Maiese
ORIGINAL ARTICLES
Safety Analysis and Improved Cardiac
Function Following Local Autologous Transplantation of CD133+
Enriched Bone Marrow Cells After Myocardial Infarction
Pp. 153-160
H. Ahmadi, H. Baharvand, S.K. Ashtiani, M. Soleimani,
H. Sadeghian, J.M. Ardekani, N.Z. Mehrjerdi, A. Kouhkan, M.
Namiri, M. Madani-Civi, F. Fattahi, A. Shahverdi and A.V.
Dizaji
[Abstract]
Cerebral Aneurysm Formation in Nitric Oxide Synthase-3
Knockout Mice Pp. 161-169
T. Abruzzo, A. Kendler, R. Apkarian, M. Workman, J.C.
Khoury and H.J. Cloft
[Abstract]
Neurohormonal Activation in Ischemic Stroke: Effects
of Acute Phase Disturbances on Long-Term Mortality Pp.
170-175
M. Anne, K. Juha, M. Timo, T. Mikko, V. Olli,
S. Kyösti, H. Heikki and M. Vilho
[Abstract]
A Non-Steroidal Anti-Inflammatory Agent Provides
Significant Protection During Focal Ischemic Stroke with Decreased
Expression of Matrix Metalloproteinases Pp. 176-183
Y. Wang, X.-L. Deng, X.-H. Xiao and B.-X. Yuan
[Abstract]
Effects of Thyroid Hormones on Memory and on Na+,
K+ -ATPase Activity in Rat
Brain Pp. 184-193
E.A. dos Reis-Lunardelli, C.C. Castro, C. Bavaresco,
A.S. Coitinho, L.S.S. da Trindade, M.F. Perrenoud, R. Roesler,
J.J.F. Sarkis, A.T. de Souza Wyse and I. Izquierdo
[Abstract]
Vascular Injury During Elevated Glucose can be
Mitigated by Erythropoietin and Wnt Signaling Pp.
194-204
Z.Z. Chong, Y.C. Shang and K. Maiese
[Abstract]
REVIEW ARTICLES
Physiology and Pathophysiology of Na+/H+
Exchange Isoform 1 in Central the Nervous System Pp.
205-215
J. Luo and D. Sun
[Abstract]
The Response of the Aged Brain to Stroke: Too
Much, Too Soon? Pp. 216-227
A. Popa-Wagner, S.T. Carmichael, Z. Kokaia ,
C. Kessler and L.C. Walker
[Abstract]
Abstracts
[Back to top]
Editorial: Exciting News from the Messenger
K. Maiese
"These chemical messengers, however, or hormones (from
[the Greek word] I excite or arouse), as we might call them,
have to be carried from the organ where they are produced
to the organ which they affect by means of the blood stream
and the continually recurring physiological needs of the organism
must determine their repeated production and circulation throughout
the body." As part of his second Croonian lecture to
the Royal College of Surgeons in 1905 entitled "The chemical
control of the functions of the body", Ernest Starling
surprisingly introduces the term "hormones" to describe
chemicals that can be set into action in the blood stream
to elicit activity in different organs of the body. The selection
of the term "hormone" by Starling is not entirely
clear, but may have developed in conversations with William
Hardy and the Greek poet scholar W. T. Vesey to use the Greek
verb "ormao" for "arouse" or "excite".
Yet, despite the absence, or at least the minimal use of the
term "hormone" in the scientific arena prior to
this point, early work during the mid-nineteenth century,
such as by Claude Bernard, depicted processes responsible
for internal secretion of chemicals as described with the
release of glucose from glycogen in the liver. During this
period, other pioneers such as Arnold Adolphe Berthold spoke
of the interaction and communication between the different
organs in the body. As these concepts became more accepted,
physicians later in the nineteenth century reported the use
of extracts of animal thyroid, pancreas, and even adrenal
glands to treat patients suspected of suffering from the loss
of circulating chemicals.
By the early twentieth century, Starling and William Bayliss
demonstrated that the duodenum, when stimulated with acid
through local application, could lead to pancreatic secretion.
They furthered these results by illustrating that duodenal
extracts injected into the blood stream in animals also resulted
in pancreatic secretion. From these studies, Starling and
Bayliss suggested that the agent released from the duodenum
should be termed "secretin". The Nobel Laureate
Pavlov was initially impressed with these results that had
suggested the presence of several mechanisms in the control
of the digestive system, but later stood firm to promote his
personal concepts that pancreatic secretion and the organs
of the gut were controlled principally by innervation of the
nervous system during his acceptance of the Nobel Peace Prize
for his work in 1904.
