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1.  Mannitol-Enhanced Delivery of Stem Cells and Their Growth Factors Across the Blood–Brain Barrier 
Cell transplantation  2014;23(0):531-539.
Ischemic brain injury in adults and neonates is a significant clinical problem with limited therapeutic interventions. Currently, clinicians have only tPA available for stroke treatment and hypothermia for cerebral palsy. Owing to the lack of treatment options, there is a need for novel treatments such as stem cell therapy. Various stem cells including cells from embryo, fetus, perinatal, and adult tissues have proved effective in preclinical and small clinical trials. However, a limiting factor in the success of these treatments is the delivery of the cells and their by-products (neurotrophic factors) into the injured brain. We have demonstrated that mannitol, a drug with the potential to transiently open the blood–brain barrier and facilitate the entry of stem cells and trophic factors, as a solution to the delivery problem. The combination of stem cell therapy and mannitol may improve therapeutic outcomes in adult stroke and neonatal cerebral palsy.
doi:10.3727/096368914X678337
PMCID: PMC4083632  PMID: 24480552
Mannitol; Stem cells; Blood–brain barrier permeability; Neurotrophic factors; Cerebral ischemia; Adult; Neonates
2.  Oligodendrocytes engineered with migratory proteins as effective graft source for cell transplantation in multiple sclerosis 
Cell medicine  2013;6(3):123-127.
Multiple sclerosis (MS) is characterized by widespread immunomodulatory demyelination of the CNS resulting in nerve cell dysfunction. Accordingly, treatment strategies have been centered on immunodulation and remyelination, with the former primarily focused on reducing the pathology rather than enhancing myelin repair which the latter targets. While conceding to the emerging view of heterogeneity in the pathology of MS, which precludes variations in degree of immune response (i.e., inflammation) and demyelination, the concept of enhancing myelin repair is appealing since it is likely to provide both disease-reducing and disease-inhibiting therapeutic approach to MS. In this regard, we and several others, have proposed that cell replacement therapy is an effective strategy to repair the myelin in MS. Here, we hypothesize that transplantation of mouse bone marrow-derived oligodendrocytes (BMDOs) and BMDOs transfected with Ephrin proteins (BMDO+Ephrin), which are known to enhance cell and axonal migratory capacity, may produce therapeutic benefits in animal models of MS.
doi:10.3727/215517913X674144
PMCID: PMC4080202  PMID: 24999443
Multiple Sclerosis; cell transplantation; bone marrow derived oligodendrocytes (BMDOs); BMDO+Ephrin
3.  ESTROGEN REPLACEMENT THERAPY FOR STROKE 
Cell medicine  2013;6(3):111-122.
Stroke is the third most common cause of death and severe disability among Western populations. Overall, the incidence of stroke is uniformly higher in men than in women. Stroke is rare in women during the reproductive years, and rapidly increases after menopause, strongly suggesting that estrogen (E2) plays an important role in the prevention of stroke. Ongoing studies are currently evaluating both the benefits and risks associated with E2 replacement therapy and hormone replacement therapy in stroke. Equally important is the role of E2 receptor (ER), as studies indicate that ER populations in several tissue sites may significantly change during stress and aging. Such changes may affect the patient’s susceptibility to neurological disorders including stroke, and greatly affect the response to selective E2 receptor modulators (SERMs). Replacement therapies may be inefficient with low ER levels.
The goal of this review paper is to discuss an animal model that will allow investigations of the potential therapeutic effects of E2 and its derivatives in stroke. We hypothesize that E2 neuroprotection is, in part, receptor mediated. This hypothesis is a proof of principle approach to demonstrate a role for specific ER subtypes in E2 neuroprotection. To accomplish this, we use a retroviral mediated gene transfer strategy that express subtypes of the ER gene in regions of the rat brain most susceptible to neuronal damage, namely the striatum and cortex. The animal model is exposed to experimental stroke conditions involving middle cerebral artery occlusion (MCAo) method, and eventually the extent of neuronal damage will be evaluated. A reduction in neuronal damage is expected when E2 is administered with specific ER subtypes. From this animal model, an optimal E2 dose and treatment regimen can be determined. The animal model can help identify potential E2-like therapeutics in stroke, and screen for beneficial or toxic additives present in commercial E2 preparations that are currently available. Such studies will be informative in designing drug therapies for stroke.
