| Current
Neurovascular Research
ISSN: 1567-2026
Current Neurovascular Research
Volume 2, Number 5, December 2005
Contents
Timing is Everything Pp.363
K. Maiese
[Abstract]
ORIGINAL ARTICLE
Aging Blunts Ischemic-Preconditioning-Induced Neuroprotection
Following Transient Global Ischemia in Rats Pp.365
Z. He, J.E. Crook, J.F. Meschia, T.G. Brott, D.W. Dickson
and M. McKinney
[Abstract]
Hyperglycemia Potentiates Carbonyl Stress-Induced
Apoptosis in Naïve PC-12 Cells: Relationship to Cellular
Redox and Activator Protease Factor-1 Expression Pp.375
M. Okouchi, N. Okayama and T.Y. Aw
[Abstract]
Erythropoietin Requires NF-κB and its Nuclear
Translocation to Prevent Early and Late Apoptotic Neuronal
Injury During β-Amyloid Toxicity Pp.387
Z.Z. Chong, F. Li and K. Maiese
[Abstract]
Increased Behavioral and Histological Variability
Arising From Changes in Cerebrovascular Anatomy of the Mongolian
Gerbil Pp.401
D.T. Laidley, F. Colbourne and D. Corbett
[Abstract]
REVIEW ARTICLES
The Function and Integrity of the Neurovascular Unit
Rests Upon the Integration of the Vascular and Inflammatory
Cell Systems Pp.409
H.S. Han and K. Suk
[Abstract]
Driving Cellular Plasticity and Survival Through the
Signal Transduction Pathways of Metabotropic Glutamate Receptors
Pp.425
K. Maiese, Z.Z. Chong and F. Li
[Abstract]
The Emerging Role of Coenzyme Q-10 in Aging, Neurodegeneration,
Cardiovascular Disease, Cancer and Diabetes Pp.447
M. Dhanasekaran and J. Ren
[Abstract]
Abstracts
[Back to top]
Timing is Everything
K. Maiese
Although it was initially Antoine Lavoisier who determined
that oxygen is the only gas in air that sustains pulmonary
respiration to prevent death and that almost 200 years later
Barcroft introduced the terms "anoxic", "anemic",
"histotoxic", and "stagnant" to designate
the various forms of anoxia, our comprehension of human anoxic
brain injury is far from complete. The term cerebral anoxia
indicates any form of inadequate oxygen delivery to the brain,
including hypoxemia and ischemia. Anoxic brain injury is extremely
complex in nature and consists of a variety of insults to
cells that involve decreased oxygen availability, systemic
acidosis, hypercapnia, and sometimes superimposed ischemia.
Other organs, such as the kidney and heart, can tolerate ischemic
periods of up to thirty minutes, but the brain can tolerate
no more than a few minutes of anoxia. Neurons survive only
for minutes after the oxygen supply is reduced below critical
levels. Pyramidal cells in the hippocampus, Purkinje cells
of the cerebellum, and pyramidal cells of the third and fifth
layers of the cerebral cortex are vulnerable to even moderate
degrees of anoxia. Widespread necrosis of the cortex with
the brainstem intact produces a vegetative state. More profound
anoxia affecting the cortex, basal ganglia, and brainstem
results in coma and subsequent death. Brief episodes of cerebral
anoxia are usually well tolerated with patients escaping any
irreversible deficits. Yet, an amnestic syndrome may follow
transient periods of global ischemia with patients experiencing
a severe antegrade amnesia and variable retrograde memory
loss.
Given the range of neurological disabilities that can ensue
during ischemic brain injury, studies that determine the cellular
mechanisms responsible for preserving both neuronal and vascular
survival are essential for the development of viable therapeutics
for this field. With this goal in mind, this issue of Current
Neurovascular Research offers a unique perspective into not
only some of the potential cellular mechanisms responsible
for injury to the brain, but also the temporal parameters
that appear to be intimately linked to a cell's fate. The
ability to identify the temporal cellular determinants of
clinical deterioration in the nervous system could bring new
insight into unexplained clinical deterioration. For example,
individuals with anoxic-ischemic coma of approximately six
hours duration, but with unremarkable insults on brain imaging,
can sometimes suffer from permanent cognitive deficits. In
addition, delayed neurologic deterioration following only
a brief injury to the nervous system also can ensue that includes
neuropsychological impairment or unconsciousness.