Politics aside, investigations since the work of early pioneers
in endocrinology and the study of hormones have fostered the
development of numerous fields that involve vascular biology,
neuroscience, physiology, genetics, metabolomics, development,
cancer, and molecular medicine. Clinically, the advances from
these fields that rely upon the understanding of the chemistry
of hormones have resulted in remarkable strides for treatment
protocols that involve the care and management of diabetes,
the replenishment of hormone deficiencies with recombinant
proteins that eliminate potential toxicity from the use of
animal or human sources, and the success of fertility treatments
that utilize in vitro fertilization. Furthermore,
our progressive knowledge of the cellular and molecular processes
that involve hormones have alerted us to the intimate relationship
we hold with the environment and its accumulation of synthetic
chemicals that can ultimately be detrimental to the endocrine
system of both animals and humans.
This issue of Current Neurovascular Research highlights
the complexity of hormones and the cellular pathways they
govern that ultimately regulate clinical health and disease.
Ahmadi et al. provides exciting evidence that administration
of a bone marrow cell population containing multipotent stem
cells is not only non-toxic in patients who have suffered
myocardial infarction, but also may result in clinical cardiac
improvement with potential myogenesis and angiogenesis. However,
hormonal systems may not always be beneficial during illness
as illustrated by Mäkikallio et al. In their
paper, they examined the hypothalamus-pituitary-adrenal axis
in patients suffering from ischemic stroke over time and report
that elevated cortisol and natriuretic peptide levels may
be detrimental to the eventual recovery from stroke, suggesting
that targeting this hormone system may offer treatment for
acute cerebral ischemia. Reis-Lunardelli et al. further
emphasize the significant effects of hormones upon the brain
not only in relation to the integrity of the brain, but also
in regards to behavior and memory by demonstrating that thyroid
function can significantly alter behavior and cognition in
animal models. In relation to metabolism and the vascular
complications of diabetes mellitus, Chong et al.
provide new insight into the cellular protective pathways
of the recombinant growth hormone erythropoietin to illustrate
that novel modulation of the Wnt signaling pathway can determine
primary vascular cell protection during elevated glucose toxicity.
It is clear that no cell, tissue, or organ is spared by the
protean and significant effects of hormones and their receptors.
The initial work by pioneers such as Starling, Bernard, Berthold,
and Bayliss has led us to remarkable advances in clinical
medicine that will continue to progress in directions that
no one can conclusively predict. It is our hope that this
issue of Current Neurovascular Research will bring
you "exciting news from the messenger" just as the
chemical messengers that were initially described by Starling
had done to "arouse" and "excite" the
multiple organs throughout the body.
Kenneth Maiese
Editor-in-Chief
[Back to top]
Safety Analysis and Improved Cardiac Function
FollowingLocal Autologous Transplantation of CD133+
Enriched Bone Marrow Cells After Myocardial Infarction
H. Ahmadi, H. Baharvand, S.K. Ashtiani, M. Soleimani,
H. Sadeghian, J.M. Ardekani, N.Z. Mehrjerdi, A. Kouhkan, M.
Namiri, M. Madani-Civi, F. Fattahi, A. Shahverdi and A.V.
Dizaji
The CD133+ bone marrow cell
(BMC) population includes primitive multipotent stem cells
which induce neoangiogenesis. Studies suggested transplantation
of these cells to infarcted myocardium can have a favorable
impact on tissue perfusion and contractile performance. We
assessed the feasibility, safety and functional outcomes of
autologus CD133+ BMC transplantation
during coronary artery bypass grafting (CABG) in patients
with recent myocardial infarction. In a prospective, nonrandomized,
open-label study, 27 patients with recent myocardial infarction
underwent CABG and intramyocardial injection of autologous
bone marrow-derived CD133+
cells (18 patients, BMC group) or CABG alone (9 patients,
control group). At 6 months after CABG, the Wall Motion Score
Index (WMSI) was significantly reduced for akinetic/dyskinetic
segments treated with CD133+
cells compared with the control group (P<0.006).
