CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 10, Issue 4, 2011

Neurotrophic factors are essential for the survival and differentiation of developing neurons and also for their protection and recovery under pathological conditions. Therefore neurotrophic factors are being considered as a crucial therapeutic strategy for neurological disorders such as dementia or stroke. Similar pharmacological effects have been shown for Cerebrolysin, a neuropeptide preparation used for the treatment of neurodegenerative and cerebrovascular disorders. Experimental studies have shown protective and restorative effects of Cerebrolysin after stroke by inhibition of calpain [1], stabilizing neuronal integrity [2] and reducing apoptotic cell death [3]. In dementia model systems Cerebrolysin modulates kinase activities, which results in decreased amyloid β-peptide deposition and tau protein phosphorylation [4,5]. Positive effects on synaptic density and neuronal cytoarchitecture correlate with improved cognitive and behavioral performance [6,7]. In addition, Cerebrolysin promotes neurogenesis, an important self-repair mechanism of the brain [8,9]. Clinical trials have consistently shown that Cerebrolysin is an effective treatment for patients suffering from dementia of different origin. In vascular dementia, Cerebrolysin improved cognitive deficits and global clinical impression, which correlated with improvements in electroencephalogram activities [10, 11]. In patients with mild to moderate Alzheimer's disease Cerebrolysin has been shown to significantly improve cognition and the overall clinical response up to three months after active treatment [12,13]. Beneficial effects were also reported in activities of daily living and in behavioral performance [12-15]. Due to the observed long-lasting treatment effects Cerebrolysin seems to delay disease progression, which is in line with its pleiotropic mode of action targeting different molecular pathways in this pathologic cascade. Direct comparison of Cerebrolysin with cholinergic treatment resulted in comparable clinical efficacy in mild to moderate Alzheimer's disease and synergistic treatment effects were observed by combining both treatment strategies [16]. Stroke trials with Cerebrolysin have shown accelerated improvement in global, neurological, and motor functions, cognitive performance and activities of daily living. Cerebrolysin was effective in both early and late hospitalization [17-19]. However, early treatment start resulted in a faster and more efficient recovery of impaired neurological functions. Cerebrolysin had a fast onset of action with significant treatment effects as early as the first days. Safety data from clinical trials suggest an excellent benefit-to-risk ratio. Cerebrolysin was safe and well-tolerated also in hemorrhagic stroke, permitting early initiation of treatment even when exact type of stroke is not yet known. Most importantly, Cerebrolysin was also safe when used in combination with recombinant tissue-type plasminogen activator without enhancing the number or severity of side effects resulting from recombinant tissue-type plasminogen activator treatment [Lang, manuscript in preparation] or when given in combination with cholinesterase inhibitors such as donepezil [16] or rivastigmine [20]. In conclusion, clinical data have strongly shown that Cerebrolysin is an effective therapeutic option for patients diagnosed with dementia, stroke or traumatic brain injury....