doi:10.3727/215517913X672263
PMCID: PMC4080307  PMID: 24999442
4.  Stem Cells for Neurovascular Repair in Stroke 
Stem cells exert therapeutic effects against ischemic stroke via transplantation of exogenous stem cells or stimulation of endogenous stem cells within the neurogenic niches of subventricular zone and subgranular zone, or recruited from the bone marrow through peripheral circulation. In this paper, we review the different sources of stem cells that have been tested in animal models of stroke. In addition, we discuss specific mechanisms of action, in particular neurovascular repair by endothelial progenitor cells, as key translational research for advancing the clinical applications of stem cells for ischemic stroke.
doi:10.4172/2157-7633.S4-004
PMCID: PMC3783263  PMID: 24077523
Cerebral ischemia; Cell-based therapies; Vasculature; Blood brain barrier; Endothelial cells
5.  ADVANCES IN THE CELL-BASED TREATMENT OF NEONATAL HYPOXIC-ISCHEMIC BRAIN INJURY 
Future neurology  2013;8(2):193-203.
Stem cell therapy for adult stroke has reached limited clinical trials. Here, we provide translational research guidance on stem cell therapy for neonatal hypoxic-ischemic brain injury requiring a careful consideration of clinically relevant animal models, feasible stem cell sources, and validated safety and efficacy endpoint assays, as well as a general understanding of modes of action of this cellular therapy. To this end, we refer to existing translational guidelines, in particular the recommendations outlined in the consortium of academicians, industry partners and regulators called Stem cell Therapeutics as an Emerging Paradigm for Stroke or STEPS. Although the STEPS guidelines are directed at enhancing the successful outcome of cell therapy in adult stroke, we highlight overlapping pathologies between adult stroke and neonatal hypoxic-ischemic brain injury. We are, however, cognizant that the neonatal hypoxic-ischemic brain injury displays disease symptoms distinct from adult stroke in need of an innovative translational approach that facilitates the entry of cell therapy in the clinic. Finally, insights into combination therapy are provided with the vision that stem cell therapy may benefit from available treatments, such as hypothermia, already being tested in children diagnosed with hypoxic-ischemic brain injury.
doi:10.2217/fnl.12.85
PMCID: PMC3615569  PMID: 23565051
cerebral palsy; stem cells; hypothermia; neurorestoration; translational; consortium; combination therapy
6.  REGENERATION OF NEURONAL CELLS FOLLOWING CEREBRAL INJURY 
Stem cells possess a definitive role in neuronal rejuvenation following a cerebral injury. Whether endogenous, from the neurogenic niches of subventricular zone and subgranular zone, or recruited from the bone marrow through peripheral circulation, accumulating evidence demonstrates that stem cells ameliorate the consequences of cerebrovascular events, particularly cerebral ischemia. In this chapter, we review milestone studies implicating the role of stem cells in response to disease. Furthermore, we outline specific mechanisms of action along with their clinical potential as therapeutic treatments for ischemic stroke.
doi:10.1159/000346407
PMCID: PMC3761218  PMID: 23859963
hematopoietic stem cells; mesenchymal stem cells; endothelial progenitor cells; very small embryonic-like stem cells; stroke; cell therapy; migration; homing; neurogenesis; angiogenesis
7.  Vasculogenesis in Experimental Stroke After Human Cerebral Endothelial Cell Transplantation 
Background and Purpose
Despite the reported functional recovery in transplanted stroke models and patients, the mechanism of action underlying stem cell therapy remains not well understood. Here, we examined the role of stem cell-mediated vascular repair in stroke.
Methods
Adult rats were exposed to transient occlusion of the middle cerebral artery and 3 hours later randomly stereotaxically transplantated with 100K, 200K, or 400K human cerebral endothelial cell 6 viable cells or vehicle. Animals underwent neurological examination and motor test up to day 7 after transplantation then euthanized for immunostaining against neuronal, vascular, and specific human antigens. A parallel in vitro study cocultured rat primary neuronal cells with human cerebral endothelial cell 6 under oxygen-glucose deprivation and treated with vascular endothelial growth factor (VEGF) and anti-VEGF.
Results
Stroke animals that received vehicle infusion displayed typical occlusion of the middle cerebral artery-induced behavioral impairments that were dose-dependently reduced in transplanted stroke animals at days 3 and 7 after transplantation and accompanied by increased expression of host neuronal and vascular markers adjacent to the transplanted cells. Some transplanted cells showed a microvascular phenotype and juxtaposed to the host vasculature. Infarct volume in transplanted stroke animals was significantly smaller than vehicle-infused stroke animals. Moreover, rat neurons cocultured with human cerebral endothelial cell 6 or treated with VEGF exhibited significantly less oxygen-glucose deprivation-induced cell death that was blocked by anti-VEGF treatment.
