| Current
Neurovascular Research
ISSN: 1567-2026
Current Neurovascular Research
Volume 7, Number 3, August 2010
Contents
ORIGINAL ARTICLES
Intravenous Implanted Neural Stem Cells Migrate to Injury Site, Reduce Infarct Volume, and Improve Behavior after Cerebral Ischemia Pp. 167-179
Chiung-Chyi Shen, Chen-Huan Lin, Ming-Tsang Chiao, Yi-Chin Yang, Wen-Yu Cheng and Jiunn-Liang Ko
[Abstract] [Purchase
Article] [PMID:
20560882 PubMed - indexed for MEDLINE]
Pitavastatin and 4’-Hydroxy-3’-Methoxyacetophenone (HMAP) Reduce Cognitive Dysfunction in Vascular Dementia During Experimental Diabetes Pp. 180-191
Bhupesh Sharma and Nirmal Singh
[Abstract] [Purchase
Article] [PMID:
20560881 PubMed - indexed for MEDLINE]
Homocysteine Enhances Transmigration of Rat Monocytes through a Brain Capillary Endothelial Cell Monolayer via ICAM-1 Pp. 192-200
Lindsay A. Hohsfield and Christian Humpel
[Abstract] [Purchase
Article] [PMID:
20560880 PubMed - indexed for MEDLINE]
Endogenous Agmatine Inhibits Cerebral Vascular Matrix Metalloproteinases Expression by Regulating Activating Transcription Factor 3 and Endothelial Nitric Oxide Synthesis Pp. 201-212
Hyun Joo Jung, Mei Zi Yang, Ki Hyo Kwon, Midori A. Yenari, Yoon Jung Choi, Won Taek Lee, Kyung
Ah Park and Jong Eun Lee
[Abstract] [Purchase
Article] [PMID:
20560878 PubMed - indexed for MEDLINE]
Angelica Injection Promotes Peripheral Nerve Structure and Function Recovery with Increased Expressions of Nerve Growth Factor and Brain Derived Neurotrophic Factor in Diabetic Rats Pp. 213-222
Ruilin Li, Junjian Zhang, Lei Zhang, Qin Cui and Hui Liu
[Abstract] [Purchase
Article] [PMID:
20560879 PubMed - indexed for MEDLINE]
Leptin and Interleukin-1β Modulate Neuronal Glutamate Release and Protect Against Glucose- Oxygen-Serum Deprivation Pp. 223-237
Chen-Hsuan Wang, Wei-Ti Wang, Shu-Yun Cheng, Wan-Ting Hung, Tzu-Lien Wu and Chi-Mei Hsueh
[Abstract] [Purchase
Article] [PMID:
20560877 PubMed - indexed for MEDLINE]
Spinal Microvascular Expression of PV-1 is Associated with Inflammation, Perivascular Astrocyte Loss, and Diminished Endothelial Cell Glucose Transport Potential in Acute Spinal Cord Injury Pp. 238-250
Anthony B. Mozer, Scott R. Whittemore and Richard L. Benton
[Abstract] [Purchase
Article] [PMID:
20590523 PubMed - indexed for MEDLINE]
REVIEW ARTICLE
Pathophysiology of the Vascular Wall and its Relevance for Cerebrovascular Disorders in Aged
Rodents Pp. 251-267
Aurel Popa-Wagner, Daniel Pirici, Eugen B. Petcu, Laurentiu Mogoanta, Ana-Maria Buga,
Charles L. Rosen, Rachel Leon and Jason D. Huber
[Abstract] [Purchase
Article] [PMID:
20590524 PubMed - indexed for MEDLINE]
Abstracts
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[Purchase
Article] [PMID:
20560882 PubMed - indexed for MEDLINE]
Intravenous Implanted Neural Stem Cells Migrate to Injury Site, Reduce Infarct Volume, and Improve Behavior after Cerebral Ischemia
Chiung-Chyi Shen, Chen-Huan Lin, Ming-Tsang Chiao, Yi-Chin Yang, Wen-Yu Cheng and Jiunn-Liang Ko
Stroke represents one of the leading causes of death and disability in humans, but despite intense research, only
a few options exist for the treatment of stroke-related infarction of brain tissue. Thus far, in experimental strokes, cell therapy appears to partly reverse some behavioral deficits. However, the mechanisms of action remain uncertain as most studies reveal only little, if any, evidence for neuronal replacement and observed behavioral improvements. This present study was performed to test rodent fetus forebrain derived neural stem cells (NSCs) implantation into rats subjected to suture-induced middle cerebral artery occlusion (MCAO). Efficacy of cell therapy was studied regarding behavior recovery, infarct volume, and protection possibility of related molecular mechanisms. Here, we show that grafted cells can home in on damaged regions by MCAO and significantly improve behavior of ischemic rats. Infarct volumes and brain atrophy were diminished after grafted NSCs treatment. Furthermore, we detected inflammation related molecules such as COX-2 and IL-1β and found that grafted NSCs treatment after ischemic stroke could repress expression of inflammation molecular protein levels. We also detected protein levels of heat shock protein 27 (HSP27) as a protective protein against apoptosis. The results showed that grafted NSCs treatment induced the protein level of HSP27 and down-regulated activity of caspase-3 compared with the vehicle control. Our results demonstrate that transplanted NSCs provide benefits in behavioral function recovery after MCAO and increase neuroprotection whilst repressing inflammatory destruction. These data reveal another essential explanation of cellular transplantation therapy in damage recovery from ischemic stroke and offer new therapeutic possibilities.