In their original article, He et al. illustrate that aged
animals may be less susceptible to ischemic cerebral injury,
but these aged animals unfortunately lose their innate ability
to respond to protective measures such as ischemic preconditioning
which can reduce cerebral infarct size in young animals. This
significantly reduced protection normally afforded by ischemic
preconditioning in young animals was markedly reduced in aged
counterparts and may be associated with a reduction in expression
of the N-methyl-D-aspartic acid receptor 1 as well as modified
tolerance to caspase mediated cell death mechanisms. Overall,
the study sheds new light on some of the temporal parameters
that can determine clinical disability following cerebral
ischemia and the multiple variables that need to be addressed
to achieve broad clinical efficacy for both young and more
senior individuals.
In our next original article, Okouchi et al. follow suit
with the lead article in regards to the temporal parameters
that can influence cell survival by showing that chronic hyperglycemia
as well as acute glucose reduction from a chronic hyperglycemic
state can contribute to cellular oxidative stress. Their work
has implications for a number of disease states, including
diabetes and Alzheimer's disease. The authors demonstrate
that chronic hyperglycemia was able to intensify methylglyoxal
apoptotic cell injury and was associated with several intracellular
processes that included mitochondrial redox balance, impaired
glucose 6-phosphate dehydrogenase activity, and enhanced basal
expression of apoptosis protease activator factor-1.
Chong et al. in their original work provide important evidence
that novel neuroprotective strategies, such as the administration
of erythropoietin, are also critically related to the temporal
modulation of intracellular apoptotic pathways. These investigators
show that erythropoietin prevents neuronal β-amyloid
toxicity, but that protection requires the early translocation
of nuclear factor-κB
from the cytosol to the nucleus to initiate an anti-apoptotic
program. Without this intracellular translocation of nuclear
factor-κB
within a tight six hour period following β-amyloid
toxicity, such as during experiments that employ the gene
silencing of nuclear factor-κB,
neuroprotection by erythropoietin is lost.
Although the original work by Laidley et al. does not focus
upon specific cellular mechanisms of ischemic cell injury,
the study by these investigators presents an important analysis
of the use of experimental animal models to yield scientifically
sound data that can approximate clinical disease. The authors
examine the use of a popular animal model for forebrain ischemia,
namely the Mongolian gerbil (Meriones unguiculatus). Their
work provides us with a refreshing perspective on both the
benefits of this model for cerebral ischemia, but also the
limitations of current commercially available strains and
the considerations that should come into play for robust data
analysis with this model.
Our three review articles for this issue of Current Neurovascular
Research complement the original articles by providing a broader
overview of several of the cellular mechanisms that can contribute
to the temporal determinants of cellular protection and plasticity.
Han and Suk provide a thorough discussion of the neurovascular
unit and the crosstalk that can occur between endothelial
cells and microglia during inflammatory disorders of the nervous
system. In particular, their review addresses the timely modulation
required of the blood brain barrier, chemokines, and microglia
for effective therapeutic strategies against neurodegenerative
disease. Maiese et al. lead us into the intricate world of
specific class of G-protein-linked receptors known as metabotropic
glutamate receptors and their interesting role during a variety
of disorders that can include amyotrophic lateral sclerosis,
Parkinson's disease, Alzheimer's disease, epilepsy, trauma,
and stroke. The authors highlight the complexity of the metabotropic
glutamate receptors in the nervous system. These receptors
can control several cellular systems that involve neuronal,
vascular, and inflammatory pathways, but function at times
as a double edge sword that can either promote or prevent
cellular function. Our final article by Dhanasekaran and Ren
focuses upon the unique role of coenzyme Q, a ubiquitous protein
in both plants and animals, that can play a vital role during
neurodegenerative disease, cardiovascular disorders, and oxidative
stress, such as during diabetes. In humans, coenzyme Q-10
is the predominant form and offers the advantages of being
a lipid-soluble antioxidant that can rapidly alter cellular
redox mechanisms, energy reserves, and stabilize mitochondrial
membrane potential to control "time sensitive" pathways
that may precipitate cellular injury. As our knowledge of
basic cellular injury mechanisms continues to grow from the
original work of Lavoisier and Barcroft, this issue of Current
Neurovascular Research allows us to become increasingly more
cognizant with the notion that "timing is everything"
at both the cellular and clinical levels to effectively treat
a broad spectrum of individuals afflicted by any disease entity.
