| Current
Neurovascular Research
ISSN: 1567-2026
Current Neurovascular Research
Volume 8, Number 1, February 2011
Contents
ORIGINAL ARTICLES
Transplantation of Adipose Tissue-Derived Stem Cells for Treatment of Focal Cerebral
Ischemia Pp. 1-13
Yi-Chin Yang, Bai-Shuan Liu, Chiung-Chyi Shen, Chen-Huan Lin, Ming-Tsang Chiao and Hsu-Chen Cheng
[Abstract] [Purchase
Article] [PMID: 21208165 PubMed - indexed for MEDLINE]
Anti-Angiogenic Effects of Resveratrol on Cerebral Angiogenesis Pp. 14-24
Pei-Lin Chen and Alexander S. Easton
[Abstract] [Purchase
Article] [PMID: 21208159 PubMed - indexed for MEDLINE]
An Arylidene-Thiazolidinedione Derivative, GPU-4, without PPARγ Activation, Reduces
Retinal Neovascularization Pp. 25-34
Shinsuke Nakamura, Kei Hayashi, Haruka Takizawa, Tetsuji Murase, Kazuhiro Tsuruma,
Masamitsu Shimazawa, Hiroki Kakuta, Hideko Nagasawa and Hideaki Hara
[Abstract] [Purchase
Article] [PMID: 21208163 PubMed - indexed for MEDLINE]
Brief Hyperthermia does not Worsen Outcome after Striatal Hemorrhage in Rats Pp.
35-43
Mark Penner, Gergely Silasi, Shannon Wowk, Lindsey Warkentin and Frederick Colbourne
[Abstract] [Purchase
Article] [PMID: 21208166 PubMed - indexed for MEDLINE]
Hypoxia-Inducible Factor-1α Contributes to Brain Edema after Stroke by Regulating
Aquaporins and Glycerol Distribution in Brain
Pp. 44-51
Tetsuhiro Higashida, Changya Peng, Jie Li, David Dornbos III, Kailing Teng, Xiaohua Li,
Harish Kinni, Murali Guthikonda and Yuchuan Ding
[Abstract] [Purchase
Article] [PMID: 21208160 PubMed - indexed for MEDLINE]
The Contribution of Mannose Binding Lectin to Reperfusion Injury after Ischemic
Stroke Pp. 52-63
Helena W. Morrison, Jennifer B. Frye, Grace F. Davis-Gorman, Janet L. Funk,
Paul F. McDonagh, Gregory L. Stahl and Leslie S. Ritter
[Abstract] [Purchase
Article] [PMID: 21208161 PubMed - indexed for MEDLINE]
Protein-Energy Malnutrition Alters Thermoregulatory Homeostasis and the Response to
Brain Ischemia Pp. 64-74
Shari E. Smith, Erin J. Prosser-Loose, Frederick Colbourne and Phyllis G. Paterson
[Abstract] [Purchase
Article] [PMID: 21208162 PubMed - indexed for MEDLINE]
REVIEW ARTICLE
The Start of a New Era for Stroke Treatment: Mechanical Thrombectomy Devices
Pp. 75-85
Sihame Benmira, Zuliana K. Banda and Vish Bhattacharya
[Abstract] [Purchase
Article] [PMID: 21208164 PubMed - indexed for MEDLINE]
Abstracts
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[Purchase
Article] [PMID: 21208165 PubMed - indexed for MEDLINE]
Transplantation of Adipose Tissue-Derived Stem Cells for Treatment of Focal Cerebral
Ischemia
Yi-Chin Yang, Bai-Shuan Liu, Chiung-Chyi Shen, Chen-Huan Lin, Ming-Tsang Chiao and Hsu-Chen Cheng
The neurological functional disabilities caused by cerebral infarction significantly deteriorate life quality and
increase the medical and socio-economic costs. Although some molecular agents show potential in acting against the
pathological mechanisms in animal studies, none has been proven effective for cerebral ischemia treatment in human
patients. New treatment strategy needs to be developed. Stem cell therapy is promising for neural regeneration and thus
become one of the current trends. More evidence has shown stem cells, such as embryonic stem cells (ESCs), skeletal
muscle satellite cells and mesenchymal stem cells, to be useful in tissue repair and regeneration. However all these stem
cells mentioned above have limitations. Adipose tissue-derived stem cells (ADSCs) are an alternative autologous stem
cell source for the characters as abundant, easy to obtain, immunological and ethic problem free. So far, this treatment
strategy has been rarely adopted on ischemic brain injury. In this study, we investigated the transplantation effects of rat
ADSCs for the treatment of cerebral ischemia in rats. ADSCs were isolated from rat adipose tissue and then induced to
initiate neural differentiation. Following neural induction, ADSCs developed neural morphology and displayed molecular
expression of Nestin, MAP2 and GFAP. We evaluate the neurobehavioral function, infarct volume and cell properties as
apoptosis, survival, migration, proliferation, differentiation and immunogenicity. Treatment with i-ADSCs (induction
from ADSCs) results in better functional recovery and more reduction in hemispheric atrophy then without i-ADSCs in
other groups. Our study demonstrates that i-ADSCs therapy is promising in stroke treatment and finally leads to an
efficacious therapeutic modalities for much better outcome in clinical patients.