[Back to top] [Purchase
Article] [PMID:
20560881 PubMed - indexed for MEDLINE]
Pitavastatin and 4’-Hydroxy-3’-Methoxyacetophenone (HMAP) Reduce Cognitive Dysfunction in Vascular Dementia During Experimental Diabetes
Bhupesh Sharma and Nirmal Singh
Diabetes has been found to increase the probability of vascular dementia in humans. We have investigated the
effect of 4’-hydroxy-3’-methoxyacetophenone (HMAP), a NADPH oxidase inhibitor and Pitavastatin, a HMG Co-A reductase inhibitor, on Streptozotocin (STZ) diabetes induced vascular dementia in rats. Donepezil served as a positive control. The rats were administered with single dose of STZ for the induction of diabetes. Drug treatment was started after one month of STZ administration and treatment was continued till the end of the study (i.e. 56th day). On 52nd day onwards, the animals were exposed to Morris water-maze (MWM) for testing learning & memory. Serum glucose, body weight, vascular endothelial function, serum nitrite / nitrate levels, aortic & brain oxidative stress levels and brain acetylcholinesterase activity were also tested. STZ treated animals performed poorly on MWM hence reflecting impairment of learning & memory. Further STZ treatment also produced a reduction in body weight, impairment of vascular endothelial function, decrease in serum nitrite / nitrate levels, along with increase in serum glucose, aortic & brain oxidative stress levels and brain acetylcholinesterase activity. Treatment of HMAP, Pitavastatin and Donepezil significantly reversed diabetes induced impairment of learning and memory, endothelial dysfunction, and changes in
various biochemical levels. It may be concluded that STZ induces vascular dementia. 4’hydroxy-3’-methoxy
acetophenone and Pitavastatin may be considered as potential pharmacological agents for the management of diabetes induced vascular dementia
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20560880 PubMed - indexed for MEDLINE]
Homocysteine Enhances Transmigration of Rat Monocytes through a Brain Capillary Endothelial Cell Monolayer via ICAM-1
Lindsay A. Hohsfield and Christian Humpel
Increased homocysteine (Hcy) levels contribute to a variety of cardiovascular and cerebrovascular diseases
including stroke and Alzheimer’s disease. Recent data has shown that elevated levels of Hcy can lead to blood-brain
barrier (BBB) dysfunction and activation. However, the mechanism for Hcy-mediated dysfunction remains unclear. The
aim of this study is to characterize the effects of moderate Hcy administration in rat brain capillary endothelial cells
(BCECs), which serve as a simple model to study blood-brain barrier functions. This present study shows that addition of
20μ M Hcy for 6 days does not significantly affect BCEC survival, as measured by acridine orange staining, propidium
iodide staining, and nitrite content. However, addition of 20μ M Hcy for 6 days does elevate lactate dehydrogenase (LDH)
activity released into the supernatant of BCECs, as well as significantly enhances the transmigration of monocytes across
the BCEC in a time-dependent manner. In addition, TNFα levels in BCEC are also elevated by Hcy, whereas
inflammatory markers MIP3α and RANTES are significantly reduced. Finally, this study shows that intercellular adhesion
molecule-1 (ICAM-1) expression is significantly enhanced by 20μ M Hcy treatment compared to control conditions.
These results suggest that moderate levels of homocysteine can affect proinflammatory patterns expressed by BCECs,
ultimately leading to BBB activation and dysfunction through enhanced monocyte transmigration and ICAM-1
expression.
