| Current
Neurovascular Research
ISSN: 1567-2026
Current Neurovascular Research
Volume 4, Number 4, November 2007
Contents
Advanced Glycation End Products, Oxidative
Stress and Metalloproteinases are altered in the Cerebral
Microvasculature during Aging Pp. 228-234
F. Safciuc, A. Constantin, A. Manea, M. Nicolae, D. Popov,
M. Raicu, D. Alexandru and E. Constantinescu
[Abstract]
Clozapine and Olanzapine but not Risperidone Impair
the Pre Frontal Striatal System in relation to Egocentric
Spatial Orientation in a Y-Maze Pp. 235-239
C.C. Castro, E.A.D. Reis-Lunardelli, W.J. Schmidt, A.S.
Coitinho and I. Izquierdo
[Abstract]
Clearance of Amyloid-β
Peptide by Neuronal and Non-Neuronal Cells: Proteolytic Degradation
by Secreted and Membrane associated Proteases Pp.
240-251
M. Panchal, N. Lazar, N. Munoz, C. Fahy, C. Clamagirand,
J.-P. Brouard, L. Dubost, P. Cohen, N. Brakch and M. Rholam
[Abstract]
Intracranial Venous Haemodynamics in Multiple Sclerosis
Pp. 252-258
P. Zamboni, E. Menegatti, I. Bartolomei, R. Galeotti,
A.M. Malagoni, G. Tacconi and F. Salvi
[Abstract]
Effects of an Acute Treatment with L-Thyroxine on
Memory, Habituation, Danger Avoidance, and on Na+,
K+-ATPase activity in Rat
Brain Pp. 259-267
E.A. dos Reis-Lunardelli, M.R. Ramirez, C.C. Castro, A.S.
Coitinho, C. Bavaresco, L.S.S. da Trindade, M.F. Perrenoud,
A.T. de Souza Wyse, J.J.F. Sarkis and I. Izquierdo
[Abstract]
Macrophage Infiltration, Lectin-Like Oxidized-LDL
Receptor-1, and Monocyte Chemoattractant Protein-1 are reduced
by Chronic HMG-CoA Reductase Inhibition Pp. 268-273
A. Tsuchiya, S. Nagotani, T. Hayashi, K. Deguchi, Y. Sehara,
T. Yamashita, H. Zhang, V. Lukic, T. Kamiya and K. Abe
[Abstract]
Increased Neuronal Injury in Transgenic Mice with
Neuronal Overexpression of Human Cyclooxygenase-2 is reversed
by Hypothermia and Rofecoxib Treatment Pp. 274-279
Z. Xiang, S. Thomas and G. Pasinetti
[Abstract]
Alterations in Cerebral Metabolomics and Proteomic
Expression during Sepsis Pp. 280-288
J. Hinkelbein, R.E. Feldmann Jr., A. Peterka, C. Schubert,
D. Schelshorn, M.H. Maurer and A. Kalenka
[Abstract]
REVIEW ARTICLES
Cardiac Dys-Synchronization and Arrhythmia in Hyperhomocysteinemia
Pp. 289-294
K.S. Moshal, C.K. Camel, G.K. Kartha, M.M. Steed, N. Tyagi,
U. Sen, Y.J. Kang, D. Lominadze, C. Maldonado and S.C. Tyagi
[Abstract]
"SLY AS A FOXO": New Paths with Forkhead
Signaling in the Brain Pp. 295-302
K. Maiese, Z.Z. Chong and Y.C. Shang
[Abstract]
Abstracts
[Back to top]
Advanced Glycation End Products, Oxidative
Stress and Metalloproteinases are altered in the Cerebral
Microvasculature during Aging
F. Safciuc, A. Constantin, A. Manea, M. Nicolae, D. Popov,
M. Raicu, D. Alexandru and E. Constantinescu
Biological aging is associated with an increased incidence
of cerebrovascular disease. Recent findings indicate that
oxidative stress promoting age-related changes of cerebral
circulation are involved in neurodegenerative disorders such
as Alzheimer’s disease (AD) and Parkinson’s disease.
