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author:("Jin, kunjin")
1.  Herbal Formula Danggui-Shaoyao-San Promotes Neurogenesis and Angiogenesis in Rat Following Middle Cerebral Artery Occlusion 
Aging and Disease  2015;6(4):245-253.
Current studies demonstrated that traditional Chinese herbal formula Danggui-Shaoyao-San (DSS) is not only used for the treatment of menstrual disorder, but has also found its use in neurological diseases. However, the neuroprotective role of DSS on ischemia-induced brain injury is still unclear. The aim of the present study is to explore the effect of DSS in ischemic brain injury. Total 30 adult female Sprague–Dawley rats underwent 90 min transient middle cerebral artery occlusion (MCAO). DSS (600 mg/kg) was administered through the intragastric route at the time of reperfusion and then performed every day thereafter until sacrifice. Results showed that DSS treatment significantly improved neurobehavioral outcomes (N=10 per group, P<0.05). Immunohistochemical staining showed that microvessel density in the perifocal region of DSS-treated rats was significantly increased compared to the saline-treated group (N=4 per group, P<0.01). Similarly, the numbers of BrdU+/DCX+ cells in the subventricular zone were increased in DSS-treated rats compared to the saline-treated group (P<0.05). Furthermore, we demonstrated that DSS treatment activated vascular endothelial growth factor (N=4 per group, P<0.05) and promoted eNOS phosphorylation (N=4 per group, P<0.05). Thus, we concluded that DSS promoted focal angiogenesis and neurogenesis, and attenuated ischemia-induced brain injury in rats after MCAO, suggesting that DSS is a potential drug for ischemic stroke therapy.
PMCID: PMC4509473
Ischemic stroke; Dangui-Shaoyao San; Angiogenesis; Neurogenesis
2.  Increasing Proliferation of Intrinsic Tubular Cells after Renal Ischemia-reperfusion Injury in Adult Rat 
Aging and Disease  2015;6(4):228-235.
The kidney is capable of regeneration following injury. However, whether renal stem/progenitor cells contribute to the repair process after injury, as well as the origin of the cells that repair and replace damaged renal tubule cells remains debated. Therefore, better understanding of the repair process will be critical to developing new strategies for the treatment of acute renal failure. Using an ischemia-reperfusion injury mode and an immunocytochemistry method, we counted the number of BrdU-positive cells in damged regions at different durations of reperfusion. We found that BrdU, a cell proliferative marker, was mainly incorporated in the tubular cells of both medulla and cortex 1 day after reperfusion. The number of BrdU-positive cells reached a peak at 3 days and lasted for two months after injury. BrdU-positive cells were barely found in the renal glomerulus and the parietal layer of Bowman’s capsule after injury, and only a few were found in the intersititium. PAX2, an embryonic renal marker, was also increased in renal tubule cells. Confocal images show that BrdU-positive cells co-expressed PAX2, but not the activated form of caspase-3, a cell death marker. Our data suggest that renal stem-like cells or dedifferentiation of surviving renal tubular cells in both the medulla and cortex may predominantly contribute to the repair process after renal ischemia-reperfusion injury in rat.
PMCID: PMC4509471
kidney; ischemia-reperfusion injury; renal stem cells; proliferative cells; Pax-2; Adult
3.  Acceleration of Tissue Plasminogen Activator-Mediated Thrombolysis by Magnetically Powered Nanomotors 
ACS Nano  2014;8(8):7746-7754.
Dose control and effectiveness promotion of tissue plasminogen activator (t-PA) for thrombolysis are vitally important to alleviate serious side effects such as hemorrhage in stroke treatments. In order to increase the effectiveness and reduce the risk of stroke treatment, we use rotating magnetic nanomotors to enhance the mass transport of t-PA molecules at the blood clot interface for local ischemic stroke therapy. The in vitro experiments demonstrate that, when combined with magnetically activated nanomotors, the thrombolysis speed of low-concentration t-PA (50 μg mL–1) can be enhanced up to 2-fold, to the maximum lysis speed at high t-PA concentration. Based on the convection enhanced transport theory due to rotating magnetic nanomotors, a theoretical model is proposed and predicts the experimental results reasonably well. The validity and efficiency of this enhanced treatment has been demonstrated in a rat embolic model.