Likewise, comparison between baseline and follow up results
of dobutamine stress echocardiography and myocardial perfusion
scintigraphy showed improvement of myocardial viability and
local perfusion of the infarcted zone of the BMC group compared
with the control group. No complications related to CD133+
cell transplantation were noted, either procedurally or during
post-operative at a mean of 14 months follow up. In patients
with recent myocardial infarction, transplantation of CD133+
cells to the peri-infarct zone during CABG surgery is feasible
and safe, with no evidence of early or late adverse events.
Moreover, these cells might restore tissue viability and improve
perfusion of the infarcted myocardium, suggesting that they
may induce myogenesis as well as angiogenesis.
[Back to top]
Cerebral Aneurysm Formation in Nitric Oxide Synthase-3
Knockout Mice
T. Abruzzo, A. Kendler, R. Apkarian, M. Workman, J.C.
Khoury and H.J. Cloft
We sought to evaluate the influence of specific vasoactive
gene knockouts on the process of intracranial aneurysm formation
in mice. Thirty wild type, 7 nitric oxide synthase (NOS)-2
knockout, 6 NOS-3 knockout, and 8 plasminogen activator inhibitor
(PAI)-1 knockout female mice underwent left common carotid
artery ligation at 2 to 6 months of age. After a survival
period (average 20.4 months ± 1.5 months), the brains
were perfusion fixed with 10% buffered formalin for 10 minutes
and then perfused with India ink. Brain and intact cerebral
circulation were surgically removed and further fixed in 10%
buffered formalin for 4 additional days. The basal cerebral
circulation of each brain was examined for the presence of
intracranial aneurysms under a surgical microscope (3x–21x).
Suspected aneurysms were further dissected for histological
analysis. Specimens were embedded in epoxy resin, cut into
0.5 and 1.0 micron sections, and stained with Toluidine blue.
A neuropathologist blinded to genotype and surgical microscopy
results examined the slides for evidence of aneurysmal pathology.
Two intracranial aneurysms in 2 NOS-3 knockout mice were confirmed
by histology. No intracranial aneurysms were confirmed in
any wild type, NOS-2 knockout, or PAI-1 knockout mice. Histological
analysis of aneurysms revealed loss of elastica, subendothelial
collagen deposition, and perivascular lymphocytic infiltration.
Our results suggest that NOS-3 knockout, but not PAI-1 or
NOS-2 knockout, predisposes to the formation of intracranial
aneurysms in mice subjected to unilateral carotid artery ligation.
Due to small sample sizes however, selection bias cannot be
excluded and further investigation is necessary to confirm
our results.
[Back to top]
Neurohormonal Activation in Ischemic Stroke:
Effects of Acute Phase Disturbances on Long-Term Mortality
M. Anne, K. Juha, M. Timo, T. Mikko, V. Olli,
S. Kyösti, H. Heikki and M. Vilho
A stress response consisting of elevated levels of cortisol
and catecholamines is common after acute stroke. The plasma
levels of natriuretic peptides are known to be elevated after
ischemic stroke, but the relations of these neurohormonal
systems in the acute phase of stroke and their impact on long-term
prognosis have not been studied previously. A series of 51
consecutive patients (mean age 68±11years) with an
ischemic first-ever stroke underwent a comprehensive clinical
investigation, scoring of their neurologic deficit by Scandinavian
Stroke Scale (SSS), Barthel Index (BI) and Modified Ranking
Scale (MRS) as well as measurements of plasma cortisol, norepinephrine,
epinephrine, ACTH and atrial (N-ANP) and brain (N-BNP) natriuretic
peptides on the 2nd and 7th days after ischemic stroke. The
patients were followed up for 44±21 months. Higher
levels of cortisol, ACTH and natriuretic peptides were observed
in the stroke patients who died (n=22) during the follow-up
than in the stroke survivors. Cortisol levels associated significantly
with the 2nd and 7th day N-ANP and N-BNP levels, catecholamine
levels (r= 0.55- 0.94, p<0.01 for all) and measures of
neurologic deficit (r= 0.36 - -0.44, p<0.05). High acute
phase cortisol levels assessed either in the morning (RR=5.4,
p<0.05) or in the evening (RR=5.8, p<0.05) predicted
long-term mortality after stroke in multivariate analysis.
Activation of the hypothalamus-pituitary-adrenal axis in ischemic
stroke is associated with elevated levels of natriuretic peptides.
High cortisol and natriuretic peptide values predict long-term
mortality after ischemic stroke, suggesting that this profound
neurohumoral disturbance is prognostically unfavourable.