The aim of this study was to evaluate the contribution of
cerebral microvessels to the oxidative stress during brain
aging, by: (i) assessment of precursors for advanced glycation
end products (AGE) formation, (ii) activities of antioxidant
enzymes, namely superoxide dismutase (SOD), glutathione peroxidase
(GPx) and glutathione disulfide reductase (GR), and (iii)
the activities of metalloproteinases (MMPs), MMP-2 and MMP-9,
involved in synaptogenesis and memory consolidation. The experiments
were performed on two groups of male Wistar rats: 15 young
(3-6 months old) and 15 aged (18-24 months old) animals. The
cerebral microvessels were isolated by mechanical homogenization,
the concentration of protein carbonyls and the activity of
antioxidant enzymes were evaluated by spectrophotometry, and
gelatin SDS-PAGE zymography was employed to evaluate MMP-2
and MMP-9 activities. The results showed that, by comparison
with young rats, aged brain microvessels contain: (i) ~ 106
% increase of protein carbonyls production; (ii) ~ 68% higher
GPx activity, unmodified activities of SOD and GR; (iii) ~
30% diminishment in MMP-2 activity, and the specific occurrence
of MMP-9 enzyme. The data suggest that the age-related changes
of microvessels could increase the propensity for cerebral
diseases and might represent, at least in part, a prerequisite
for the deterioration of mental and physical status in the
elderly.
[Back to top]
Clozapine and Olanzapine but not Risperidone Impair
the Pre Frontal Striatal System in relation to Egocentric
Spatial Orientation in a Y-Maze
C.C. Castro, E.A.D. Reis-Lunardelli, W.J. Schmidt, A.S.
Coitinho and I. Izquierdo
Many studies indicate a dissociation between two forms of
orientation: allocentric orientation, in which an organism
orients on the basis of cues external to the organism, and
egocentric spatial orientation (ESO) by which an organism
orients on the basis of proprioceptive information. While
allocentric orientation is mediated primarily by the hippocampus
and its afferent and efferent connections, ESO is mediated
by the prefronto-striatal system. Striatal lesions as well
as classical neuroleptics, which block dopamine receptors,
act through the prefronto-striatal system and impair ESO.
The purpose of the present study was to determine the effects
of the atypical antipsychotics clozapine, olanzapine and risperidone
which are believed to exert its antipsychotic effects mainly
by dopaminergic, cholinergic and serotonergic mechanisms.
A delayed-two-alternative-choice-task, under conditions that
required ESO and at the same time excluded allocentric spatial
orientation was used. Clozapine and olanzapine treated rats
made more errors than risperidone treated rats in the delayed
alternation in comparison with the controls. Motor abilities
were not impaired by any of the drugs. Thus, with regard to
the delayed alternation requiring ESO, clozapine and olanzapine
but not risperidone affects the prefronto-striatal system
in a similar way as classical neuroleptics does.
[Back to top]
Clearance of Amyloid-β
Peptide by Neuronal and Non-Neuronal Cells: Proteolytic Degradation
by Secreted and Membrane associated Proteases
M. Panchal, N. Lazar, N. Munoz, C. Fahy, C. Clamagirand,
J.-P. Brouard, L. Dubost, P. Cohen, N. Brakch and M. Rholam
Deposition of amyloid-βpeptide
(Aβ)
in the brain is an early and invariant feature of all forms
of Alzheimer’s disease (AD). As for all proteins or
peptides, the steady-state level of Aβ
peptide is determined not only by its production, but also
by its degradation. So, overactive proteases involved in generating
Aβ
from amyloid precursor protein or underactive Aβ-degrading
enzymes could lead to abnormal Aβ
deposition in the brain. Since in the sporadic forms of AD
(90% of all AD cases) an impaired clearance of Aβ
appears to be at the origin of its aggregation and tissue
deposition, we have investigated its proteolytic degradation
by several neuronal and non-neuronal cells. In this report,
we show that these cell types exhibit a similar profile of
Aβ-degradation
by cell-surface and secreted proteases which were respectively
characterized as metallo- and serine proteases. By using a
combination of the liquid chromatography/on-line mass spectrometry,
we demonstrate that: (i)-the membrane associated protease(s)
hydrolizes Aβ40
essentially at Lys28↓Gly29,
Phe19↓Phe20
and Val18↓Phe19
bonds; and (ii)-the secreted protease(s) cleaves the generating
fragments Aβ(1-28),
Aβ(1-19),
Aβ(1-18)
at His14↓Gln15
bond and also Aβ(1-28)
at Phe20↓Ala21
and Asp23↓Val24
sites. This is the first time our results define a proteolytic
degradation process of Aβ40
that appears to be independent of the cell type and may represent
a general pattern of its enzymatic clearance.
[Back to top]
Intracranial Venous Haemodynamics in Multiple Sclerosis
P. Zamboni, E. Menegatti, I. Bartolomei, R. Galeotti,
A.M. Malagoni, G. Tacconi and F. Salvi
In multiple sclerosis (MS) plaques are known to be venocentric;
in addition, MS lesions and peripheral venous disorders share
a number of key features. To date, however, despite the anatomical
relationship between MS lesions and the venous system, no
information on the intracranial venous haemodynamics of MS
is available. Eighty-nine consecutive MS patients (58 relapsing-remitting,
31 secondary progressive) matched with 60 controls underwent
transcranial color-coded duplex sonography (TCCS). We assessed,
in supine as well as in sitting positions, the direction of
flow at the activation of the thoracic pump in the deep middle
cerebral veins (dMCVs), and in the transverse sinus (TS).