PMCID: PMC4148143  PMID: 25006696
nanomotor; magnetic nanorods; stroke; acceleration of thrombolysis; enhanced mass transport
4.  Neural stem cell protects aged rat brain from ischemia–reperfusion injury through neurogenesis and angiogenesis 
Neural stem cells (NSCs) show therapeutic potential for ischemia in young-adult animals. However, the effect of aging on NSC therapy is largely unknown. In this work, NSCs were transplanted into aged (24-month-old) and young-adult (3-month-old) rats at 1 day after stroke. Infarct volume and neurobehavioral outcomes were examined. The number of differentiated NSCs was compared in aged and young-adult ischemic rats and angiogenesis and neurogenesis were also determined. We found that aged rats developed larger infarcts than young-adult rats after ischemia (P<0.05). The neurobehavioral outcome was also worse for aged rats comparing with young-adult rats. Brain infarction and neurologic deficits were attenuated after NSC transplantation in both aged and young-adult rats. The number of survived NSCs in aged rats was similar to that of the young-adult rats (P>0.05) and most of them were differentiated into glial fibrillary acidic protein+ (GFAP+) cells. More importantly, angiogenesis and neurogenesis were greatly enhanced in both aged and young-adult rats after transplantation compared with phosphate-buffered saline (PBS) control (P<0.05), accompanied by increased expression of vascular endothelial growth factor (VEGF). Our results showed that NSC therapy reduced ischemic brain injury, along with increased angiogenesis and neurogenesis in aged rats, suggesting that aging-related microenvironment does not preclude a beneficial response to NSCs transplantation during cerebral ischemia.
PMCID: PMC4083376  PMID: 24714034
aged rats; behavioral recovery; ischemia; neural stem cell transplantation
5.  mTOR signaling inhibition modulates macrophages/microglia-mediated neuroinflammation and secondary injury via regulatory T cells after focal ischemia 
Signaling by the mammalian target of rapamycin (mTOR) plays an important role in the modulation of both innate and adaptive immune responses. However, the role and underlying mechanism of mTOR signaling in post-stroke neuroinflammation is largely unexplored. Here, we injected rapamycin, an mTOR inhibitor, by the intracerebroventricular route 6 hours after focal ischemic stroke in rats. We found that rapamycin significantly reduced lesion volume and improved behavioral deficits. Notably, infiltration of gamma delta T (γδ T) cells and granulocytes, which are detrimental to the ischemic brain, was profoundly reduced after rapamycin treatment, as was the production of pro-inflammatory cytokines and chemokines by macrophages and microglia. Rapamycin treatment prevented brain macrophage polarization towards the M1 type. In addition, we also found that rapamycin significantly enhanced anti-inflammation activity of regulatory T cells (Tregs), which decreased production of pro-inflammatory cytokines and chemokines by macrophages and microglia. Depletion of Tregs partially elevated macrophage/microglia-induced neuroinflammation after stroke. Our data suggest that rapamycin can attenuate secondary injury and motor deficits after focal ischemia by enhancing the anti-inflammation activity of Tregs to restrain post-stroke neuroinflammation.
PMCID: PMC4128178  PMID: 24829408
Brain research  2014;1551:45-58.
Reactive astrogliosis is an essential feature of astrocytic response to all forms of central nervous system (CNS) injury and disease, which may benefit or harm surrounding neural and non-neural cells. Despite extensive study, its molecular triggers remain largely unknown in term of ischemic stroke. In the current study we investigated the role p38 mitogen-activated protein kinase (MAPK) in astrogliosis both in vitro and in vivo. In a mouse model of middle cerebral artery occlusion (MCAO), p38 MAPK activation was observed in the glia scar area, along with increased glial fibrillary acidic protein (GFAP) expression. In primary astrocyte cultures, hypoxia and scratch injury-induced astrogliosis was attenuated by both p38 inhibition and knockout of p38 MAPK. In addition, both knockout and inhibition of p38 MAPK also reduced astrocyte migration, but did not affect astrocyte proliferation. In a mouse model of permanent MCAO, no significant difference in motor function recovery and lesion volume was observed between conditional GFAP/p38 MAPK knockout mice and littermates. While a significant reduction of astrogliosis was observed in the GFAP/p38 knockout mice compared with the littermates. Our findings suggest that p38 MAPK signaling pathway plays an important role in the ischemic stroke-induced astrogliosis and thus may serve as a novel target to control glial scar formation.