Kenneth Maiese
Editor-in-Chief
[Back to top]
Aging Blunts Ischemic-Preconditioning-Induced Neuroprotection
Following Transient Global Ischemia in Rats
Z. He, J.E. Crook, J.F. Meschia, T.G. Brott, D.W. Dickson
and M. McKinney
The present study examines the hypothesis that aging defined
by the 50% survival age compromises neuroprotection afforded
by ischemic preconditioning (IPC). Sixty-four male F344 rats
aged 4- and 24-months, respectively, were subjected to IPC,
(3-min ischemia) or sham-surgery followed by 10-min (full)
ischemia or sham-surgery 2 days later. There were 4 groups
at each age: sham-surgery-sham-surgery (SS), preconditioning-sham-surgery
(PS), preconditioning-ischemia (PI) and sham-surgery-ischemia
(SI) groups. Assessments of histology and immunoreactivities
of N-methyl-D-aspartic acid receptor 1 (NMDAr1) and caspase-3
active peptide (C3AP) in the hippocampal CA1 region were performed
8 days after full ischemia. The CA1 “living cell ratio”
was greater in the aged SI group than in the young SI group
(32±6% vs. 17±5%, p<0.05), whereas the degree
of protection against full ischemia afforded by IPC was reduced
in the aged compared with the young (53±17% vs. 241±25%,
P<0.0001). The basal level of NMDAr1 immunofluorescence
was significantly higher in young animals, while the numbers
of C3AP-positive cells were greater in all three aged ischemic
groups as compared to respective young groups (p<0.01,
p=0.055 and p<0.05). A fourth method of assess-ing cell
damage using Fluoro Jade C labeled degenerating neurons that
were also intensively eosinophilic. Counts of Fluoro Jade
C-positive cells were higher in the young SI group than in
the aged SI group (P<0.05), suggesting that mechanisms
of ischemic cell death may change with aging. In conclusion,
aging alters mechanisms of ischemic cell death in CA1 neurons
and ischemic tolerance mechanisms are blunted by aging.
[Back to top]
Hyperglycemia Potentiates Carbonyl Stress-Induced
Apoptosis in Naïve PC-12 Cells: Relationship to Cellular
Redox and Activator Protease Factor-1 Expression
M. Okouchi, N. Okayama and T.Y. Aw
The mechanism(s) of central nervous system complication associated
with neurodegenerative disorders such as diabetes is unknown.
Previous studies demonstrated that carbonyl stress induced
by methylglyoxal (MG) mediates differential apoptosis of rat
pheochromocytoma (PC12) cells in the naïve or differentiated
transition states. Since chronic hyperglycemia is central
to diabetic complications, and poorly differentiated cells
are oxidatively more vulnerable, we currently investigated
the effect of glycemic status on MG-induced apoptosis in naïve
(nPC12) cells focusing on glutathione-to-glutathione disulfide
(GSH/GSSG) redox signaling. nPC12 cells were exposed to 25
mM glucose acutely for 24h or chronically for 1 week. A role
for glycemic fluctuation was tested in chronic high glucose-adapted
cells subjected to acute reduction in glucose availability.
Acute hyperglycemia potentiated MG-induced nPC12 apoptosis
in accordance with cellular redox (GSH-to-Disulfide (GSSG
plus protein-bound SSG)) imbalance. Chronic hyperglycemia
exacerbated baseline and MG-induced apoptosis that corresponded
to exaggerated loss of cytosolic and mitochondrial redox balance,
impaired glucose 6-phosphate dehydrogenase (G6PD) activity,
and enhanced basal expression of apoptosis protease activator
factor-1 (Apaf-1). Reduced glucose availability in hyperglycemia-adapted
nPC12 cells induced by acute lowering of glucose or by dehydroepiandrosterone
(DHEA, G6PD inhibitor) further enhanced MG-induced apoptosis
in associa-tion with greater cytosolic and mitochondrial redox
and G6PD impairment and elevated basal Apaf-1 expression.
These findings demonstrate that chronic hyperglycemia or acute
glucose reduction from the chronic hyperglycemic state poten-tiates
carbonyl stress, which collectively contribute to oxidative
susceptibility of poorly differentiated cells such as that
which occurs in brain neurons of neurodegenerative disorders
like diabetes and Alzheimer’s disease.