[Back to top]
A Non-Steroidal Anti-Inflammatory Agent Provides Significant
Protection During Focal Ischemic Stroke with Decreased Expression
of Matrix Metalloproteinases
Y. Wang, X.-L. Deng, X.-H. Xiao and B.-X. Yuan
The present study was designed to investigate whether the
neuroprotective effect of nimesulide was mediated by inhibiting
expression of matrix metalloproteinase-9 (MMP-9) and/or matrix
metalloproteinase-2 (MMP-2) in a rat model of thrombolytic
reperfusion after the embolic focal cerebral ischemia (FCI).
It was found that nimesulide at therapeutically relevant doses
(3, 6 and 12 mg/kg) decreased neurological deficits, infarct
volume, brain index and brain water content in a dose-dependent
manner. Hemorrhagic transformation was reduced by 64% with
treatment of 12 mg/kg nimesulide. Quantitative analysis of
immunohistochemical staining of brain slices showed that the
neuron number expressing MMP-9 and MMP-2 increased in the
model animals treated with vehicle (p<0.01 vs
sham group), and significantly decreased in nimesulide-treated
animals (p<0.05 or p<0.01 vs vehicle
group). Our results demonstrate that nimesulide significantly
reduces the degree of neuronal injury and hemorrhage transformation
caused by thrombolytic reperfusion after the embolic FCI,
and that inhibition of MMP-9 and MMP-2 expression contributes
at least in part to the neuroprotection.
[Back to top]
Effects of Thyroid Hormones on Memory and on Na+,K+
-ATPase Activity in Rat Brain
E.A. dos Reis-Lunardelli, C.C. Castro, C. Bavaresco,
A.S. Coitinho, L.S.S. da Trindade, M.F. Perrenoud, R. Roesler,
J.J.F. Sarkis, A.T. de Souza Wyse and I. Izquierdo
Thyroid hormones (THs), including triiodothyronine (T3) and
tetraiodothyronine (T4), are recognized as key metabolic hormones
of the body. THs are essential for normal maturation and function
of the mammalian central nervous system (CNS) and its deficiency,
during a critical period of development, profoundly affects
cognitive function. Sodium-potassium adenosine 5'-triphosphatase
(Na+, K+-ATPase)
is a crucial enzyme responsible for the active transport of
so-dium and potassium ions in the CNS necessary to maintain
the ionic gradient for neuronal excitability. Studies suggest
that Na+, K+-ATPase
might play a role on memory formation. Moreover, THs were
proposed to stimulate Na+,
K+ -ATPase activity in the
heart of some species. In this work we investigated the effect
of a chronic administration of L-thyroxine (L-T4) or propylthiouracil
(PTU), an antithyroid drug, on some behavioral paradigms:
inhibitory avoidance task, open field task, plus maze and
Y-maze, and on the activity of Na+,
K+ -ATPase in the rat parietal
cortex and hippocampus. By using treatments which have shown
to induce alterations in THs levels similar to those found
in hyperthyroid and hypothyroid patients, we aimed to understand
the effect of an altered hyperthyroid and hypothyroid state
on learning and memory and on the activity of Na+,
K+-ATPase. Our results showed
that a hyper and hypothyroid state can alter animal behavior
and they also might indicate an effect of THs on learning
and memory.
[Back to top]
Vascular Injury During Elevated Glucose can be Mitigated
by Erythropoietin and Wnt Signaling
Z.Z. Chong, Y.C. Shang and K. Maiese
Impacting a significant portion of the world's population
with increasing incidence in minorities, the young, and the
physically active, diabetes mellitus (DM) and its complications
affect approximately 20 million individuals in the United
States and over 100 million individuals worldwide. In particular,
vascular disease from DM may lead to some of the most serious
complications that can extend into both the cardiac and nervous
systems. Unique strategies that can prevent endothelial cell
(EC) demise and elucidate novel cellular mechanisms for vascular
cytoprotection become vital for the prevention and treatment
of vascular DM complications. Here, we demonstrate that erythropoietin
(EPO), an agent that has recently been shown to extend cell
viability in a number of systems extending beyond hematopoietic
cells, prevents EC injury and apoptotic nuclear DNA degradation
during elevated glucose exposure. More importantly, EPO employs
Wnt1, a cysteine-rich glycosylated protein involved in gene
expression, cell differentiation, and cell apoptosis, to confer
EC cytoprotection and maintains the integrity of Wnt1 expression
during elevated glucose exposure. In addition, application
of anti-Wnt1 neutralizing antibody abrogates the protective
capacity of both EPO and Wnt1, illustrating that Wnt1 is an
important component in the cytoprotection of ECs during elevated
glucose exposure. Intimately linked to this cytoprotection
is the downstream Wnt1 pathway of glycogen synthase kinase
(GSK-3β) that requires phosphorylation of GSK-3β
and inhibition of its activity by EPO. Interestingly, inhibition
of GSK-3β activity during elevated glucose leads to enhanced
EC survival, but does not synergistically improve protection
by EPO or Wnt1, suggesting that EPO and Wnt1 are closely tied
to the blockade of GSK-3β activity. Our work exemplifies
an exciting potential application for EPO in regards to the
treatment of DM vascular disease complications and highlights
a previously unrecognized role for Wnt1 and the modulation
of the downstream pathway of GSK-3β to promote vascular
cell viability during DM.