In the dMCVs, we also measured peak systolic velocity (PSV),
peak diastolic velocity (PDV), as well as the resistance index
(RI). Reflux/bidirectional flow rate was significantly higher
in the MS population determining also significant differences
in PDV, characterized by negative values (16.2±1 cm/sec
in controls vs. –1.3 ±2.6 cm/sec in MS, respectively,
p<0.0001). Consequently, RI was dramatically increased
in the MS group, affecting impedance of cerebral venous drainage
(0.48±0.04 in controls vs. 1.1 ±0.08 in MS,
respectively p<0.0001). Therefore, the detection of reflux
directed toward the subcortical grey matter was significantly
associated to highest disability scores (p < 0.0001). Our
study of MS patients demonstrated significant haemodynamic
alterations detected in veins anatomically related to plaque
disposition. Our findings should contribute towards understanding
the role of altered venous flow and tissue drainage in the
MS inflammatory chain, as well as in the neurodegenerative
process.
[Back to top]
Effects of an Acute Treatment with L-Thyroxine on
Memory, Habituation, Danger Avoidance, and on Na+,
K+-ATPase activity in Rat
Brain
E.A. dos Reis-Lunardelli, M.R. Ramirez, C.C. Castro, A.S.
Coitinho, C. Bavaresco, L.S.S. da Trindade, M.F. Perrenoud,
A.T. de Souza Wyse, J.J.F. Sarkis and I. Izquierdo
Thyroid hormones (THs) have a relevant action on brain development
and maintenance. By using an acute treatment to induce a hyperthyroid
animal model, we aimed at investigating the effect of an altered
THs levels on learning and memory and on the activity of Na+,
K+-ATPase in the rat brain.
Our results have shown that the acute treatment with L-T4
did not alter the retrieval of the inhibitory avoidance task,
but had a significant effect on the elevated plus maze and
on open-field performance in rats. We suggest that animals
subjected to L-T4 administration improved the habituation
to a novel environment as well as a better evaluation of a
dangerous environment, respectively. Na+,
K+-ATPase activity is increased
in parietal cortex (30%), but it is not altered in hippocampus
in L-T4 treated group. These both brain structures are involved
in memory processing and it was previously demonstrated that
there is a double dissociation be-tween them for spatial location
information, perceptual and episodic memory. We propose the
hypothesis that this increase of Na+,
K+-ATPase activity in parietal
cortex may be correlated to our results in behavior tests,
which suggest a role of THs as well as of the Na+,
K+-ATPase in the cognitive
process.
[Back to top]
Macrophage Infiltration, Lectin-Like Oxidized-LDL
Receptor-1, and Monocyte Chemoattractant Protein-1 are reduced
by Chronic HMG-CoA Reductase Inhibition
A. Tsuchiya, S. Nagotani, T. Hayashi, K. Deguchi, Y. Sehara,
T. Yamashita, H. Zhang, V. Lukic, T. Kamiya and K. Abe
Statin reduces cerebrovascular events independent of its cholesterol
lowering effect. We hypothesized that statin inhibits early
atherosclerotic change in common carotid artery (CCA), and
investigated its effect on lectin-like oxidized-LDL receptor-1
(LOX-1) and monocyte chemoattractant protein-1 (MCP-1) expression,
both of which are early atherosclerotic markers. Stroke-prone
spontaneous hypertensive rats (SHR-SP) of 8 weeks old were
orally treated with vehicle or simvastatin (20mg/kg) daily.
After 4 weeks of simvastatin or vehicle treatment, or 2 weeks
of vehicle and 2 weeks of simvastatin treatment, CCA was removed.
LOX-1 and MCP-1 expression as well as macrophage infiltration
were histologically investigated. Lipid deposition was also
investigated by Sudan III staining. Simvastatin groups showed
significantly smaller amount of lipid deposition and LOX-1
and MCP-1 expression, independent of serum lipid levels. Macrophage
infiltration was also decreased. Reduction of cerebrovascular
events by statins may be brought by the direct inhibition
of atherosclerotic change.
[Back to top]
Increased Neuronal Injury in Transgenic Mice with
Neuronal Overexpression of Human Cyclooxygenase-2 is reversed
by Hypothermia and Rofecoxib Treatment
Z. Xiang, S. Thomas and G. Pasinetti
Cyclooxygenase-2 (COX-2) is up-regulated during ischemia.
However, the role of COX-2 in neuronal injury is still unclear.