[Back to top]
Erythropoietin Requires NF-κB and its Nuclear
Translocation to Prevent Early and Late Apoptotic Neuronal
Injury During β-Amyloid Toxicity
Z.Z. Chong, F. Li and K. Maiese
No longer considered exclusive for the function of the hematopoietic
system, erythropoietin (EPO) is now considered as a viable
agent to address central nervous system injury in a variety
of cellular systems that involve neuronal, vascular, and inflammatory
cells. Yet, it remains unclear whether the protective capacity
of EPO may be effective for chronic neurodegenerative disorders
such as Alzheimer's disease (AD) that involve β-amyloid
(Aβ)
apoptotic injury to hippocampal neurons. We therefore investigated
whether EPO could prevent both early and late apoptotic injury
during Aβ
exposure in primary hippocampal neurons and assessed potential
cellular pathways responsible for this protection. Primary
hippocampal neuronal injury was evaluated by trypan blue dye
exclusion, DNA fragmentation, membrane phosphatidylserine
(PS) exposure, and nuclear factor-κB
(NF-κB)
expression with subcellular translocation. We show that EPO,
in a concentration specific manner, is able to prevent the
loss of both apoptotic genomic DNA integrity and cellular
membrane asymmetry during Aβ
exposure. This blockade of Aβ
generated neuronal apoptosis by EPO is both necessary and
sufficient, since protection by EPO is completely abolished
by co-treatment with an anti-EPO neutralizing antibody. Furthermore,
neuroprotection by EPO is closely linked to the expression
of NF-κB
p65 by preventing the deg-radation of this protein by Aβ
and fostering the subcellular translocation of NF-κB
p65 from the cytoplasm to the nu-cleus to allow the initiation
of an anti-apoptotic program. In addition, EPO intimately
relies upon NF-κB
p65 to promote neuronal survival, since gene silencing of
NF-κB
p65 by RNA interference removes the protective capacity of
EPO during Aβ
exposure. Our work illustrates that EPO is an effective entity
at the neuronal cellular level against Aβ
toxicity and requires the close modulation of the NF-κB
p65 pathway, suggesting that either EPO or NF-?B may be used
as fu-ture potential therapeutic strategies for the management
of chronic neurodegenerative disorders, such as AD.
[Back to top]
Increased Behavioral and Histological Variability
Arising From Changes in Cerebrovascular Anatomy of the Mongolian
Gerbil
D.T. Laidley, F. Colbourne and D. Corbett
The Mongolian gerbil (Meriones unguiculatus) has
been used extensively as a model of forebrain ischemia. Its
unique susceptibility to ischemia was suggested to be due
to an incomplete circle of Willis. The relative ease to which
ischemia can be induced combined with highly reproducible
delayed CA1 cell death following a 5 min occlusion made the
model popular in neuroprotection studies. Presently, this
assumption was tested that complete forebrain ischemia occurs
in all gerbils because increased variability was noticed in
neuronal injury and behavioral outcome using this model in
the last several years. Here it is reported that gerbils obtained
from Charles River, the largest supplier in North America,
show a high incidence (22.7% with bilateral and 38.6% with
unilateral anastomoses) of posterior communicating arteries
compared to another supplier of gerbils (High Oak Farms, 2.6%
with bilateral and 13.2% with unilateral anastomoses, P<0.0001).
This increased incidence of complete or partial circle of
Willis led to less severe CA1 cell loss in Charles River gerbils
(P<0.0001) compared to High Oak gerbils, with an unacceptably
high level of inter-animal variability. Similarly, behavioral
indices of CA1 ischemic injury (increased locomotion, habituation
deficits) were also significantly attenuated in the Charles
River animals. High Oak gerbils also displayed increased histological
and behavioral variability relative to the pattern obtained
several years ago. Thus, the gerbil model of forebrain ischemia,
at least using Charles River animals, no longer produces consistent
injury and behavioral alterations. Investigators are urged
to consider adopting other models in future neuroprotection
studies or ensure that their gerbil population lacks communicating
arteries.
[Back to top]
The Function and Integrity of the Neurovascular Unit
Rests Upon the Integration of the Vascular and Inflammatory
Cell Systems
H.S. Han and K. Suk
The neurovascular unit is composed of a microvascular endothelium,
neuron, and glial cell elements that are in physical proximity
to the endothelium. The vascular system provides oxygen, glucose,
and hormones for brain cells and guides the cells to appropriately
respond to the local environment. Conversely, the brain cells,
especially glial cells, can regulate the function of blood
vessels in response to local requirements. The disruption
of the neurovascular coordi-nation was observed in a variety
of inflammation-related diseases in brain, such as infectious
diseases, stroke, vascular dementia, and multiple sclerosis.