Conclusions
We found attenuation of behavioral and histological deficits coupled with robust vasculogenesis and neurogenesis in endothelial cell-transplanted stroke animals, suggesting that targeting vascular repair sets in motion a regenerative process in experimental stroke possibly via the VEGF pathway.
doi:10.1161/STROKEAHA.113.001943
PMCID: PMC4083631  PMID: 24130140
endothelial cells; neurogenesis; stem cells; stroke
8.  DJ-1 ameliorates ischemic cell death in vitro possibly via mitochondrial pathway 
Neurobiology of disease  2013;62:56-61.
DJ-1 is an important redox-reactive neuroprotective protein implicated in regulation of oxidative stress after ischemia. However the molecular mechanism, especially the mitochondrial function, by which DJ-1 protects neuronal cells in stroke remains to be elucidated. The aim of this study was to reveal whether DJ-1 translocates into the mitochondria in exerting neuroprotection against an in vitro model of stroke. Human neural progenitor cells (hNPCs) were initially exposed to oxygen–glucose deprivation and reperfusion injury, and thereafter, DJ-1 translocation was measured by immunocytochemistry and its secretion by hNPCs was detected by enzyme-linked immunosorbant assay (ELISA). Exposure of hNPCs to experimental stroke injury resulted in DJ-1 translocation into the mitochondria. Moreover, significant levels of DJ-1 protein were secreted by the injured hNPCs. Our findings revealed that DJ-1 principally participates in the early phase of stroke involving the mitochondrial pathway. DJ-1 was detected immediately after stroke and efficiently translocated into the mitochondria offering a new venue for developing treatment strategies against ischemic stroke.
doi:10.1016/j.nbd.2013.09.007
PMCID: PMC4083678  PMID: 24060818
Stroke; Mitochondria; Stem cells; Cell death; Neuroprotection
9.  Recent preclinical evidence advancing cell therapy for Alzheimer's disease 
Experimental neurology  2012;237(1):142-146.
Alzheimer's disease (AD) causes brain degeneration, primarily depleting cholinergic cells, and leading to cognitive and learning dysfunction. Logically, to augment the cholinergic cell loss, a viable treatment for AD has been via drugs boosting brain acetylcholine production. However, this is not a curative measure. To this end, nerve growth factor (NGF) has been examined as a possible preventative treatment against cholinergic neuronal death while enhancing memory capabilities; however, NGF brain bioavailability is challenging as it does not cross the blood–brain barrier. Investigations into stem cell- and gene-based therapy have been explored in order to enhance NGF potency in the brain. Along this line of research, a genetically modified cell line, called HB1.F3 transfected with the cholinergic acetyltransferase or HB1.F3.ChAT cells, has shown safety and efficacy profiles in AD models. This stem cell transplant therapy for AD is an extension of the neural stem cells' use in other neurological treatments, such as Parkinson's disease and stroke, and recently extended to cancer. The HB1 parent cell and its associated cell lines have been used as a vehicle to deliver genes of interest in various neurological models, and are highly effective as they can differentiate into neurons and glial cells. A focus of this mini-review is the recent demonstration that the transplantation of HB1.F3.ChAT cells in an AD animal model increases cognitive function coinciding with upregulation of acetylcholine levels in the cerebrospinal fluid. In addition, there is a large dispersion throughout the brain of the transplanted stem cells which is important to repair the widespread cholinergic cell loss in AD. Some translational caveats that need to be satisfied prior to initiating clinical trials of HB1.F3.ChAT cells in AD include regulating the host immune response and the possible tumorigenesis arising from the transplantation of this genetically modified cell line. Further studies are warranted to test the safety and effectiveness of these cells in AD transgenic animal models. This review highlights the recent progress of stem cell therapy in AD, not only emphasizing the significant basic science strides made in this field, but also providing caution on remaining translational issues necessary to advance this novel treatment to the clinic.