PMCID: PMC3987968  PMID: 24440774
p38 MAPK; astrocytes; astrogliosis; glial fibrillary acidic protein; stroke; ischemia
7.  Cross-Talk between Human Neural Stem/Progenitor Cells and Peripheral Blood Mononuclear Cells in an Allogeneic Co-Culture Model 
PLoS ONE  2015;10(2):e0117432.
Transplantation of human neural stem/progenitor cells (hNSCs) as a regenerative cell replacement therapy holds great promise. However, the underlying mechanisms remain unclear. We, here, focused on the interaction between hNSCs and allogeneic peripheral blood mononuclear cells (PBMCs) in a co-culture model. We found that hNSCs significantly decrease the CD3+ and CD8+ T cells, reduce the gamma delta T cells and increase the regulatory T cells, along with reduced pro-inflammatory cytokines and increased anti-inflammatory cytokines after co-culture. We also found that PBMCs, in turn, significantly promote the proliferation and differentiation of hNSCs. Our data suggest that hNSCs cross-talk with immune cells.
PMCID: PMC4319716  PMID: 25658950
8.  The Critical Need to Promote Research of Aging and Aging-related Diseases to Improve Health and Longevity of the Elderly Population 
Aging and Disease  2014;6(1):1-5.
Due to the aging of the global population and the derivative increase in aging-related non-communicable diseases and their economic burden, there is an urgent need to promote research on aging and aging-related diseases as a way to improve healthy and productive longevity for the elderly population. To accomplish this goal, we advocate the following policies: 1) Increasing funding for research and development specifically directed to ameliorate degenerative aging processes and to extend healthy and productive lifespan for the population; 2) Providing a set of incentives for commercial, academic, public and governmental organizations to foster engagement in such research and development; and 3) Establishing and expanding coordination and consultation structures, programs and institutions involved in aging-related research, development and education in academia, industry, public policy agencies and at governmental and supra-governmental levels.
PMCID: PMC4306469  PMID: 25657847
aging; aging-related diseases; health; longevity; elderly; population
9.  Contra-Directional Expression of Serum Homocysteine and Uric Acid as Important Biomarkers of Multiple System Atrophy Severity: A Cross-Sectional Study 
Serum Hcy was higher in MSA patients when compared to healthy subjects, particularly in male patients.
Serum UA was lower in MSA patients when compared healthy subjects, particularly in male patients.
Serum Hcy levels were significantly positively correlated with the severity of MSA.
The ROC curve for the combination of Hcy and UA showed potential diagnostic value in discriminating MSA from healthy subjects.
There is evidence suggesting that inflammatory responses play a critical role in the pathogenesis of multiple system atrophy (MSA). Whether inflammatory mediators can be used as reliable biomarkers to detect the severity and progression of MSA remains largely unknown.
We performed a cross-sectional study that included 47 patients with MSA and 50 healthy age-matched controls. Serum levels of homocysteine (Hcy), uric acid (UA), and C-reactive protein (CRP) were measured. These levels positively correlated with the severity of MSA, based on both motor and non-motor symptoms. Several scales were used to rate the severity of MSA, including the Unified multiple system atrophy rating scale, Parkinson’s disease sleep scale, Non-motor Symptoms Scale, the Schwab & England activities of daily living scale, Webster Scale, modified Hoehn and Yahr staging scale, and the Mini-Mental State Examination. Receiver operating characteristic (ROC) curves was applied to map the diagnostic accuracy of MSA against healthy subjects.
Compared with healthy subjects, we found that serum Hcy was higher, UA was lower, and CRP levels were unchanged in MSA patients. These findings were especially prominent in male patients. No significant differences of serum Hcy and UA were observed between patients of MSA and PD. Interestingly, there was a significant correlation between Hcy levels and MSA severity such as movement dysfunction, declined cognition, and cardiovascular symptoms. Additionally, the ROC curve for the combination of Hcy and UA (AUC 0.736) showed potential diagnostic value in discriminating MSA from healthy subjects.