Human neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease (HD) result from progressive death of specific populations of CNS neurons, and represent a fast growing health challenge. Current therapeutics relieve disease symptoms, but fail to halt disease progression or cure these deliberating diseases. Stem cell strategies hold strong promise for human neurodegenerative diseases, which may be achieved by transplantation of stem cells and manipulation of neurogenesis processing. While natural neurogenesis declines markedly with aging and the low efficiency of new neural cell generation limits its regenerative capability [1], multipotent stem cells, i.e. embryonic stem (ES) cells, are capable of inducing pluripotent stem cells and mesenchymal stem cells and represent a promising source for cell replacement therapy due to their ability to generate various types of functional neural cells [2-4]. Many critical questions regarding basic stem cell biology, mechanisms, development, reprogramming, and clinical safety (for example, concern over the tumorigenicity of pluripotent stem cells) of their transplantation still remain, and should be properly addressed before the translational applications in the treatment of human neurodegenerative diseases [4-6]. Even so, successful translational clinical trials utilizing stem cell therapy are already coming to light,.and new cell replacement strategies based on advanced stem cell technology and translational application will hopefully overcome these incurable human neurodegenerative diseases in future regenerative medicine [5, 6]. This special issue presents a collection of comprehensive reviews to highlight the neural induction and patterning, cell reprogramming, molecular targeting regulation for specific neuronal differentiation, neural repair or regeneration, and stem cell transplant applications to the neurodegenerative diseases. This special issue begins with Fumitaka Osakada and Masayo Takahashi reviewing the neural induction and patterning in mammalian pluripotent stem cells. The acquisition of neural fates in ES cells can be controlled by bone morphogenetic protein, fibroblast growth factor, and Wnt signaling, while the production of specific neural cell types can also be regulated by exogenous patterning signals such as Wnt, bone morphogenetic protein, sonic hedgehog protein, fibroblast growth factor, and retinoic acid. Spatiotemporal neural patterning of ES cells in embryogenesis and in in vitro neural differentiation in response to these signals are reviewed. Oscar Arias-Carrion follows with a discussion of adult neurogenesis in the hypothalamus and its possible functions and implications. Adult neurogenesis occurs actively in the dentate gyrus of hippocampus and the subventricular zone in a constitutive manner under physiological conditions. The author presents recent evidence of low proliferative neurogenesis in the hypothalamus and points out the potential contribution of these new neurons to neural processing, suggesting that the hypothalamus may serve as a new source and target for stem cell transplantation. Jeremy M. Crook reviews human embryonic stem cell therapies for neurodegenerative diseases. The author discusses putative clinicallycompliant strategies for human ES cell maintenance and directed differentiation, greater understanding and accessibility to cells through formal cell registries and centralized cell banking for distribution, and the revised US government policy on funding human ES cell research. Considering the practical and fiscal constraints of delivering cell therapies for global healthcare, a more efficient and economical application will bolster the clinical entry of human ES cell derivatives. Advances and challenges of translating human ES cells into novel therapies for neurodegenerative diseases are summarized, with the suggestion that PD be considered as a primary candidate for human ES cell therapy. L.W. Chen and colleagues review the potential application of induced pluripotent stem (iPS) cells in cell replacement therapy for PD. While the difficulty in securing donor dopamine neurons and immuno-rejection of neural transplants hinder application of ES cells, iPS cells offers a new source for cell replacement therapies in human neurodegenerative diseases. This review summarizes current methods and modifications in producing iPS cells from somatic cells, safety concerns of reprogramming procedures, and animal studies for testing the therapeutic value of iPS cells in the treatment of PD. Patient-specific iPS cells and efficient inducement of dopamine neurons may further benefit diseasespecific screening and personalized stem cell therapy for human PD. Omar M.E. Abdel-Salam contributes a review on stem cell therapy for human AD. There is evidence for inefficient adult neurogenesis in the pathogenesis of AD, and grafted stem cells can survive, migrate, and differentiate into cholinergic neurons, astrocytes, and oligodendrocytes, with amelioration of learning and memory deficits. In addition to replacement of lost or damaged cells, grafted stem cells might stimulate endogenous neural precursors and enhance neuroplasticity. Furthermore, antidepressant drugs, lithium, acetyl cholinesterase inhibitors and ginkgo biloba enhance the impaired neurogenesis in this disease process. This review points out that pharmacological manipulation of neurogenesis