doi:10.1016/j.expneurol.2012.06.024
PMCID: PMC4082718  PMID: 22766481
Alzheimer's disease; Neural stem cell; Neural growth factor; ChAT cells; Gene therapy
10.  The Battle of the Sexes for Stroke Therapy: Female- Versus Male-Derived Stem Cells 
Cell therapy is a major discipline of regenerative medicine that has been continually growing over the last two decades. The aging of the population necessitates discovery of therapeutic innovations to combat debilitating disorders, such as stroke. Menstrual blood and Sertoli cells are two gender-specific sources of viable transplantable cells for stroke therapy. The use of autologous cells for the subacute phase of stroke offers practical clinical application. Menstrual blood cells are readily available, display proliferative capacity, pluripotency and angiogenic features, and, following transplantation in stroke models, have the ability to migrate to the infarct site, regulate the inflammatory response, secrete neurotrophic factors, and have the possibility to differentiate into neural lineage. Similarly, the testis-derived Sertoli cells secrete many growth and trophic factors, are highly immunosuppressive, and exert neuroprotective effects in animal models of neurological disorders. We highlight the practicality of experimental and clinical application of menstrual blood cells and Sertoli cells to treat stroke, from cell isolation and cryopreservation to administration.
PMCID: PMC4059004  PMID: 23469849
menstrual blood; Sertoli cells; autologous; ischemic stroke; regenerative
11.  One Small Baby STEPS, A Giant Leap for Cell Therapy in Neonatal Brain Injury 
Pediatric research  2011;70(1):3-9.
We advance Baby STEPS or Stem cell Therapeutics as an Emerging Paradigm for Stroke as a guide in facilitating the critical evaluation in the laboratory of the safety and efficacy of cell therapy for neonatal encephalopathy. The need to carefully consider the clinical relevance of the animal models in mimicking human neonatal brain injury, selection of the optimal stem cell donor, and the application of functional outcome assays in small and large animal models serve as the foundation for preclinical work and beginning to understand the mechanism of this cellular therapy. The preclinical studies will aid our formulation of a rigorous human clinical trial which encompasses not only efficacy testing but also monitoring of safety indices and demonstration of mechanisms of action. This schema forms the basis of Baby STEPS. Our goal is to resonate the urgent call to enhance the successful translation of cell therapy from the laboratory to the clinic.
doi:10.1203/PDR.0b013e31821d0d00
PMCID: PMC3117246  PMID: 21659957
12.  THE CASE FOR AN ETHICS RESEARCH CONSORTIUM FOR EMERGING TECHNOLOGIES: PUBLIC PERCEPTION OF STEM CELL RESEARCH AND DEVELOPMENT 
Technology and innovation  2010;12:21-28.
Emerging technologies have gained notoriety as a catalyst of socioeconomic progress, but have also inspired a revolution in ethics. Here, we provide an overview of ethics in stem cell-based therapies and offer a compelling argument for a need to establish an Ethics Research Consortium that will be tasked to assemble an interdisciplinary panel of experts who will apply ethical principles to analyze the social merit relative to the economic incentives of this emerging technology. Milestone studies on cell therapy in Parkinson’s disease and stroke over the last two decades were the focus of this commentary. The major criterion for study selection was based on public opinion, scientific discussion, and government reactions generated by these pioneering studies. Original data from the selected studies are presented. Interpretation and discussion of data captured the prevailing views of the public and scientific community, as well as the government regulatory and oversight decisions (i.e., ban on embryonic stem cell research funding). Lessons learned from two decades of cell-based therapies indicate that poor management of the public discourse of ethics concerning emerging technologies might have contributed to misperceptions within both the public and the research community that have hindered the progress of scientific innovation and even delayed the clinical application of potentially life-saving treatments to critically ill patients. We propose the creation of a Consortium that will evaluate how these novel ethical issues in emerging technologies are addressed under current oversight and regulatory structures and where there may be gaps and need for revised or new public policy approaches.
PMCID: PMC3043602  PMID: 21359115
Ethics; Embryonic stem cells; Adult stem cells; Transplantation
13.  Stroke in the Eye of the Beholder 
Medical hypotheses  2013;80(4):411-415.
The pathophysiological changes that occur during ischemic stroke can have a profound effect on the surrounding nerve tissue. To this end, we advance the hypothesis that retinal damage can occur as a consequence of ischemic stroke in animal models. We discuss the preclinical evidence over the last 3 decades supporting this hypothesis of retinal damage following ischemic stroke. In our evaluation of the hypothesis, we highlight the animal models providing evidence of pathological and mechanistic link between ischemic stroke and retinal damage. That retinal damage is closely associated with ischemic stroke, yet remains neglected in stroke treatment regimen, provides the impetus for recognizing the treatment of retinal damage as a critical component of stroke therapy.