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Article] [PMID: 21208159 PubMed - indexed for MEDLINE]
Anti-Angiogenic Effects of Resveratrol on Cerebral Angiogenesis
Pei-Lin Chen and Alexander S. Easton
Angiogenesis is implicated in diseases of the central nervous system, and its modulation represents an attractive
therapeutic strategy. This is the first report of the effects of resveratrol (trans-3,4’,5-trihydroxystilbene) on cerebral
angiogenesis, using an in vitro model. Processes associated with angiogenesis were studied in cerebrovascular endothelial
cells (EC), using the human brain EC line hCMEC/D3 and primary bovine brain microvessel EC (BBMEC). Comparisons
were made to human umbilical vein EC (HUVEC). In cerebral cultures, resveratrol (24h) induced a dose dependent
reduction in BrdU incorporation and cell numbers (MTT assay) between 10-100μM, while lower doses (100nM-5µM) had
no effect. Cell migration (scratch assay) was inhibited between 10-100μM depending on cell type. Doses between 10-
100µM reduced average tubule length on Matrigel, while higher doses (50,100μM) also inhibited process formation
around explanted rat aortic rings (ex vivo assay). Cell cycle analysis in hCMEC/D3 (propidium iodide) showed reduced
progression to the G2/M phase, with a maximal effect at 25µM. Resveratrol did not induce apoptosis in hCMEC/D3,
based on caspase-3 activity. Cytotoxicity (LDH release) was induced by resveratrol (50,100μM) in hCMEC/D3 and
HUVEC, peaking at ~20% in hCMEC/D3 and ~35% in HUVEC. Cytotoxic effects were not detected in BBMEC.
Resveratrol (10-50μM) inhibited phosphorylation of the serine/threonine kinase Akt, by Western blot (15min, 1h) with a
prolonged inhibition (24h) for 25μM. In conclusion, this study shows inhibitory effects of resveratrol on cerebral
angiogenesis, using an in vitro model. This is discussed in terms of dosage, in vivo equivalence and therapeutic potential.
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Article] [PMID: 21208163 PubMed - indexed for MEDLINE]
An Arylidene-Thiazolidinedione Derivative, GPU-4, without PPARγ Activation, Reduces
Retinal Neovascularization
Shinsuke Nakamura, Kei Hayashi, Haruka Takizawa, Tetsuji Murase, Kazuhiro Tsuruma,
Masamitsu Shimazawa, Hiroki Kakuta, Hideko Nagasawa and Hideaki Hara
Retinal angiogenesis is a leading cause of blindness, including retinopathy of prematurity, diabetic retinopathy,
and age-related macular degeneration. Vascular endothelial growth factor (VEGF) is one of the major angiogenesis
factors, and induces endothelial cell proliferation and migration. VEGF stimulates NADPH oxidase to produce reactive
oxygen species (ROS), and ROS induce the transcription factors and genes involved in angiogenesis. In the present study,
we demonstrated that GPU-4, 5-arylidene-2,4-thiazolidinedione derivative, demonstrates anti-angiogenic activity
regarding human retinal microvascular endothelial cells (HRMECs) and retinal neovascularization in a mouse model of
retinopathy of prematurity. GPU-4 inhibited the VEGF-induced radicals, proliferation, and migration in HRMECs without
a PPARγ-mediated effect. Furthermore, systemic administration of GPU-4 inhibited the development of retinal
neovascularization in a murine oxygen-induced retinopathy model but did not exert revascularization of the capillary-free
area, which shows normal physiological revascularization. These findings indicate that GPU-4 suppressed in vitro and in
vivo retinal neovascularization partly by a radical scavenging effect, suggesting that GPU-4 might be a potential
therapeutic agent candidate for proliferative diseases of the retinal vasculature.