Our findings suggest that the inflammatory mediators Hcy and UA may play important roles in the pathogenesis of MSA. The measurement of serum Hcy and UA levels could then be a useful tool to accurately distinguish MSA from healthy subjects.
PMCID: PMC4492156  PMID: 26217177
multiple system atrophy; homocysteine; uric acid; cognition; inflammation
10.  Notch1 Signaling Modulates Neuronal Progenitor Activity in the Subventricular Zone in Response to Aging and Focal Ischemia 
Aging cell  2013;12(6):10.1111/acel.12134.
Neurogenesis diminishes with aging and ischemia-induced neurogenesis also occurs, but reduced in aged brain. Currently, the cellular and molecular pathways mediating these effects remain largely unknown. Our previous study has shown that Notch1 signaling regulates neurogenesis in subventricular zone (SVZ) of young-adult brain after focal ischemia, but whether a similar effect occurs in aged normal and ischemic animals is unknown. Here, we used normal and ischemic aged rat brains to investigate whether Notch1 signaling was involved in the reduction of neurogenesis in response to aging and modulates neurogenesis in aged brains after focal ischemia. By Western blot, we found that Notch1 and Jagged1 expression in the SVZ of aged brain was significantly reduced compared with young-adult brain. Consistently, the activated form of Notch1(Notch intracellular domain;NICD) expression was also declined. Immunohistochemistry confirmed that expression and activation of Notch1 signaling in the SVZ of aged brain were reduced. Double or triple immunostaining showed that that Notch1 was mainly expressed in DCX-positive cells, whereas Jagged1 was predominantly expressed in astroglial cells in the SVZ of normal aged rat brain. In addition, disruption or activation of Notch1 signaling altered the number of proliferating cells labeled by bromodeoxyuridine (BrdU) and doublecortin (DCX) in the SVZ of aged brain. Moreover, ischemia-induced cell proliferation in the SVZ of aged brain was enhanced by activating the Notch1 pathway, and was suppressed by inhibiting the Notch1 signaling. Reduced infarct volume and improved motor deficits were also observed in Notch1 activator-treated aged ischemic rats. Our data suggest that Notch1 signaling modulates the SVZ neurogenesis in aged brain in normal and ischemic conditions.
PMCID: PMC3838489  PMID: 23834718
Notch1 signaling pathway; aged rat brain; neurogenesis; focal cerebral ischemia
11.  Neurogenesis in Adult Human Brain after Traumatic Brain Injury 
Journal of Neurotrauma  2013;30(22):1872-1880.
While much work has been conducted regarding the neurogenesis response to traumatic brain injury (TBI) in rodents, it remains largely unknown whether neurogenesis in adult human brain also responds to TBI in a similar manner. Here, we performed immunocytochemistry on 11 brain specimens from patients with traumatic brain injury, who underwent surgical intervention. We found that expression of neural stem/progenitor cell (NSC) protein markers, including DCX, TUC4, PSA-NCAM, SOX2 and NeuroD, was increased in the perilesional cortex of human brain after TBI compared to that of normal brain. Confocal images showed that these NSC proteins were expressed in one single cell. We also found that proliferative markers were expressed in NSC protein-positive cells after TBI, and the number of proliferative NSCs was significantly increased after TBI. Our data suggest that TBI may also induce neurogenesis in human brain.
PMCID: PMC3815038  PMID: 21275797
brain trauma; human; injury; neurogenesis; stem cells
12.  Notch4 is Activated in Endothelial and Smooth Muscle Cells in Human Brain Arteriovenous Malformations 
Journal of cellular and molecular medicine  2013;17(11):10.1111/jcmm.12115.
Upregulation of Notch4 was observed in the endothelial cells in the arteriovenous malformations (AVMs) in mice. However, whether Notch4 is also involved in brain AVMs in humans remains unclear. Here, we performed immunohistochemistry on normal brain vascular tissue and surgically-resection brain AVMs and found that Notch4 was upregulated in the subset of abnormal vessels of the brain AVM nidus, compared with control brain vascular tissue. Two-photon confocal images show that Notch4 was expressed not only in the endothelial but also in the smooth muscle cells of the vascular wall in brain AVMs. Western blotting shows that Notch 4 was activated in brain AVMs, but not in middle cerebral artery of normal human brain, which was confirmed by immunostaining. Our findings suggest a possible contribution of Notch4 signaling to the development of brain AVMs in human.