doi:10.1016/j.mehy.2012.12.030
PMCID: PMC3595340  PMID: 23395299
14.  The Neuroprotective Role of Acupuncture and Activation of the BDNF Signaling Pathway 
Recent studies have been conducted to examine the neuroprotective effects of acupuncture in many neurological disorders. Although the neuroprotective effects of acupuncture has been linked to changes in signaling pathways, accumulating evidence suggest the participation of endogenous biological mediators, such as the neurotrophin (NT) family of proteins, specifically, the brain derived neurotrophic factor (BDNF). Accordingly, acupuncture can inhibit neurodegeneration via expression and activation of BDNF. Moreover, recent studies have reported that acupuncture can increase ATP levels at local stimulated points. We have also demonstrated that acupuncture could activate monocytes and increase the expression of BDNF via the stimulation of ATP. The purpose of this article is to review the recent findings and ongoing studies on the neuroprotective roles of acupuncture and therapeutic implications of acupuncture-induced activation of BDNF and its signaling pathway.
doi:10.3390/ijms15023234
PMCID: PMC3958908  PMID: 24566146
acupuncture; brain derived neurotrophic factor; neuroprotective; cyclophilin A
15.  Luteolin Reduces Alzheimer’s Disease Pathologies Induced by Traumatic Brain Injury 
Traumatic brain injury (TBI) occurs in response to an acute insult to the head and is recognized as a major risk factor for Alzheimer’s disease (AD). Indeed, recent studies have suggested a pathological overlap between TBI and AD, with both conditions exhibiting amyloid-beta (Aβ) deposits, tauopathy, and neuroinflammation. Additional studies involving animal models of AD indicate that some AD-related genotypic determinants may be critical factors enhancing temporal and phenotypic symptoms of TBI. Thus in the present study, we examined sub-acute effects of moderate TBI delivered by a gas-driven shock tube device in Aβ depositing Tg2576 mice. Three days later, significant increases in b-amyloid deposition, glycogen synthase-3 (GSK-3) activation, phospho-tau, and pro-inflammatory cytokines were observed. Importantly, peripheral treatment with the naturally occurring flavonoid, luteolin, significantly abolished these accelerated pathologies. This study lays the groundwork for a safe and natural compound that could prevent or treat TBI with minimal or no deleterious side effects in combat personnel and others at risk or who have experienced TBI.
doi:10.3390/ijms15010895
PMCID: PMC3907845  PMID: 24413756
traumatic brain injury; Alzheimer’s disease; amyloidogenesis; tauopathy; GSK; neuroinflammation; luteolin
16.  Stem cell-paved biobridge facilitates neural repair in traumatic brain injury 
Modified mesenchymal stromal cells (MSCs) display a unique mechanism of action during the repair phase of traumatic brain injury by exhibiting the ability to build a biobridge between the neurogenic niche and the site of injury. Immunohistochemistry and laser capture assay have visualized this biobridge in the area between the neurogenic subventricular zone and the injured cortex. This biobridge expresses high levels of extracellular matrix metalloproteinases (MMPs), which are initially co-localized with a stream of transplanted MSCs, but later this region contains only few to non-detectable grafts and becomes overgrown by newly recruited host cells. We have reported that long-distance migration of host cells from the neurogenic niche to the injured brain site can be attained via these transplanted stem cell-paved biobridges, which serve as a key regenerative process for the initiation of endogenous repair mechanisms. Thus, far the two major schools of discipline in stem cell repair mechanisms support the idea of “cell replacement” and the bystander effects of “trophic factor secretion.” Our novel observation of stem cell-paved biobridges as pathways for directed migration of host cells from neurogenic niche toward the injured brain site adds another mode of action underlying stem cell therapy. More in-depth investigations on graft-host interaction will likely aid translational research focused on advancing this stem cell-paved biobridge from its current place, as an equally potent repair mechanism as cell replacement and trophic factor secretion, into a new treatment strategy for traumatic brain injury and other neurological disorders.
doi:10.3389/fnsys.2014.00116
PMCID: PMC4068001
trauma; cell transplantation; regenerative medicine; neurogenesis; extracellular matrix
17.  Influence of Post-Traumatic Stress Disorder on Neuroinflammation and Cell Proliferation in a Rat Model of Traumatic Brain Injury 
PLoS ONE  2013;8(12):e81585.