[Back to top] [Purchase
Article] [PMID: 21208166 PubMed - indexed for MEDLINE]
Brief Hyperthermia does not Worsen Outcome after Striatal Hemorrhage in Rats
Mark Penner, Gergely Silasi, Shannon Wowk, Lindsey Warkentin and Frederick Colbourne
Hyperthermia accelerates and increases ischemic brain damage. Owing to overlapping mechanisms of injury,
many assume that hyperthermia also worsens outcome after intracerebral hemorrhage (ICH). However, clinical data do
not conclusively prove this, and there is only one animal study examining the impact of hyperthermia. In that study
(MacLellan and Colbourne, 2005), several hyperthermia protocols were administered after collagenase-induced ICH in
rats; none worsened injury. While the collagenase model is widely used, it differs in important ways from another
common model – injecting autologous blood directly into the brain. Thus, we evaluated the impact of immediate
hyperthermia (HYP, 39 ºC for 3 hr) after a 100-μL infusion of blood into the striatum of rats. This treatment, which
markedly increases ischemic damage, was compared to control rats kept normothermic (NOR, 37 ºC). Three separate
experiments were done to measure: 1) edema at 24 hr, 2) edema at 72 hr, and 3) behavioral impairment and lesion size out
to 1 month post-ICH. The HYP treatment did not significantly affect edema at 24 hr, but surprisingly, it modestly reduced
edema at 72 hr and partly improved behavioral outcome. However, there were no lasting effects of HYP on behavior (e.g.,
skilled reaching) or the volume of tissue lost (NOR: 14.0 mm3 vs. HYP: 14.5 mm3). In summary, our findings do not
support the common belief that hyperthermia worsens outcome after ICH. Additional research is needed to determine
whether more severe or prolonged heating or fever and its cause (e.g., infection) affect morbidity and mortality after ICH.
[Back to top] [Purchase
Article] [PMID: 21208160 PubMed - indexed for MEDLINE]
Hypoxia-Inducible Factor-1α Contributes to Brain Edema after Stroke by Regulating
Aquaporins and Glycerol Distribution in Brain
Tetsuhiro Higashida, Changya Peng, Jie Li, David Dornbos III, Kailing Teng, Xiaohua Li,
Harish Kinni, Murali Guthikonda and Yuchuan Ding
Brain edema following stroke is a critical clinical problem due to its association with increased morbidity and
mortality. Despite its significance, present treatment for brain edema simply provides symptomatic relief due to the fact
that molecular mechanisms underlying brain edema remain poorly understood. The present study investigated the role of
hypoxia-inducible factor-1α (HIF-1α) and aquaporins (AQP-4 and -9) in regulating cerebral glycerol accumulation and
inducing brain edema in a rodent model of stroke.
Two-hours of middle cerebral artery occlusion (MCAO) followed by reperfusion was performed in male Sprague-Dawley
rats (250-280g). Anti-AQP-4 antibody, anti-AQP-9 antibody, or 2-Methoxyestradiol (2ME2, an inhibitor of HIF-1α) was
given at the time of MCAO. The rats were sacrificed at 1 and 24 hours after reperfusion and their brains were examined.
Extracellular and intracellular glycerol concentration of brain tissue was calculated with an enzymatic glycerol assay. The
protein expressions of HIF-1α, AQP-4 and AQP-9 were determined by Western blotting. Brain edema was measured by
brain water content. Compared to control, edema (p < 0.01), increased glycerol (p < 0.05), and enhanced expressions of
HIF-1α, AQP-4, and AQP-9 (p < 0.05) were observed after stroke. With inhibition of AQP-4, AQP-9 or HIF-1α, edema
and extracellular glycerol were significantly (p < 0.01) decreased while intracellular glycerol was increased (p < 0.01) 1
hour after stroke. Inhibition of HIF-1α with 2ME2 suppressed (p < 0.01) the expression of AQP-4 and AQP-9. These
findings suggest that HIF-1α serves as an upstream regulator of cerebral glycerol concentrations and brain edema via a
molecular pathway involving AQP-4 and AQP-9. Pharmacological blockade of this pathway in stroke patients may
provide novel therapeutic strategies.
