| Current
Neurovascular Research
ISSN: 1567-2026
Current Neurovascular Research
Volume 2, Number 4, October 2005
Contents
From The Editor's Perspective: Unlocking the Secrets
to Cell Survival and Longevity Pp.269
K. Maiese
[Abstract]
ORIGINAL ARTICLE
The Sirtuin Inhibitor Nicotinamide Enhances Neuronal
Cell Survival During Acute Anoxic Injury Through Akt, Bad,
PARP, and Mitochondrial Associated "Anti-Apoptotic"
Pathways Pp.271
Z.Z. Chong, S.-H. Lin, F. Li and K. Maiese
[Abstract]
REVIEW ARTICLES
Estrogen Activates Classical and Alternative Mechanisms to
Orchestrate Neuroprotection Pp.287
R. Marin, B. Guerra, R. Alonso, C.M. Ramírez and
M. Díaz
[Abstract]
Sympathetic Nervous System, Genes and Human Essential
Hypertension Pp.303
H. Zhu, J. Poole, Y. Lu, G. Harshfield, F. Treiber, H.
Snieder and Y. Dong
[Abstract]
Stromal Derived Growth Factor-1alpha as a Beacon for
Stem Cell Homing in Development and Injury Pp.319
C.M. Claps, K.E. Corcoran, K.J. Cho and P. Rameshwar
[Abstract]
Vital Elements of the Wnt-Frizzled Signaling Pathway
in the Nervous System Pp.331
F. Li, Z.Z. Chong and K. Maiese
[Abstract]
Cerebrovascular Damage as a Cause for Alzheimer's
Disease? Pp.341
C. Humpel and J. Marksteiner
[Abstract]
Experimental Models of Relapsing-Remitting Multiple
Sclerosis: Current Concepts and Perspective Pp.349
D.S. Skundric
[Abstract]
Abstracts
[Back to top]
From The Editor's Perspective: Unlocking the Secrets
to Cell Survival and Longevity
K. Maiese
Although our present knowledge of the cellular pathways
that modulate injury in the nervous system continues to unfold
at an exponential rate, reversal or even prevention of cellular
injury in the brain can be less than desired under many circumstances.
As a result, elucidating novel therapeutic targets for the
treatment of neuronal and vascular injury could be highly
beneficial to eliminate disability incurred during acute or
chronic degenerative disorders of the nervous system. In this
issue of Current Neurovascular Research, we present exciting
new work and reviews of the literature of unique neuronal
and vascular cellular systems that can have a substantial
role during disease entities such as cerebral ischemia, hypertension,
Alzheimer's disease, and multiple sclerosis. Further understanding
of these cellular pathways should foster the safe and efficacious
translation of this knowledge into robust therapeutic regimens
that allow clinical research to become "practice"
rather than only "promise".
In an original article by Chong et al., we learn that nicotinamide,
a precursor for the coenzyme ß-nicotinamide adenine
dinucleotide (NAD+), has a double life in regards to its effects
on cell biology. Nicotinamide is utilized by the body for
cellular metabolism through the generation of adenosine triphosphate
in the mitochondrial electron transport chain. Yet, this interesting
nutrient also is linked to cellular lifespan. Increased longevity,
at least in yeast and adult metazoans, is dependent upon sirtuin
2 (Sir2) protein expression and an enzyme that deaminates
nicotinamide to convert it into nicotinic acid, namely pyrazinamidase/nicotinamidase
1 (PNC1). When nicotinamide cell concentrations are absent
or minimal, Sir2 is activated and PNC1 expression is increased
to lead to yeast lifespan extension during calorie restriction.