Long-term consequences of traumatic brain injury (TBI) are closely associated with the development of severe psychiatric disorders, such as post-traumatic stress disorder (PTSD), yet preclinical studies on pathological changes after combined TBI with PTSD are lacking. In the present in vivo study, we assessed chronic neuroinflammation, neuronal cell loss, cell proliferation and neuronal differentiation in specific brain regions of adult Sprague-Dawley male rats following controlled cortical impact model of moderate TBI with or without exposure to PTSD. Eight weeks post-TBI, stereology-based histological analyses revealed no significant differences between sham and PTSD alone treatment across all brain regions examined, whereas significant exacerbation of OX6-positive activated microglial cells in the striatum, thalamus, and cerebral peduncle, but not cerebellum, in animals that received TBI alone and combined TBI-PTSD compared with PTSD alone and sham treatment. Additional immunohistochemical results revealed a significant loss of CA3 pyramidal neurons in the hippocampus of TBI alone and TBI-PTSD compared to PTSD alone and sham treatment. Further examination of neurogenic niches revealed a significant downregulation of Ki67-positive proliferating cells, but not DCX-positive neuronally migrating cells in the neurogenic subgranular zone and subventricular zone for both TBI alone and TBI-PTSD compared to PTSD alone and sham treatment. Comparisons of levels of neuroinflammation and neurogenesis between TBI alone and TBI+PTSD revealed that PTSD did not exacerbate the neuropathological hallmarks of TBI. These results indicate a progressive deterioration of the TBI brain, which, under the conditions of the present approach, was not intensified by PTSD, at least within our time window and within the examined areas of the brain. Although the PTSD manipulation employed here did not exacerbate the pathological effects of TBI, the observed long-term inflammation and suppressed cell proliferation may evolve into more severe neurodegenerative diseases and psychiatric disorders currently being recognized in traumatized TBI patients.
doi:10.1371/journal.pone.0081585
PMCID: PMC3857205  PMID: 24349091
18.  Inhibition of Phosphatase and Tensin Homolog Deleted on Chromosome 10 Decreases Rat Cortical Neuron Injury and Blood-Brain Barrier Permeability, and Improves Neurological Functional Recovery in Traumatic Brain Injury Model 
PLoS ONE  2013;8(11):e80429.
Background and Purpose
Recent evidence has supported the neuroprotective effect of bpV (pic), an inhibitor of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), in models of ischemic stroke. However, whether PTEN inhibitors improve long-term functional recovery after traumatic brain injury (TBI) and whether PTEN affects blood brain barrier (BBB) permeability need further elucidation. The present study was performed to address these issues.
Methods
Adult Sprague-Dawley rats were subjected to fluid percussion injury (FPI) after treatment with a well-established PTEN inhibitor bpV (pic) or saline starting 24 h before FPI. Western blotting, real-time quantitative PCR, or immunostaining was used to measure PTEN, p-Akt, or MMP-9 expression. We determined the presence of neuron apoptosis by TUNEL assay. Evans Blue dye extravasation was measured to evaluate the extent of BBB disruption. Functional recovery was assessed by the neurological severity score (NSS), and Kaplan-Meier analysis was used for survival analysis.
Results
PTEN expression was up-regulated after TBI. After bpV (pic) treatment, p-Akt was also up-regulated. We found that bpV (pic) significantly decreased BBB permeability and reduced the number of TUNEL-positive cells. We further demonstrated that PTEN inhibition improved neurological function recovery in the early stage after TBI.
Conclusion
These data suggest that treatment with the PTEN inhibitor bpV (pic) has a neuroprotective effect in TBI rats.
doi:10.1371/journal.pone.0080429
PMCID: PMC3842922  PMID: 24312220
19.  Traumatic Brain Injury Precipitates Cognitive Impairment and Extracellular Aβ Aggregation in Alzheimer's Disease Transgenic Mice 
PLoS ONE  2013;8(11):e78851.
Traumatic brain injury (TBI) has become a signature wound of the wars in Iraq and Afghanistan. Many American soldiers, even those undiagnosed but likely suffering from mild TBI, display Alzheimer's disease (AD)-like cognitive impairments, suggesting a pathological overlap between TBI and AD. This study examined the cognitive and neurohistological effects of TBI in presymptomatic APP/PS1 AD-transgenic mice. AD mice and non-transgenic (NT) mice received an experimental TBI on the right parietal cortex using the controlled cortical impact model. Animals were trained in a water maze task for spatial memory before TBI, and then reevaluated in the same task at two and six weeks post-TBI. The results showed that AD mice with TBI made significantly more errors in the task than AD mice without TBI and NT mice regardless of TBI. A separate group of AD mice and NT mice were evaluated neurohistologically at six weeks after TBI. The number of extracellular beta-amyloid (Aβ)-deposits significantly increased by at least one fold in the cortex of AD mice that received TBI compared to the NT mice that received TBI or the AD and NT mice that underwent sham surgery. A significant decrease in MAP2 positive cells, indicating neuronal loss, was observed in the cortex of both the AD and NT mice that received TBI compared to the AD and NT mice subjected to sham surgery. Similar changes in extracellular Aβ deposits and MAP2 positive cells were also seen in the hippocampus. These results demonstrate for the first time that TBI precipitates cognitive impairment in presymptomatic AD mice, while also confirming extracellular Aβ deposits following TBI. The recognition of this pathological link between TBI and AD should aid in developing novel treatments directed at abrogating cellular injury and extracellular Aβ deposition in the brain.