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Article] [PMID: 21208161 PubMed - indexed for MEDLINE]
The Contribution of Mannose Binding Lectin to Reperfusion Injury after Ischemic
Stroke
Helena W. Morrison, Jennifer B. Frye, Grace F. Davis-Gorman, Janet L. Funk,
Paul F. McDonagh, Gregory L. Stahl and Leslie S. Ritter
After complement system (CS) activation, the sequential production of complement products increases cell
injury and death through opsonophagocytosis, cytolysis, adaptive, and inflammatory cell responses. These responses
potentiate cerebral ischemia-reperfusion (IR) injury after ischemic stroke and reperfusion. Activation of the CS via
mannose binding lectin (MBL)-initiated lectin pathway is known to increase tissue damage in response to IR in muscle,
myocardium and intestine tissue. In contrast, the contribution of this pathway to cerebral IR injury, a neutrophil-mediated
event, is less clear. Therefore, we investigated the potential protective role of MBL deficiency in neutrophil-mediated
cerebral injury after IR. Using an intraluminal filament method, neutrophil activation and cerebral injury were compared
between MBL-deficient and wild type C57Bl/6 mice subjected to 60 minutes of MCA ischemia and reperfusion. Systemic
neutrophil activation was not decreased in MBL-deficient animals after IR. In MBL-deficient animals, cerebral injury was
significantly decreased only in the striatum (p < 0.05). Despite MBL deficiency, C3 depositions were evident in the
injured hemisphere during reperfusion. These results indicate that while MBL deficiency results in a modest protection of
a sub-cortical brain region during IR, redundant complement pathway activation may overwhelm further beneficial effects
of MBL deficiency during reperfusion.
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Protein-Energy Malnutrition Alters Thermoregulatory Homeostasis and the Response to
Brain Ischemia
Shari E. Smith, Erin J. Prosser-Loose, Frederick Colbourne and Phyllis G. Paterson
Co-existing protein-energy malnutrition (PEM), characterized by deficits in both protein and energy status,
impairs functional outcome following global ischemia and has been associated with increased reactive gliosis. Since
temperature is a key determinant of brain damage following an ischemic insult, the objective was to investigate whether
alterations in post-ischemic temperature regulation contribute to PEM-induced reactive gliosis following ischemia. Male
Sprague-Dawley rats (190-280g) were assigned to either control diet (18% protein) or PEM induced by feeding a low
protein diet (2% protein) for 7 days prior to either global ischemia or sham surgery. There was a rapid disruption in
thermoregulatory function in rats fed the low protein diet as assessed by continuous recording of core temperature with
bio-electrical sensor transmitters. Both daily temperature fluctuation and mean temperature increased within the first 24
hours, and these remained significantly elevated throughout the 7 day pre-ischemic period (p < 0.027). In the immediate
post-surgical period, PEM decreased body temperature to a greater extent than that in well-nourished controls (p = 0.003).
The increase in daily temperature fluctuation caused by PEM persisted throughout the 7 day post-surgical period (p <
0.001), and this interacted with the effects of global ischemia on days 8 (p = 0.018) and 11 (p = 0.021). The astrocytic and
microglial responses induced at 7 days after global ischemia were not influenced by PEM, but this preliminary analysis
needs to be confirmed with a more reliable global ischemia model. In conclusion, exposure to a low protein diet rapidly
impairs the ability to maintain thermoregulatory homeostasis, and the resultant PEM also diminishes the ability to
thermoregulate in response to a challenge. Since temperature regulation is a key determinant of brain injury following
ischemia, these findings suggest that the pathophysiology of brain injury could be altered in stroke victims with coexisting
PEM.
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The Start of a New Era for Stroke Treatment: Mechanical Thrombectomy Devices
Sihame Benmira, Zuliana K. Banda and Vish Bhattacharya
Stroke is a major cause of mortality in the U.K. accounting for 53,000 deaths every year. There are few options
for the treatment of acute ischemic stroke and recombinant tissue plasminogen activator (rt-PA) remains the only
approved and currently available thrombolytic therapy given within the first 3 hours after symptom onset. Mechanical
thrombectomy is a promising new treatment modality for patients who are ineligible for or failing intravenous rt-PA, or
presenting beyond the narrow 3-hour therapeutic window, and emerged with the development of the Merci retrieval
system. A number of devices are now available and can be divided into two major subgroups according to their mode of
action. Those using a proximal approach such as aspiration devices (Penumbra system) act by applying a vacuum to the
proximal aspect of the thrombus whereas distal devices (Merci retrieval system, Phenox clot retriever, and Catch device)
such as coil-like and basket-like devices are advanced through the thrombus thereby contacting its distal aspect. In this
review, we discuss the procedure and technique, as well as evidence associated with four mechanical retrieval systems
currently available: the Merci Retriever System, the Penumbra system, the Catch device, and the Phenox clot retriever.
We also consider potential novel approaches for stroke treatment including waterjet thrombectomy and laser
recanalization.
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