On the flip side, when nicotinamide is present in the cell
at higher concentrations, this essential nutrient can function
as an inhibitor of sirtuins and offer protection against cerebral
ischemia, spinal cord injury, brain trauma, excitotoxicity,
and oxidative stress. Chong et al. provide us with further
insight into the cellular mechanisms responsible for the ability
of nicotinamide to offer cellular protection. In an anoxic
cellular model, they show that a cascade of pathways controlled
by nicotinamide are intimately connected to involve activation
of Akt1, phosphorylation of Bad, prevention of mitochondrial
permeability, and the maintenance of poly(ADP-ribose) polymerase
integrity to protect against early apoptotic membrane phosphatidylserine
residue exposure and subsequent genomic DNA degradation.
Interestingly, other endogenous systems of the body are also
tied to protection of the brain as exemplified on the cover
of this issue. In their review article, Marin et al. discuss
for us the protective role of estradiol in regards to a number
of insults of the nervous system. They note that protection
can ensue through classical estrogen receptor activation and
mechanisms that involve gene transcription stimulated by estradiol.
However, non-genomic (alternative) signalling pathways that
involve extranuclear plasma membrane estrogen receptors can
play a significant role with mitogen-activated protein kinases,
phosphatidylinositol 3-kinase, protein kinase C, and additional
signal transduction systems. Zhu et al. take us to the sympathetic
nervous system to gain further insight into the genetic mechanisms
that can control vascular resistance and essential hypertension.
They describe how minimal changes in several genes that regulate
the sympathetic nervous system by single nucleotide polymorphisms
can significantly impact the cardiovascular system and the
development of hypertension.
In the next paper, Claps et al. lead us from the cardiovascular
system to cellular pathways of the hematopoietic system that
can extend into the control of neuronal development and repair.
They provide us with a unique perspective into the role of
the novel chemokine, stromal derived growth factor alpha (SDF-1α),
and its receptor, CXCR4, during cell migration, proliferation,
and differentiation. Yet, they caution us on the potential
detrimental effects of SDF-1α
when considering the therapeutic potential of this pathway,
since SDF-1α
under some conditions can lead to tumor formation. Li et al.
further complement the discussion of cellular pathways that
can transcend multiple biological systems with their analysis
of the Wnt-Frizzled signaling pathway. Wnt proteins are cysteine-rich
glycosylated proteins named after the Drosophilia Wingless
(Wg) and the mouse Int-1 genes that are critical for processes
that range from cellular patterning to cellular apoptosis.
Through a variety of pathways that include intracellular calcium,
glycogen synthase kinase-3β, adenomatous polyposis coli,
and β-catenin, Wnt proteins modulate cell survival and
fate through novel mechanisms that control cytokines and growth
factors during disorders such as neuropsychiatric disease,
retinal disease, and Alzheimer's disease. In regards to Alzheimer's
disease, Humpel and Marksteiner shed new light on this disease
and propose that dysfunction of the vascular system in conjunction
with amyloid pathology may be essential for the development
of Alzheimer's disease and, at the very least, interface closely
with an individual's decline during other forms of cognitive
loss. In our last paper, Skundric discusses the course of
development to optimize knowledge gained from experimental
models for the eventual treatment of clinical disease. In
particular, discussion focuses upon the pathophysiology of
acute and relapsing demyelinating disease as well as the molecular
mechanisms that control neuroinflammatory processes to effectively
translate this work into viable clinical treatments for multiple
sclerosis.