PMCID: PMC3877925  PMID: 24373503
Notch4; AVM; human; brain; signaling
13.  A positive allosteric modulator of α7 nAChRs augments neuroprotective effects of endogenous nicotinic agonists in cerebral ischaemia 
British Journal of Pharmacology  2013;169(8):1862-1878.
Background and Purpose
Activation of α7 nicotinic acetylcholine receptors (nAChRs) can be neuroprotective. However, endogenous choline and ACh have not been regarded as potent neuroprotective agents because physiological levels of choline/ACh do not produce neuroprotective levels of α7 activation. This limitation may be overcome by the use of type-II positive allosteric modulators (PAMs-II) of α7 nAChRs, such as 1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)-urea (PNU-120596). This proof-of-concept study presents a novel neuroprotective paradigm that converts endogenous choline/ACh into potent neuroprotective agents in cerebral ischaemia by inhibiting α7 nAChR desensitization using PNU-120596.
Experimental Approach
An electrophysiological ex vivo cell injury assay (to quantify the susceptibility of hippocampal neurons to acute injury by complete oxygen and glucose deprivation; COGD) and an in vivo middle cerebral artery occlusion model of ischaemia were used in rats.
Key Results
Choline (20–200 μM) in the presence, but not absence of 1 μM PNU-120596 significantly delayed anoxic depolarization/injury of hippocampal CA1 pyramidal neurons, but not CA1 stratum radiatum interneurons, subjected to COGD in acute hippocampal slices and these effects were blocked by 20 nM methyllycaconitine, a selective α7 antagonist, thus, activation of α7 nAChRs was required. PNU-120596 alone was ineffective ex vivo. In in vivo experiments, both pre- and post-ischaemia treatments with PNU-120596 (30 mg·kg−1, s.c. and 1 mg·kg−1, i.v., respectively) significantly reduced the cortical/subcortical infarct volume caused by transient focal cerebral ischaemia. PNU-120596 (1 mg·kg−1, i.v., 30 min post-ischaemia) remained neuroprotective in rats subjected to a choline-deficient diet for 14 days prior to experiments.
Conclusions and Implications
PNU-120596 and possibly other PAMs-II significantly improved neuronal survival in cerebral ischaemia by augmenting neuroprotective effects of endogenous choline/ACh.
PMCID: PMC3753841  PMID: 23713819
PNU120596; PNU-120596; neuroprotection; anoxic depolarization; choline; α7 nAChR; hippocampus; cortex; ischaemia
14.  Vascular Endothelial Growth Factors (VEGFs) and Stroke 
Vascular endothelial growth factors (VEGFs) have been shown to participate in atherosclerosis, arteriogenesis, cerebral edema, neuroprotection, neurogenesis, angiogenesis, postischemic brain and vessel repair, and the effects of transplanted stem cells in experimental stroke. Most of these actions involve VEGF-A and the VEGFR-2 receptor, but VEGF-B, placental growth factor, and VEGFR-1 have been implicated in some cases as well. VEGF signaling pathways represent important potential targets for the acute and chronic treatment of stroke.
PMCID: PMC3634892  PMID: 23475070
vascular endothelial growth factor; stroke; ischemia; neuroprotection; neurogenesis; angiogenesis
15.  Expression Level of Vascular Endothelial Growth Factor in Hippocampus is Associated with Cognitive Impairment in Patients with Alzheimer’s Disease 
Neurobiology of aging  2012;34(5):1412-1415.