doi:10.1371/journal.pone.0078851
PMCID: PMC3817089  PMID: 24223856
20.  Epidemiological Survey-Based Formulae to Approximate Incidence and Prevalence of Neurological Disorders in the United States: a Meta-Analysis 
PLoS ONE  2013;8(10):e78490.
Background
This study aims to create a convenient reference for both clinicians and researchers so that vis-à-vis comparisons between brain disorders can be made quickly and accurately. We report here the incidence and prevalence of the major adult-onset brain disorders in the United States using a meta-analysis approach.
Material and Methods
Epidemiological figures were collected from the most recent, reliable data available in the research literature. Population statistics were based on the most recent census from the US Census Bureau. Extrapolations were made only when necessary. The most current epidemiological studies for each disorder were chosen. All effort was made to use studies based on national cohorts. Studies reviewed were conducted between 1950 and 2009. The data of the leading studies for several neurological studies was compiled in order to obtain the most accurate extrapolations. Results were compared to commonly accepted values in order to evaluate validity.
Results
It was found that 6.75% of the American adult population is afflicted with brain disorders. This number was eclipsed by the 8.02% of Floridians with brain disorders, which is due to the large aged population residing in the state.
Conclusions
There was a noticeable lack of epidemiological data concerning adult-onset brain disorders. Since approximately 1 out of every 7 households is affected by brain disorders, increased research into this arena is warranted.
doi:10.1371/journal.pone.0078490
PMCID: PMC3812041  PMID: 24205243
21.  Stem Cell Transplantation for Neuroprotection in Stroke 
Brain sciences  2013;3(1):239-261.
Stem cell-based therapies for stroke have expanded substantially over the last decade. The diversity of embryonic and adult tissue sources provides researchers with the ability to harvest an ample supply of stem cells. However, the optimal conditions of stem cell use are still being determined. Along this line of the need for optimization studies, we discuss studies that demonstrate effective dose, timing, and route of stem cells. We recognize that stem cell derivations also provide uniquely individual difficulties and limitations in their therapeutic applications. This review will outline the current knowledge, including benefits and challenges, of the many current sources of stem cells for stroke therapy.
doi:10.3390/brainsci3010239
PMCID: PMC3800120  PMID: 24147217
stem cells; stroke; cerebral ischemia; transplantation
22.  Permeability Transition Pore-Mediated Mitochondrial Superoxide Flashes Regulate Cortical Neural Progenitor Differentiation 
PLoS ONE  2013;8(10):e76721.
In the process of neurogenesis, neural progenitor cells (NPCs) cease dividing and differentiate into postmitotic neurons that grow dendrites and an axon, become excitable, and establish synapses with other neurons. Mitochondrial biogenesis and aerobic metabolism provide energy substrates required to support the differentiation, growth and synaptic activity of neurons. Mitochondria may also serve signaling functions and, in this regard, it was recently reported that mitochondria can generate rapid bursts of superoxide (superoxide flashes), the frequency of which changes in response to environmental conditions and signals including oxygen levels and Ca2+ fluxes. Here we show that the frequency of mitochondrial superoxide flashes increases as embryonic cerebral cortical neurons differentiate from NPCs, and provide evidence that the superoxide flashes serve a signaling function that is critical for the differentiation process. The superoxide flashes are mediated by mitochondrial permeability transition pore (mPTP) opening, and pharmacological inhibition of the mPTP suppresses neuronal differentiation. Moreover, superoxide flashes and neuronal differentiation are inhibited by scavenging of mitochondrial superoxide. Conversely, manipulations that increase superoxide flash frequency accelerate neuronal differentiation. Our findings reveal a regulatory role for mitochondrial superoxide flashes, mediated by mPTP opening, in neuronal differentiation.
doi:10.1371/journal.pone.0076721
PMCID: PMC3792897  PMID: 24116142
23.  Stem Cell-Like Dog Placenta Cells Afford Neuroprotection against Ischemic Stroke Model via Heat Shock Protein Upregulation 
PLoS ONE  2013;8(9):e76329.