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Article] [PMID:
20560878 PubMed - indexed for MEDLINE]
Endogenous Agmatine Inhibits Cerebral Vascular Matrix Metalloproteinases Expression by Regulating Activating Transcription Factor 3 and Endothelial Nitric Oxide Synthesis
Hyun Joo Jung, Mei Zi Yang, Ki Hyo Kwon, Midori A. Yenari, Yoon Jung Choi, Won Taek Lee, Kyung Ah Park and Jong Eun Lee
Earlier investigations from our laboratory demonstrated that the expression of matrix metalloproteinases
(MMPs) was down-regulated by exogenously administered agmatine against ischemia-like injuries in the murine brain
capillary endothelial (bEnd.3) cells. In our present study, we intended to investigate the mechanism involved in the
inhibition of MMPs in bEnd.3 cells infected with retroviral containing human arginine decarboxylase (hADC) gene which
can synthesize agmatine endogenously (ADC△bEnd.3 cells). The ADC△bEnd.3 cells were subjected to oxygen glucose
deprivation (OGD, 6 hrs) with reperfusion (18 hrs). High performance liquid chromatography (HPLC) analysis revealed
the high levels of agmatine in the ADC△bEnd.3 cells compared to other experimental groups. The results demonstrated
significant decrease in cell death and increase in the nitric oxide (NO) production in the ADC△bEnd.3 cells. The
increased expression of MMP-2 and MMP-9, and decreased expression of endothelial nitric oxide synthase (eNOS) by
ischemic injury was attenuated in ADC△bEnd.3 cells. Moreover, the expression of activating transcription factor 3
(ATF3) was increased significantly in ADC△bEnd.3 cells. In addition, the suppression of the MMP-2 and MMP-9
expression in ADC△bEnd.3 cells was prevented with ATF3 small interfering RNA (siRNA) treatment. These results
suggest that the endogenous agmatine in ADC△bEnd.3 cells inhibits the MMPs expression mediated via the regulation of eNOS, NO and ATF3.
[Back to top] [Purchase
Article] [PMID:
20560879 PubMed - indexed for MEDLINE]
Angelica Injection Promotes Peripheral Nerve Structure and Function Recovery with Increased Expressions of Nerve Growth Factor and Brain Derived Neurotrophic Factor in Diabetic Rats
Ruilin Li, Junjian Zhang, Lei Zhang, Qin Cui and Hui Liu
Several nervous system injury models, such as sciatic crush and chronic cerebral hypoperfusion have been well
studied in terms of neuroprotective effect of angelica injection. However, definitive experimental studies are lacking on
diabetic peripheral neuropathy (DPN). This study sought to investigate the effects of angelica injection on DPN in type 1
diabetic rats. Diabetes was induced by single intraperitoneal injection of streptozotocin (STZ). To examine whether DPN
model successed, tail-flick latency (TFL) and motor nerve conduction velocity (MNCV) were measured at 6 weeks after
diabetes induction. Then, diabetic rats were treated with high- and low-dose angelica injection for 4 weeks. TFL, MNCV,
morphology of sciatic nerve, myelinated nerve fiber density and the expressions of nerve growth factor (NGF) and brain
derived neurotrophic factor (BDNF) in soleus and sciatic nerve were measured at 10 weeks after diabetes induction. The
results showed the TFL was significantly shortened (p<0.001) and the MNCV was reduced (p<0.01) in diabetic rats
compared with normal control rats at 6 weeks after diabetes induction. The TFL was obviously prolonged and the MNCV
was further reduced in diabetic control group at 10 weeks after diabetes induction. TFL, MNCV and morphology of
sciatic nerve were remarkably ameliorated and myelinated nerve fiber density and the expressions of NGF and BDNF in
soleus and sciatic nerve were increased in the angelica treatment groups. This study suggests angelica injection has
potential therapeutic effects on DPN, and the mechanism might be related to direct increase in NGF expression and direct
or indirect increase in BDNF expression.
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Article] [PMID:
20560877 PubMed - indexed for MEDLINE]
Leptin and Interleukin-1β Modulate Neuronal Glutamate Release and Protect Against Glucose- Oxygen-Serum Deprivation
Chen-Hsuan Wang, Wei-Ti Wang, Shu-Yun Cheng, Wan-Ting Hung, Tzu-Lien Wu and Chi-Mei Hsueh
Molecular mechanism underlying leptin-mediated neuronal protection against glucose-oxygen-serum
deprivation (GOSD) insult was investigated by focusing on the interactions among leptin, Interleukin-1β (IL-1β) and
glutamate and their impacts on the growth of neurons under GOSD. The trypan blue dye exclusion assay, 4', 6-diamidino-
2-phenylindole (DAPI) assay, cytokine antibody array assay, immunocytochemical staining assay, glutamate
determination kit, immunoblocking and chemical blocking strategies were applied to serve the study goal. Results showed
that in response to 6 h of GOSD, cortical neurons can secrete significant amounts of leptin and IL-1β to protect neurons
from GOSD-induced cell damage. Serine/threonine kinase Akt (Akt) and extracellular signal-related kinase (ERK)
inhibitors significantly reversed leptin-mediated neuroprotection. GOSD-induced IL-1β was further enhanced by leptin in
Akt/ERK-dependent manner. Blockade of endogenous leptin with specific antibodies significantly inhibited GOSDinduced
IL-1β expression and increased glutamate release from GOSD neurons. IL-1 blockade with IL-1 receptor
antagonist (IL-1ra) on the other hand, inhibited leptin-mediated neuroprotection and suppression of glutamate release
from GOSD neurons. Pre-treating GOSD neurons with leptin and IL-1β in combined significantly increased their survival
but decreased their releases of glutamate. The results indicate that leptin may act through Akt and ERK signaling
pathways to protect neurons from GOSD insult; the protection was in part IL-1 dependent and through which the
glutamate release from GOSD neurons was inhibited. Therapeutic values of leptin and IL-1β were suggested in the
treatment of cerebral ischemia at early stage.