Inflammatory responses resulting from infections or injury
of the brain activate the en-dothelium and glial cells to
various degrees depending on the type, titer, or strength
and duration of exposure to the agents or insults. The activation
of endothelial and microglial cells may be modulated by the
action of cytokines or other substances secreted from these
cells. In an effort to understand the pathogenesis and find
rational treatments against in-flammatory disorders in brain,
studies have been separately carried out using either endothelial
cells or microglia. In-creasing evidence, however, indicates
that a crosstalk between these two cell types is important
for the brain inflamma-tion. Here, we review recent advances
that provide insights into the coordinated interaction between
the vascular and microglial systems, including the role of
the specialized endothelium in regulating the immune response
that occurs within CNS, the influence of microglial cells
on the properties of endothelial cells, and the effects of
endothelium on the state of microglial activation.
[Back to top]
Driving Cellular Plasticity and Survival Through the
Signal Transduction Pathways of Metabotropic Glutamate Receptors
K. Maiese, Z.Z. Chong and F. Li
Metabotropic glutamate receptors (mGluRs) share a common
molecular morphology with other G protein–linked receptors,
but there expression throughout the mammalian nervous system
places these receptors as essential mediators not only for
the initial development of an organism, but also for the vital
determination of a cell's fate during many disorders in the
nervous system that include amyotrophic lateral sclerosis,
Parkinson's disease, Alzheimer's disease, Huntington's disease,
Multiple Sclerosis, epilepsy, trauma, and stroke. Given the
ubiquitous distribution of these receptors, the mGluR system
impacts upon neuronal, vascular, and glial cell function and
is activated by a wide variety of stimuli that includes neurotransmitters,
peptides, hormones, growth factors, ions, lipids, and light.
Employing signal transduction pathways that can modulate both
excitatory and inhibitory responses, the mGluR system drives
a spectrum of cellular pathways that involve protein kinases,
endonucleases, cellular acidity, energy metabolism, mitochondrial
membrane potential, caspases, and specific mitogen-activated
protein kinases. Ultimately these pathways can converge to
regulate genomic DNA degradation, membrane phosphatidylserine
(PS) residue exposure, and inflammatory microglial activation.
As we continue to push the envelope for our understanding
of this complex and critical family of metabotropic receptors,
we should be able to reap enormous benefits for both clinical
disease as well as our understanding of basic biology in the
nervous system.
[Back to top]
The Emerging Role of Coenzyme Q-10 in Aging, Neurodegeneration,
Cardiovascular Disease, Cancer and Diabetes
M. Dhanasekaran and J. Ren
Coenzyme Q (ubiquinone, 2-methyl-5,6-dimethoxy-1,4-benzoquinone),
soluble natural fat quinine, is crucial to optimal biological
function. The coenzyme Q molecule has amphipathic (biphasic)
properties due to the hydrophilic benzoquinone ring and the
lipophilic poly isoprenoid side-chain. The nomenclature of
coenzyme Q-n is based on the amount of isoprenoid
units attached to 6-position on the benzoquinone ring. It
was demonstrated that coenzyme Q, in addition to its role
in electron transport and proton transfer in mitochondrial
and bacterial respiration, acts in its reduced form (ubiquinol)
as an antioxidant. Coenzyme Q-10 functions as a lipid antioxidant
regulating membrane fluidity, recycling radical forms of vitamin
C and E, and protecting membrane phospholipids against peroxidation.
The antioxidant property, high degree of hydrophobicity and
universal occurrence in biological system, suggest an important
role for ubiquinone and ubiquinol in cellular defense against
oxidative damage. Coenzyme Q-10 is a ubiquitous and endogenous
lipid-soluble antioxidant found in all organisms. Neurodegenerative
disorders, cancer, cardiovascular diseases and diabetes mellitus
and especially aging and Alzheimer’s disease exhibit
altered levels of ubiquinone or ubiquinol, indicating their
likely crucial role in the pathogenesis and cellular mechanisms
of these ailments. This review is geared to discuss the biological
effect of coenzyme Q with an emphasis on its impact in initiation,
progression, treatment and prevention of neurodegenerative,
cardiovascular and carcinogenic diseases.
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