In this study we tested whether neuronal overexpression of
human COX-2 in a transgenic mouse model potentiates neuronal
injury after global ischemic insult. Further, we tested whether
the neuronal injury could be ameliorated by intra-ischemic
mild hypothermia (33-34°C) alone or in combination with
diet treatment of rofecoxib, a COX-2 specific inhibitor. Global
ischemia with intra-ischemic normothermia (36-37°C) resulted
in significantly higher neuronal damage in the CA1 region
of hippocampus of transgenic mice than in wild type controls,
confirming a deleterious role of COX-2 in ischemic neuronal
damage. Hypothermia significantly reduced neuronal damage
in both transgenic mice and wild type controls to the same
extent, suggesting that the aggravating effect of COX-2 could
be largely eliminated by hypothermia. When hypothermia was
combined with rofecoxib treatment, neuronal damage was further
reduced in response to global ischemia. The results suggest
that COX-2 inhibition by prophylactic treatment with rofecoxib
coupled with hypothermia at the time of acute stroke insult
could be an effective therapeutic approach in early stages
of stroke treatment in high risk patients.
[Back to top]
Alterations in Cerebral Metabolomics and Proteomic
Expression during Sepsis
J. Hinkelbein, R.E. Feldmann Jr., A. Peterka, C. Schubert,
D. Schelshorn, M.H. Maurer and A. Kalenka
The cause of brain dysfunction during sepsis and septic encephalopathy
is still under ongoing research. Sepsis induced changes in
cerebral protein expression may play a significant role in
the understanding of septic encephalopathy. The aim of the
present study was to explore cerebral proteome alterations
in septic rats. Fifty-six male Wistar rats were randomly assigned
to a sepsis group (coecal ligature and puncture, CLP) or a
control group (sham). Surviving rats were killed 24 or 48
hours after surgery and whole-brain lysates were used for
two-dimensional gel electrophoresis and subsequent protein
identification. Differentially expressed proteins were identified
by mass spectrometry. Using the Ingenuity Pathways Analysis
(IPA) tool, the relationship and interaction between the identified
proteins was analyzed. Mortality was 53 % in septic rats.
No rat of the control group was lost. More than 1,100 spots
per gel were discriminated of which 29 different proteins
were significantly (2-fold, P<0.01) changed: 24 proteins
down-regulated after 24 hours; two proteins up-regulated and
three down-regulated after 48 hours. IPA identified 11 of
35 differentially regulated proteins allocating them to an
existing inflammatory pathway. In the analysis of septic rat
brains, multiple differentially expressed proteins associated
with metabolism, signaling, and cell stress can be identified
via proteome analysis, that may help to understand
the development of septic encephalopathy.
[Back to top]
Cardiac Dys-Synchronization and Arrhythmia in Hyperhomocysteinemia
K.S. Moshal, C.K. Camel, G.K. Kartha, M.M. Steed, N. Tyagi,
U. Sen, Y.J. Kang, D. Lominadze, C. Maldonado and S.C. Tyagi
Although cardiac synchronization is important in maintaining
myocardial performance, the mechanism of dys-synchronization
in ailing to failing myocardium is unclear. It is known that
the cardiac myocyte contracts and relaxes individually; however,
it synchronizes only when connected to one another by low
resistance communications called gap junction protein (connexins)
and extra cellular matrix (ECM). Therefore, the remodeling
of connexins and ECM in heart failure plays an important role
in cardiac conduction, synchronization and arrhythmias. This
review for the first time addresses the role of systemic accumulation
of homocysteine (Hcy) in vasospasm, pressure and volume overload
heart failure, hypertension and cardiac arrhythmias. The attenuation
of calcium-dependent mitochondrial (mt), endothelial and neuronal
nitric oxide synthase (mtNOS, eNOS and nNOS) by Hcy plays
a significant role in cardiac arrhythmias. The signal transduction
mechanisms in Hcy-induced matrix metalloproteinase (MMP) activation
in cardiac connexin remodeling are discussed.
[Back to top]
"SLY AS A FOXO": New Paths with Forkhead
Signaling in the Brain
K. Maiese, Z.Z. Chong and Y.C. Shang
The Forkhead transcription factor FOXO3a has emerged as a
versatile target for diseases that impact upon neuronal survival,
vascular integrity, immune function, and cellular metabolism.
Enthusiasm is high to fill a critical treatment void through
FOXO3a signaling for several neurodegenerative disorders that
include aging, neuromuscular disease, systemic lupus erythematosus,
stroke, and diabetic complications. Here we discuss the influence
of FOXO3a upon cell survival and longevity, the intricate
signal transduction pathways of FOXO3a, insights into present
disease models, and the potential clinical translation of
FOXO3a signaling into novel therapeutic strategies.
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