Although the enhanced expression of VEGF in the brains of patients with Alzheimer’s disease (AD) has been reported, the functional significance of VEGF level in the progression of AD is still unclear. We examined the VEGF expression in the hippocampus of patients with AD at different stages of progression by Western blot, and found that VEGF (VEGF189) was barely detectable in normal hippocampus, but significantly increased at the early stage of patients with AD. VEGF189 was decreased with advancing stages of AD. Immunostaining shows that VEGF was significantly increased in the cells in the CA1, CA3 and dentate gyrus regions of hippocampus and the layer III and V of entorhinal cortex of patient with AD, compared to normal brain. Confocal images show that VEGF was predominantly expressed in neurons and astrocyte in the hippocampus and entorhinal cortex of patients with AD. Our data suggest that VEGF level is associated with progressive loss of cognitive function in patients with AD.
PMCID: PMC3570710  PMID: 23182805
VEGF; Alzheimer’s disease; Human; brain; expression
16.  Inhibition of mammalian target of rapamycin improves neurobehavioral deficit and modulates immune response after intracerebral hemorrhage in rat 
Mammalian target of rapamycin (mTOR), a serine/threonine kinase, regulates many processes, including cell growth and the immune response. mTOR is also dysregulated in several neurological diseases, such as traumatic brain injury (TBI), stroke, and neurodegenerative disease. However, the role of mTOR in intracerebral hemorrhage (ICH) remains unexplored. The aims of our study were to determine whether inhibiting mTOR signaling could affect the outcome after ICH and to investigate the possible underlying mechanism.
A rat ICH model was induced by intracerebral injection of collagenase IV into the striatum, and mTOR activation was inhibited by administration of rapamycin. mTOR signaling activation was determined by western blotting. Neurobehavioral deficit after ICH was determined by a set of modified Neurological Severity Scores (mNSS). The levels of CD4+CD25+Foxp3+ regulatory T cells (Tregs) and cytokines were examined using flow cytometry and ELISA, respectively.
Our results demonstrated thatmTOR signaling was activated 30 minutes and returned to its basal level 1 day after ICH. Increased p-mTOR, which mean that mTOR signaling was activated, was predominantly located around the hematoma. Rapamycin treatment significantly improved the neurobehavioral deficit after ICH, increased the number of Tregs, increased levels of interleukin-10 and transforming growth factor-β and reduced interferon-γ both in peripheral blood and brain.
Our study suggests that mTOR improves ICH outcome and modulates immune response after ICH.
PMCID: PMC3975837  PMID: 24602288
ICH; mTOR; Rapamycin; Outcome; Immune response
17.  Glial Scar Formation Occurs in the Human Brain after Ischemic Stroke 
Reactive gliosis and glial scar formation have been evidenced in the animal model of ischemic stroke, but not in human ischemic brain. Here, we have found that GFAP, ED1 and chondroitin sulphate proteoglycans (CSPG) expression were significantly increased in the cortical peri-infarct regions after ischemic stroke, compared with adjacent normal tissues and control subjects. Double immunolabeling showed that GFAP-positive reactive astrocytes in the peri-infarct region expressed CSPG, but showed no overlap with ED1-positive activated microglia. Our findings suggest that reactive gliosis and glial scar formation as seen in animal models of stroke are reflective of what occurs in the human brain after an ischemic injury.
PMCID: PMC3936028  PMID: 24578611
glial scar; reactive gliosis; ischemic stroke; human; patients
18.  Methylene blue promotes quiescence of rat neural progenitor cells 
Neural stem cell-based treatment holds a new therapeutic opportunity for neurodegenerative disorders. Here, we investigated the effect of methylene blue on proliferation and differentiation of rat neural progenitor cells (NPCs) both in vitro and in vivo. We found that methylene blue inhibited proliferation and promoted quiescence of NPCs in vitro without affecting committed neuronal differentiation. Consistently, intracerebroventricular infusion of methylene blue significantly inhibited NPC proliferation at the subventricular zone (SVZ). Methylene blue inhibited mTOR signaling along with down-regulation of cyclins in NPCs in vitro and in vivo. In summary, our study indicates that methylene blue may delay NPC senescence through enhancing NPCs quiescence.
PMCID: PMC4188130  PMID: 25339866
methylene blue; neural progenitor cell; quiescence; proliferation; neurogenesis
19.  17β-Estradiol Attenuates Poststroke Depression and Increases Neurogenesis in Female Ovariectomized Rats 
BioMed Research International  2013;2013:392434.