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20590523 PubMed - indexed for MEDLINE]
Spinal Microvascular Expression of PV-1 is Associated with Inflammation, Perivascular Astrocyte Loss, and Diminished Endothelial Cell Glucose Transport Potential in Acute Spinal Cord Injury
Anthony B. Mozer, Scott R. Whittemore and Richard L. Benton
The endothelial-specific expression of plasmalemmal vesicle associated protein-1 (PV-1) is typical of
fenestrated endothelium observed in pulmonary capillaries and some endocrine organs. In the central nervous system
(CNS) it is expressed during development but disappears concomitant with maturation of the blood-CNS barrier [1].
Consistent with observations made in models of stroke, Alzheimer’s disease, and tumorigenesis, we show PV-1 expression in the spinal cord specifically upregulated by pathologically-activated endothelial cells (ECs) in response to
traumatic spinal cord injury (SCI). Adult female C57Bl/6 mice received a moderate T9/10 contusive SCI. PV-1 assessed
by qRT-PCR and immunohistochemistry 3 hours to 14 days post-injury showed expression as early as 1 day post-SCI,
with levels decreasing by 14 days. This expression was associated with microvessels in the injury epicenter and
penumbral zone, with the time course and distribution correlated with progressing peripheral inflammatory cell
infiltration. PV-1-immunoreactive ECs were angiogenic as demonstrated by intravascular binding of Griffonia simplicifolia isolectin B4 (IB4). ECs expressing high levels of PV-1 were anatomically and physiologically abnormal with
altered/absent immunostaining for occludin and zonula occludens-1 (ZO-1), and decreased expression of glial fibrillary
acidic protein (GFAP) and aquaporin-4 (AQP4). Glucose transporter type I (Glut-1) expression decreased in affected, PV-
1 positive microvessels with little colocalization of PV-1 and Glut-1 apparent by 7 days post-SCI. These data suggest that
upregulation of microvascular expression of PV-1 post-SCI may promote major components of secondary injury
including extravasation of cellular and acellular mediators of inflammation and may accelerate loss of neuropil and
decline in the functional and anatomical integrity of the neurovascular unit (NVU).
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20590524 PubMed - indexed for MEDLINE]
Pathophysiology of the Vascular Wall and its Relevance for Cerebrovascular Disorders in Aged Rodents
Aurel Popa-Wagner, Daniel Pirici, Eugen B. Petcu, Laurentiu Mogoanta, Ana-Maria Buga, Charles L. Rosen, Rachel Leon and Jason D. Huber
Chronic hypertension and cerebral amyloid angiopathy (CAA) are the main pathologies which can induce the
rupture of cerebral vessels and intracerebral hemorrhagies, as a result of degenerative changes in the vascular wall. A lot
of progress has been made in this direction since the successful creation of the first mouse model for the study of
Alzheimer’s disease (AD), as the spectrum of AD pathology includes a plethora of changes found in pure cerebrovascular
diseases. We describe here some of these mouse models having important vascular changes that parallel human AD
pathology, and more importantly, we show how these models have helped us understand more about the mechanisms that
lead to CAA formation. An important cellular event associated with reduced structural and functional recovery after
stroke in aged animals is the early formation of a scar in the infarcted region that impairs subsequent neural recovery and
repair. We review recent evidence showing that the rapid formation of the glial scar following stroke in aged rats is
associated with premature cellular proliferation that originates primarily from the walls of capillaries in the corpus
callosum adjacent to the infarcted region. After stroke several vascular mechanisms are turned-on immediately to protect
the brain from further damage and help subsequent neuroregeration and functional recovery. Although does occur after
stroke, vasculogenesis is overshadowed in its protective/restorative role by the angiogenesis and arteriogenesis.
Understanding the basic mechanisms underlying functional recovery after cerebral stroke in aging subjects is likely to
yield new insights into the treatment of brain injury in the clinic.
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