[Back to top]
Physiology and Pathophysiology of Na+/H+
Exchange Isoform 1 in Central the Nervous System
J. Luo and D. Sun
Na+/H+
exchangers (NHEs) conduct the electroneutral exchange of proton
(H+) and sodium (Na+)
ions across cellular membranes down their concentration gradients.
To date, nine NHE family members have been cloned from mammals
and share a common secondary structure. The ubiquitous exclusive
plasma membrane NHE isoform 1 (NHE1) is a major membrane transport
mechanism in regulation of intracellular pH (pHi)
and volume. In addition to its role in regulation of ionic
homeostasis, NHE1 can directly interact with other regulatory
cellular signaling pathways, including modulation of the activity
of mitogen-activated protein kinases (MAPKs) and Akt/protein
kinase B (PKB). Thus, NHE1 is a multifaceted regulator of
cell migration, proliferation, and cell death. NHE1 also plays
pivotal roles under a number of pathophysiological conditions
such as osmotic stress, acidosis, and mechanical stress. NHE1
is the most abundant NHE isoform in the rat central nervous
system (CNS). This review discusses distribution and regulation
of NHE1, and its physiological roles in the CNS. Moreover,
it includes an extensive presentation of studies on activation
of NHE1 under ischemic conditions in the CNS and its impact
on Na+ and Ca2+ ionic homeostasis as
well as on cell survival and damage.
[Back to top]
The Response of the Aged Brain to Stroke: Too Much,
Too Soon?
A. Popa-Wagner, S.T. Carmichael, Z. Kokaia ,
C. Kessler and L.C. Walker
Old age is associated with an enhanced susceptibility
to stroke and poor recovery from brain injury, but the cellular
processes underlying these phenomena are only recently coming
to light. Potential mechanisms include changes in brain plasticity-promoting
factors, unregulated expression of neurotoxic factors, or
differences in the generation of scar tissue that impedes
the formation of new axons and blood vessels in the infarcted
region. Behaviorally, aged rats are more severely impaired
by stroke than are young rats, and they also show diminished
functional recovery. Infarct volume does not differ significantly
in young and aged animals, but critical differences are apparent
in the cytological response to stroke, most notably an age-related
acceleration of the establishment of the glial scar. The early
infarct in older rats is associated with a premature accumulation
of BrdU-positive microglia and astrocytes, persistence of
activated oligodendrocytes, a high incidence of neuronal degeneration,
and accelerated apoptosis. Regeneration-associated mechanisms
in the rat brain are active thoughout life, albeit at lower
levels in the aged animals. However; after stroke in aged
rats, neuroepithelial marker-positive cells emanating largely
from capillaries did not make a significant contribution to
neurogenesis in the infarcted cortex of aged animals. Furthermore,
the expression of plasticity-associated proteins, such as
MAP1B, was delayed in aged rats. Tissue recovery was further
delayed by the upregulation of Nogo, ephrin-A5 and MAG, which
exert a powerful negative effect on axonal sprouting in the
aged peri-infarct cortex, and by an age-related increase in
the amount of the neurotoxic C-terminal fragment of the β-amyloid
precursor protein (βAPP) at 2 wks post-stroke. Our findings
indicate that the aged brain has the capability to mount a
cytoproliferative response to injury, but the timing of the
cellular and genetic response to cerebral insult is dysregulated
in aged animals, thereby further compromising functional recovery.
Elucidating the molecular basis of this phenomenon in the
aging brain could yield novel approaches to neurorestoration
following stroke or head injury in the elderly.
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