In this study, we investigated the dog placenta as a viable source of stem cells for stroke therapy. Immunocytochemical evaluation of phenotypic markers of dog placenta cells (DPCs) cultured in proliferation and differentiation medium revealed that DPCs expressed both stem cell and neural cell markers, respectively. Co-culture with DPCs afforded neuroprotection of rat primary neural cells in a dose-dependent manner against oxygen-glucose deprivation. Subsequent in vivo experiments showed that transplantation of DPCs, in particular intravenous and intracerebral cell delivery, produced significant behavioral recovery and reduced histological deficits in ischemic stroke animals compared to those that received intra-arterial delivery of DPCs or control stroke animals. Furthermore, both in vitro and in vivo studies implicated elevated expression of heat shock protein 27 (Hsp27) as a potential mechanism of action underlying the observed therapeutic benefits of DPCs in stroke. This study supports the use of stem cells for stroke therapy and implicates a key role of Hsp27 signaling pathway in neuroprotection.
doi:10.1371/journal.pone.0076329
PMCID: PMC3783428  PMID: 24086730
24.  Fate Analysis of Adult Hippocampal Progenitors in a Murine Model of Fetal Alcohol Spectrum Disorder (FASD) 
PLoS ONE  2013;8(9):e73788.
Prenatal alcohol exposure can lead to fetal alcohol spectrum disorder (FASD) and associated behavioral impairments that may be linked to disruptions in adult hippocampal neurogenesis. Social and physical enrichment has been proposed as a potential therapeutic approach toward reversing behavioral deficits associated with FASD and is also a potent stimulator of adult hippocampal neurogenesis. In the present study, we utilized a genetic fate mapping approach in nestin-CreERT2/YFP bitransgenic mice to identify the stage-specific impact of prenatal alcohol exposure on the stepwise maturation of adult hippocampal progenitors. Using a limited alcohol access “drinking-in-the-dark” model of FASD, we confirm previous findings that moderate prenatal alcohol exposure has no effect on adult neurogenesis under standard housing conditions, but abolishes the neurogenic response to enriched environment (EE). Furthermore, we demonstrate that this effect is primarily due to failed EE-mediated survival of postmitotic neurons. Finally, we demonstrate that the neurogenic deficit is associated with impaired spatial pattern recognition, as demonstrated by delayed learning of FASD-EE mice in an A–B contextual discrimination task. These results identify a potential maturational stage-specific mechanism(s) underlying impaired neurogenic function in a preclinical model of FASD, and provide a basis for testing regulatory pathways in this model through conditional and inducible manipulation of gene expression in the adult hippocampal progenitor population.
doi:10.1371/journal.pone.0073788
PMCID: PMC3770701  PMID: 24040071
25.  Stem Cell Recruitment of Newly Formed Host Cells via a Successful Seduction? Filling the Gap between Neurogenic Niche and Injured Brain Site 
PLoS ONE  2013;8(9):e74857.
Here, we report that a unique mechanism of action exerted by stem cells in the repair of the traumatically injured brain involves their ability to harness a biobridge between neurogenic niche and injured brain site. This biobridge, visualized immunohistochemically and laser captured, corresponded to an area between the neurogenic subventricular zone and the injured cortex. That the biobridge expressed high levels of extracellular matrix metalloproteinases characterized initially by a stream of transplanted stem cells, but subsequently contained only few to non-detectable grafts and overgrown by newly formed host cells, implicates a novel property of stem cells. The transplanted stem cells manifest themselves as pathways for trafficking the migration of host neurogenic cells, but once this biobridge is formed between the neurogenic site and the injured brain site, the grafted cells disappear and relinquish their task to the host neurogenic cells. Our findings reveal that long-distance migration of host cells from the neurogenic niche to the injured brain site can be achieved through transplanted stem cells serving as biobridges for initiation of endogenous repair mechanisms. This is the first report of a stem cell-paved “biobridge”. Indeed, to date the two major schools of discipline in stem cell repair mechanism primarily support the concept of “cell replacement” and bystander effects of “trophic factor secretion”. The present novel observations of a stem cell seducing a host cell to engage in brain repair advances basic science concepts on stem cell biology and extracellular matrix, as well as provokes translational research on propagating this stem cell-paved biobridge beyond cell replacement and trophic factor secretion for the treatment of traumatic brain injury and other neurological disorders.
doi:10.1371/journal.pone.0074857
PMCID: PMC3762783  PMID: 24023965

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