may offer an alternative approach in combination with stem cell therapy for human AD. Yvona Mazurova reviews interventions of proliferation and differentiation of endogenous neural stem cells in the neurodegenerative process of HD phenotype. HD is characterized by degeneration of a relatively well-defined neuronal cell population in the caudate nucleus, which is adjacent to the neurogenic subependymal zone (SEZ) region. The possibility to harness endogenous neural stem cell capacity for repair by promoting SEZ neurogenesis paves the way for a new clinical management of this disorder. This article points out characterization of the neurogenic niche of SEZ in reaction to brain injury and HD disease process, showing new insights into potential application of SEZ neurogenesis, migration of progenitor cells, and generation of new neurons in the treatment of human HD. Daisy K.Y. Shum and Y.S Chan contribute a comprehensive review on derivation of clinically applicable Schwann cells from bone marrow stromal cells for neural repair and regeneration. Schwann cells are critically important for neural repair, axonal regrowth and remyelination in peripheral nerve lesions. The absence of Schwann cells in the CNS limits the regenerative capacity of central neurons. The authors have expertise in the development of Schwann cell phenotype from mesenchymal stem cells (MSCs), and discuss methods for derivation of Schwann cell-like cells from MSCs, issues related to instability of the derived Schwann cell phenotype, apoptosis of derived cells in transplants, and the inability to predict with confidence how the cells will behave after transplantation. They suggest that further elucidation of biological signaling by Schwann cells derived from MSCs will promote establishing a new therapeutic strategy based on Schwann cell properties for CNS injury and/or neurodegenerative diseases. Q.Y. Xu and J.P. Zhao review possible restorative treatment for PD by inducement of dopamine neurons from adult stem cells. Recent progress in adult stem cell studies indicate that functional neurons derived from adult tissue stem cells may expand stem cell therapy application for neurodegenerative diseases. The authors summarize various types of adult tissue stem cells, basic biological properties, and differentiation inducement of dopaminergic neuronal cells. They point out that using adult stem cells should overcome the ethical problem of human fetal tissue or ES cells, and open the possibility of patient-specific autologous transplantation and personalized treatment for PD. Y.X. Ding, X Wang and colleagues close this issue with a discussion of molecular manipulation targeting dopamine phenotype differentiation of stem cells. Focusing on understanding the differentiation mechanism and controlled proliferation of stem cells, they present advances on candidate signaling molecules and transcription factors in potential regulation processes of dopamine differentiation and proliferation of stem cells, with emphasis on Wnt/β-catenin, Notch, sonic hedgehog signaling, and several dopaminergic cell fate-related transcription factors. Additionally, activation of oncogenes in abnormal cell proliferation or tumorigenicity of pluripotent stem cells are also discussed. It suggested that selective molecular targeting interventions will greatly benefit stem cell therapy for human PD. ACKNOWLEDGEMENTS L.-W. Chen is supported by grants from the National Science Basic Research Program of China (No. 2011CB504103) and National Natural Science Foundation (Nos. 30772279, 30970862 and 81071609). The Guest Editor would like to thank all authors for their comprehensive review contributions to this special issue, and also Ms. H. Wahaj and Editor-in-Chief Dr. S.D. Skaper for their excellent coordination of this special issue of CNS & Neurological Disorders-Drug Targets.

Embryonic stem (ES) cells are derived from the inner cell mass (ICM) of blastocyst stage embryos, while induced pluripotent stem (iPS) cells are generated from somatic cells through transient overexpression of defined transcription factors. When transplanted into a preimplantation embryo, ES cells and iPS cells can differentiate into any cell type, including germ cells. Moreover, they can grow in culture indefinitely while maintaining pluripotency. In vitro differentiation of ES cells and iPS cells recapitulates many aspects of in vivo embryogenesis. The acquisition of neural fates (neural induction) in ES cells can be controlled by bone morphogenetic protein (BMP), fibroblast growth factor (FGF), and Wnt signaling, while the production of specific neural cell types (neural patterning) can be controlled by exogenous patterning signals such as Wnt, BMP, Shh, FGF, and retinoic acid. In response to these signals, ES cells can differentiate into a wide range of neural cell types that correlate with their positions along the anterior-posterior and dorsal-ventral axes. ES cell and iPS cell culture systems will provide materials for cell replacement therapy, and can be used as in vitro models for disease and drug testing as well as development. Here we review spatiotemporal control of neural differentiation of mammalian pluripotent stem cells, with a special emphasis on the relationship between in vivo embryogenesis and in vitro ES cell differentiation. Retinal differentiation from ES cells and iPS cells is also outlined.