The work presented in this issue of Current Neurovascular
Research should continue to bring us closer to the exciting
developments of new therapeutic approaches for a host of neurovascular
disorders that may be linked to cellular development, metabolism,
survival, and longevity. It is our hope that these future
clinical strategies will continue to mature from the "bench"
to the "bedside". In this vein, I am also extremely
proud to announce the continued successful maturity of Current
Neurovascular Research. The journal has greatly exceeded expectations
to not only fill a critical void in today's scientific literature
to publish novel work that bridges the gap between basic science
research and clinical discovery, but also has provided a high
caliber resource for international researchers in several
cross disciplines that may focus upon investigations of the
brain, cardiovascular system, immune system, and hematopoetic
system. Since the brief period from its initial launch, Current
Neurovascular Research has garnered the support of well recognized
investigators and has achieved a significant feat by being
awarded citation in leading indexing services that boast only
a ten percent acceptance rate for evaluated journals such
as Science Citation Index Expanded, ISI Alerting Services,
Neuroscience Citation Index, Chemical Abstracts, Current Contents,
and MEDLINE. The journal continues to cover a wide breadth
of research topics dedicated to a broad audience of both basic
scientists and physicians that maintain either primary or
secondary interest in the nervous system. As a result, Current
Neurovascular Research has been the recipient of highly competitive
submissions from respected leaders in a variety of fields
that shape the progress of world health. As a testament of
the enthusiasm and high regard for Current Neurovascular Research
by the international community, published articles from Current
Neurovascular Research during its inaugural year have been
cited in a number of other high impact publications. I am
sincerely indebted to the great efforts of my extremely dedicated
publishing staff and our renowned Editorial Board to help
foster the wonderful success and longevity of Current Neurovascular
Research.
[Back to top]
The Sirtuin Inhibitor Nicotinamide Enhances Neuronal
Cell Survival During Acute Anoxic Injury Through AKT, BAD,
PARP, and Mitochondrial Associated "Anti-Apoptotic"
Pathways
Zhao-Zhong Chong, Shi-Hua Lin, Faqi Li and Kenneth Maiese
Understanding the role of nicotinamide (NIC) in different
cell systems represents a significant challenge in several
respects. Recently, NIC has been reported to have diverse
roles during cell biology. In the absence of NIC, sirtuin
protein activity is enhanced and pyrazinamidase/nicotinamidase
1 (PNC1) expression, an enzyme that deaminates NIC to convert
NIC into nicotinic acid, is increased to lead to lifespan
extension during calorie restriction, at least in yeast. Yet,
NIC may be critical for cell survival as well as the modulation
of inflammatory injury during both experimental models as
well as in clinical studies. We therefore investigated some
of the underlying signal transduction pathways that could
be critical for the determination of the neuroprotective properties
of NIC. We examined neuronal injury by trypan blue exclusion,
DNA fragmentation, phosphatidylserine (PS) exposure, Akt1
phosphorylation, Bad phosphorylation, mitochondrial membrane
potential, caspase activity, cleavage of poly(ADP-ribose)
polymerase (PARP), and mitogen-activated protein kinases (MAPKs)
phosphorylation. Application of NIC (12.5 mM) significantly
increased neuronal survival from 38 ± 3% of anoxia
treated alone to 68 ± 3%, decreased DNA fragmentation
and membrane PS exposure from 67 ± 4% and 61 ±
5% of anoxia treated alone to 30 ± 4% and 26 ±
4% respectively. We further demonstrate that NIC functions
through Akt1 activation, Bad phosphorylation, and the downstream
modulation of mitochrondrial membrane potential, cytochrome
c release, caspase 1, 3, and 8 - like activities, and PARP
integrity to prevent genomic DNA degradation and PS externalization
during anoxia. Yet, NIC does not alter the activity of either
the MAPKs p38 or JNK, suggesting that protection by NIC during
anoxia is independent of the p38 and JNK pathways. Additional
investigations targeted to elucidate the cellular pathways
responsible for the ability of NIC to modulate both lifespan
extension and cytoprotection may offer critical insight for
the development of new therapies for nervous system disorders.
[Back to top]
Estrogen Activates Classical and Alternative Mechanisms
to Orchestrate Neuroprotection
Raquel Marin, Borja Guerra, Rafael Alonso, Cristina M.