Studies have linked neurogenesis to the beneficial actions of specific antidepressants. However, whether 17β-estradiol (E2), an antidepressant, can ameliorate poststroke depression (PSD) and whether E2-mediated improvement of PSD is associated with neurogenesis are largely unexplored. In the present study, we found that depressive-like behaviors were observed at the first week after focal ischemic stroke in female ovariectomized (OVX) rats, as measured by sucrose preference and open field test, suggesting that focal cerebral ischemia could induce PSD. Three weeks after middle cerebral artery occlusion (MCAO), rats were treated with E2 for consecutive 14 days. We found that E2-treated rats had significantly improving ischemia-induced depression-like behaviors in the forced-swimming test and sucrose preference test, compared to vehicle-treated group. In addition, we also found that BrdU- and doublecortin (DCX)-positive cells in the dentate gyrus of the hippocampus and the subventricular zone (SVZ) were significantly increased in ischemic rats after E2 treatment, compared to vehicle-treated group. Our data suggest that focal cerebral ischemia can induce PSD, and E2 can ameliorate PSD. In addition, newborn neurons in the hippocampus may play an important role in E2-mediated antidepressant like effect after ischemic stroke.
PMCID: PMC3838842  PMID: 24307996
20.  Notch4 is activated in endothelial and smooth muscle cells in human brain arteriovenous malformations 
Up-regulation of Notch4 was observed in the endothelial cells in the arteriovenous malformations (AVMs) in mice. However, whether Notch4 is also involved in brain AVMs in humans remains unclear. Here, we performed immunohistochemistry on normal brain vascular tissue and surgically resected brain AVMs and found that Notch4 was up-regulated in the subset of abnormal vessels of the brain AVM nidus, compared with control brain vascular tissue. Two-photon confocal images show that Notch4 was expressed not only in the endothelial but also in the smooth muscle cells of the vascular wall in brain AVMs. Western blotting shows that Notch4 was activated in brain AVMs, but not in middle cerebral artery of normal human brain, which was confirmed by immunostaining. Our findings suggest a possible contribution of Notch4 signalling to the development of brain AVMs in human.
PMCID: PMC3877925  PMID: 24373503
Notch4; AVM; human; brain; signalling
21.  Comparative protein interactomics of neuroglobin and myoglobin 
Journal of neurochemistry  2012;123(1):192-198.
Neuroglobin is a hypoxia-inducible O2-binding protein with neuroprotective effects in cell and animal models of stroke and Alzheimer’s disease. The mechanism underlying neuroglobin’s cytoprotective action is unknown, although several possibilities have been proposed, including antioxidative and antiapoptotic effects. We used affinity purification-mass spectrometry methods to identify neuroglobin-interacting proteins in normoxic and hypoxic murine neuronal (HN33) cell lysates, and to compare these interactions with those of a structurally and functionally related protein, myoglobin. We report that the protein interactomes of neuroglobin and myoglobin overlap substantially and are modified by hypoxia. In addition, neuroglobin-interacting proteins include partners consistent with both antioxidative and antiapoptotic functions, as well as with a relationship to several neurodegenerative diseases.
PMCID: PMC3438380  PMID: 22816983
hypoxia; ischemia; myoglobin; neuroglobin; proteome
22.  A Type-II Positive Allosteric Modulator of α7 nAChRs Reduces Brain Injury and Improves Neurological Function after Focal Cerebral Ischemia in Rats 
PLoS ONE  2013;8(8):e73581.
In the absence of clinically-efficacious therapies for ischemic stroke there is a critical need for development of new therapeutic concepts and approaches for prevention of brain injury secondary to cerebral ischemia. This study tests the hypothesis that administration of PNU-120596, a type-II positive allosteric modulator (PAM-II) of α7 nicotinic acetylcholine receptors (nAChRs), as long as 6 hours after the onset of focal cerebral ischemia significantly reduces brain injury and neurological deficits in an animal model of ischemic stroke. Focal cerebral ischemia was induced by a transient (90 min) middle cerebral artery occlusion (MCAO). Animals were then subdivided into two groups and injected intravenously (i.v.) 6 hours post-MCAO with either 1 mg/kg PNU-120596 (treated group) or vehicle only (untreated group). Measurements of cerebral infarct volumes and neurological behavioral tests were performed 24 hrs post-MCAO. PNU-120596 significantly reduced cerebral infarct volume and improved neurological function as evidenced by the results of Bederson, rolling cylinder and ladder rung walking tests. These results forecast a high therapeutic potential for PAMs-II as effective recruiters and activators of endogenous α7 nAChR-dependent cholinergic pathways to reduce brain injury and improve neurological function after cerebral ischemic stroke.