Neurogenesis occurs in the adult brain in a constitutive manner under physiological circumstances within two regions: the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricles. In contrast to these two so-called neurogenic areas, other regions of the brain were considered to be primarily non-neurogenic in nature, implying that no new neurons were formed there under normal conditions. Recently, low proliferative activity was reported in the hypothalamus and the cell layers surrounding the third ventricle. This review summarizes recent evidence for adult neurogenesis in the hypothalamus, and points out the potential contributions of these new neurons to neural processing. We also discussed some technical considerations in investigating neurogenesis in the adult hypothalamus. It is believed that the hypothalamus could serve as a new source and target for stem cell transplantation.

There is a renewed enthusiasm for the clinical translation of human embryonic stem (hES) cells. This is abetted by putative clinically-compliant strategies for hES cell maintenance and directed differentiation, greater understanding of and accessibility to cells through formal cell registries and centralized cell banking for distribution, the revised US government policy on funding hES cell research, and paradoxically the discovery of induced pluripotent stem (iPS) cells. Additionally, as we consider the constraints (practical and fiscal) of delivering cell therapies for global healthcare, the more efficient and economical application of allogeneic vs autologous treatments will bolster the clinical entry of hES cell derivatives. Neurodegenerative disorders such as Parkinson's disease are primary candidates for hES cell therapy, although there are significant hurdles to be overcome. The present review considers key advances and challenges to translating hES cells into novel therapies for neurodegenerative diseases, with special consideration given to Parkinson's disease and Alzheimer's disease. Importantly, despite the focus on degenerative brain disorders and hES cells, many of the issues canvassed by this review are relevant to systemic application of hES cells and other pluripotent stem cells such as iPS cells.

Parkinson's disease (PD), a common degenerative disease in humans, is known to result from loss of dopamine neurons in the substantia nigra and is characterized by severe motor symptoms of tremor, rigidity, bradykinsia and postural instability. Although levodopa administration, surgical neural lesion, and deep brain stimulation have been shown to be effective in improving parkinsonian symptoms, cell replacement therapy such as transplantation of dopamine neurons or neural stem cells has shed new light on an alternative treatment strategy for PD. While the difficulty in securing donor dopamine neurons and the immuno-rejection of neural transplants largely hinder application of neural transplants in clinical treatment, induced pluripotent stem cells (iPS cells) derived from somatic cells may represent a powerful tool for studying the pathogenesis of PD and provide a source for replacement therapies in this neurodegenerative disease. Yamanaka et al. [2006, 2007] first succeeded in generating iPS cells by reprogramming fibroblasts with four transcription factors, Oct4, Sox2, Klf4, and c-Myc in both mouse and human. Animal studies have further shown that iPS cells from fibroblasts could be induced into dopamine neurons and transplantation of these cells within the central nervous system improved motor symptoms in the 6-OHDA model of PD. More interestingly, neural stem cells or fibroblasts from patients can be efficiently reprogrammed and subsequently differentiated into dopamine neurons. Derivation of patient-specific iPS cells and subsequent differentiation into dopamine neurons would provide a disease-specific in vitro model for disease pathology, drug screening and personalized stem cell therapy for PD. This review summarizes current methods and modifications in producing iPS cells from somatic cells as well as safety concerns of reprogramming procedures. Novel reprogramming strategies that deter abnormal permanent genetic and epigenetic alterations are essential for propagating clinically-qualified iPS cells. Future investigation into cell transforming and reprogramming processes are needed to generate the disease-specific iPS cells for personalized regeneration medicine of PD patients by disclosing detailed reprogramming mechanisms.