Ramírez and Mario Díaz
Evidence for a protective role of estradiol in neurodegenerative
diseases has steadily increased over the past decade, though
the mechanisms of action and the participation of true estrogen
receptors (ERs) have proven a complex score. The protective
effects of estrogens take place partly through pathways involving
canonical ER activation, which is constitutively expressed
in many brain regions and is able to initiate gene transcription
after specifically binding to estradiol. In addition, non-genomic
(or alternative) signalling pathways, involving extranuclear
ERs, respond to physiological concentration of estrogens to
elicit neuroprotection. Often, rapid activation of intracellular
signallers such as mitogen-activated protein kinase (MAPK)
or phosphatidylinositol 3-kinase (PI3K) underlie alternative
estrogen-induced neuroprotection upon activation of specific
binding sites at the plasma membrane. Although the molecular
characteristics of these unconventional ERs are still largely
unknown, the generally held view maintains that plasma membrane
ER (mER) originates from, or is related to, classical nuclear
ERs. The present article will review some of the most recent
evidence revealing the relevance of alternative mechanisms
in estrogen-dependent neuroprotection. Special emphasis will
be paid to cellular models of amyloid-β toxicity where
classical and alternative pathways activated by estrogens
seem to coexist to orchestrate neuroprotection.
[Back to top]
Sympathetic Nervous System, Genes and Human Essential
Hypertension
Haidong Zhu, Joseph Poole, Yanhui Lu, Gregory A. Harshfield,
Frank A. Treiber, Harold Snieder and Yanbin Dong
The sympathetic nervous system (SNS) is the first line of
defense in the response to environmental stress through its
regulation of second-to-second changes in blood pressure (BP).
Both the activity of the SNS and the therapeutic responses
to SNS agonists and antagonists are known to be highly variable
in the population. “Small” changes caused by single
nucleotide polymorphisms (SNPs) of SNS genes may have considerable
impact on SNS function and individualized hypertension treatment.
In this review, we first describe the physiology of the SNS
and its influence on cardiovascular and renal mechanisms of
BP regulation. A thorough review of the role of genetic variability
of various SNS genes in relation to the development of BP
and essential hypertension (EH) follows. Given the vast number
of SNS components, evaluations of multiple SNPs from multiple
SNS genes are necessary for future association studies of
BP and EH. One way to surpass the limitations and inconsistencies
of previous association studies is to use a gene-based approach
also referred to as indirect association, which takes all
common variation within a candidate gene into account. In
order to determine how SNS genes are differentially expressed
or silenced, activated or inactivated against various environmental
backgrounds, it is important to assess not only environmental
and lifestyle risk factors such as diet, climate, chronic
stress, but also personality characteristics such as hostility
and coping styles. Uncovering relevant gene-gene and gene-environment
interactions within the SNS cascade will not only enable early
detection of EH risk but will also aid in the treatment of
hypertensives through both non-pharmacological and pharmacological
means.
[Back to top]
Stromal Derived Growth Factor-1alpha as a Beacon for
Stem Cell Homing in Development and Injury
Christopher M. Claps, Kelly E. Corcoran, Kyung Jin Cho
and Pranela Rameshwar
This review extrapolates the functions of SDF-1α
and its receptor, CXCR4, as regulators of hematopoietic stem
cells and discusses their potential roles in the development
and regeneration of tissues. The discussion focuses on the
repair of neural tissues while parallels are made with bone
marrow hematopoietic stem cells. Overall, the organization
links the basic biology of SDF-1α
and CXCR4 to topics in medicine and show how any disease processes
involving the SDF-1α-CXCR4
system could be central points in medicine. Discussions focused
on potential therapies for SDF-1 and CXCR4 in clinical disorders.
Breast and prostate cancers are selected as examples of solid
tumors while leukemia is discussed as an example of hematological
malignancies. Diffuse macular edema is discussed as potential
therapy for a non-malignant disease.