PMCID: PMC3739732  PMID: 23951360
23.  Interactions between Vascular Endothelial Growth Factor and Neuroglobin 
Neuroscience Letters  2012;519(1):47-50.
Vascular endothelial growth factor (VEGF) and neuroglobin (Ngb) participate in neuronal responses to hypoxia and ischemia, but the relationship between their effects, if any, is unknown. To address this issue, we measured Ngb levels in VEGF-treated mouse cerebrocortical cultures and VEGF levels in cerebrocortical cultures from Ngb-overexpressing transgenic mice. VEGF stimulated Ngb expression in a VEGFR2/Flk1 receptor-dependent manner, whereas Ngb overexpression suppressed expression of VEGF. These findings provide further insight into hypoxia-stimulated neuronal signaling pathways.
PMCID: PMC3371093  PMID: 22583764
Vascular endothelial growth factor; neuroglobin; hypoxia
24.  Astroglial PTEN Loss Disrupts Neuronal Lamination by Dysregulating Radial Glia-guided Neuronal Migration 
Aging and Disease  2013;4(3):113-126.
PTEN plays an important role not only in tumorigenesis but also in the normal development of central nervous system. PTEN loss in neural progenitor cells during embryogenesis disrupts migration and proper formation of the brain laminar structure. We generated a conditional PTEN knockout mouse by crossing mice that express Cre recombinase driven by the human GFAP promoter to a floxed PTEN gene to investigate the role of astroglial PTEN signaling pathway in neuronal patterning and lamination. We found PTEN loss not only in astroglial cells, but also in radial glia-derived neurons in hGFAP-Cre+/−/PTENloxp/loxp transgenic mice. Homozygous hGFAP-Cre+/−/PTENloxp/loxp transgenic mice showed progressive brain enlargement with cellular disorganization that occurred predominantly in hippocampus and cerebellum and died by postnatal day 20. Confocal images show that nestin-positive radial glial cells were observed in the hippocampus, cortex, and cerebellum at postnatal day 0 in homozygous hGFAP-Cre+/−/PTENloxp/loxp, but not in heterozygous hGFAP-Cre+/−/PTENloxp/− and hGFAP-Cre−/−/PTENloxp/loxp mice. Homozygous hGFAP-Cre+/−/PTENloxp/loxp transgenic mouse eyes, which lack radial glial lineage, were able to develop normal architectonics after birth. In addition, we also found that neuronal progenitor migration was defected at postnatal day 0 in homozygous hGFAP-Cre+/−/PTENloxp/loxp mice. These results suggest that PTEN has a critical role in regulating radial glial differentiation, proliferation, maturation, and eventually neuronal patterning in central nervous system in a spatio-temporal dependent manner.
PMCID: PMC3660121  PMID: 23730527
PTEN; radial glia; neurogenesis; neuronal lamination
25.  Effect of a contralateral lesion on neurological recovery from stroke in rats 
Clinical studies suggest a correlation between changes in activity of the contralesional cerebral cortex and spontaneous recovery from stroke, but whether this is a causal relationship is uncertain.
Young adult Sprague-Dawley male rats underwent unilateral or bilateral permanent distal middle cerebral artery occlusion (dMCAO). Infarct volume was determined by 2,3,5-triphenyltetrazolium chloride (TTC) staining 24 hr after dMCAO, and functional outcome was assessed 1–28 days after dMCAO using the ladder rung walking and limb placing tests.
Infarct volume was unchanged, but functional neurological deficits were reduced 1 day after bilateral compared to unilateral dMCAO.
Activity in the contralesional cerebral cortex may inhibit functional motor recovery acutely after experimental stroke.
PMCID: PMC3652379  PMID: 22868223
Stroke; ischemia; recovery; rat

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