[Back to top]
Vital Elements of the Wnt-Frizzled Signaling Pathway
in the Nervous System
Faqi Li, Zhao Zhong Chong and Kenneth Maiese
Wnt proteins are cysteine-rich glycosylated proteins named
after the Drosophilia Wingless (Wg) and the mouse
Int-1 genes that play a role in embryonic cell patterning,
proliferation, differentiation, orientation, adhesion, survival,
and programmed cell death (PCD). Wnt proteins involve at least
two intracellular signaling pathways. One pathway controls
target gene transcription through β-catenin,
generally referred to as the canonical pathway and a second
pathway pertains to intracellular calcium (Ca2+)
release which is termed the non-canonical or Wnt/ Ca2+
pathway. The majority of Wnt proteins activate gene
transcription through the canonical signaling pathway regulated
by pathways that include the Frizzled transmembrane receptor
and the co-receptor LRP-5/6, Dishevelled, glycogen synthase
kinase-3β
(GSK-3β),
adenomatous polyposis coli (APC), and β-catenin.
In contrast, the non-canonical Wnt signaling pathway has two
intracellular signaling cascades that consist of the Wnt/
Ca2+ pathway with protein kinase C (PKC) and the
Wnt/PCP pathway involving Rho/Rac small GTPase and Jun N-terminal
kinase (JNK). Through a series of signaling pathways, Wnt
proteins modulate cell development, proliferation, and cell
fate. In regards to cell survival and fate through PCD, Wnt
may be critical for the prevention of tissue pathology that
involves cytokine and growth factor control during disorders
such as neuropsychiatric disease, retinal disease, and Alzheimer's
disease. Elucidation of the vital elements that shape and
control the Wnt-Frizzled signaling pathway may provide significant
prospects for the treatment of disorders of the nervous system.
[Back to top]
Cerebrovascular Damage as a Cause for Alzheimer’s
Disease
Christian Humpel and Josef Marksteiner
Alzheimer´s disease is a progressive brain disorder
that gradually destroys a patient´s memory function
and ability to carry out daily activities. According to the
prevailing amyloid cascade hypothesis, Alzheimer´s disease
is initiated by amyloid ß-peptide accumulation leading
to neuronal toxicity. The neurofibrillary tangle deriving
from hyperphosphorylated tau and synapse loss are also key
features for Alzheimer´s disease. Recent studies revealed
a significant co-morbidity of Alzheimer´s disease and
cerebrovascular disease suggesting that cerebrovascular dysregulation
is an important feature of Alzheimer´s disease. This
mini-review will discuss the hypothesis that a dysfunction
of the vascular system may result in damage of the neurovascular
unit, initiating a cascade of events. An overlap with other
forms of cognitive impairment, such as mild cognitive impairment,
or vascular dementia will be discussed.
[Back to top]
Experimental Models of Relapsing-Remitting Multiple
Sclerosis: Current Concepts and Perspective
Dusanka S. Skundric
Multiple sclerosis (MS) and its model experimental autoimmune
encephalomyelitis (EAE) are debilitating paralytic diseases
caused by inflammation, demyelination and axonal degeneration
of the central nervous system (CNS). Whilst the autoimmune
nature of MS is strongly suggested by evidence of myelin specific
autoreactive T cells and antibodies, EAE is an experimentally
induced CNS specific autoimmune disease. As opposed to the
majority of MS patients, which exhibit a relapsing-remitting
course of the disease, only a handful of available EAE models
displays relapsing-remitting course. In this review, we will
summarize differences in regulation of acute and relapsing
disease with emphasis on relapsing-remitting EAE models, and
outline advantages and limitations of available relapsing
EAE models pertinent for studies of relapsing human disease.
We will discuss current concepts of relapse regulation by
focusing on immune and molecular mechanisms of neuroinflammation,
oligodendrocyte damage, myelin loss and axonal degeneration.
This review will compare our present understanding of relapse
regulation in human versus experimental autoimmune disease.
Translation of mechanisms learned from relapsing EAE into
development of new therapies for MS will be evaluated. Finally,
perspectives in further optimization and development of more
suitable experimental models to study human relapsing-remitting
MS will be discussed.
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