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder which impairs the memory and intellectual abilities of the affected individuals. Loss of episodic as well as semantic memory is an early and principal feature. The basal forebrain cholinergic system is the population of neurons most affected by the neurodegenerative process. Extracellular as well as intracellular deposition of β- amyloid or Abeta (Aβ) protein, intracellular formation of neurofibrillary tangles and neuronal loss are the neuropathological hallmarks of AD. In the last few years, hopes were raised that cell replacement therapy would provide cure by compensating the lost neuronal systems. Stem cells obtained from embryonic as well as adult tissue and grafted into the intact brain of mice or rats were mostly followed by their incorporation into the host parenchyma and differentiation into functional neural lineages. In the lesioned brain, stem cells exhibited targeted migration towards the damaged regions of the brain, where they engrafted, proliferated and matured into functional neurones. Neural precursor cells can be intravenously administered and yet migrate into brain damaged areas and induce functional recovery. Observations in animal models of AD have provided evidence that transplanted stem cells or neural precursor cells (NPCs) survive, migrate, and differentiate into cholinergic neurons, astrocytes, and oligodendrocytes with amelioration of the learning/memory deficits. Besides replacement of lost or damaged cells, stem cells stimulate endogenous neural precursors, enhance structural neuroplasticity, and down regulate proinflammatory cytokines and neuronal apoptotic death. Stem cells could also be genetically modified to express growth factors into the brain. In the last years, evidence indicated that the adult brain of mammals preserves the capacity to generate new neurons from neural stem/progenitor cells. Inefficient adult neurogenesis may contribute to the pathogenesis of AD and other neurodegenerative disorders. An attempt at mobilizing this endogenous pool of resident stem-like cells provides another attractive approach for the treatment of AD. Studies in patients with AD indicated decreased hippocampal volume derived by neurodegeneration. Intriguingly, many drugs including antidepressants, lithium, acetyl cholinesterase inhibitors, and ginkgo biloba, were able to enhance the impaired neurogenesis in this disease process. This paved the way towards exploring the possible pharmacological manipulation of neurogenesis which would offer an alternative approach for the treatment of AD.

The evidence for the existence of neurogenesis in the adult mammalian brain, including humans is now widely accepted. Despite the fact that adult neural stem cells appear to be very promising, a wide range of their unrevealed properties, abilities but also limitations under physiological and especially pathological conditions still need to be investigated and explained. Huntington's disease (HD) is characterized by successive degeneration of relatively well-defined neuronal population. Moreover, the most affected region, the caudate nucleus, is adjacent to the subependymal zone (SEZ) neurogenic region. Therefore, the possibility to harness the endogenous neural stem cell capacity for repairing, or at least restricting, the fatal neurodegenerative process in HD patients using promoted neurogenesis in the adult SEZ represent the exciting new possibility in clinical management of this disorder. On the other hand, many questions have to be answered before neuronal replacement therapies using endogenous precursors become a reality, particularly in relation to neurodegenerative diseases. Fundamental for all experimental, functional and future clinical studies is detailed morphological description of structures involved in the process of neurogenesis. The objectives of this review are to describe neurogenesis in the adult murine and human brain (with particular emphasis to morphological aspects of this process) and to determine to what extent it is affected in animal models of HD and in the human HD brain. Due to very limited evidence referring to the impact of striatal pathology of HD phenotype on the adult neurogenesis in the SEZ, some results gained from our studies on two rat models of HD, i.e. the neurotoxic lesion and transgenic HD rats, and on human HD brains are discussed.

Schwann cells are critically important for tissue repair, axonal regrowth and remyelination following injury to peripheral nerves. The absence of Schwann cells or an equivalent cell type in the central nervous system (CNS) may limit the regeneration capacity of the CNS. Mesenchymal stem cells (MSCs) have therefore been investigated for their potential to be induced to develop a Schwann cell phenotype. The methods for derivation of Schwann cell-like cells from MSCs and the benefits and limitations of each of these methods are presented in this review. Issues related to instability of the derived Schwann cell phenotype, apoptosis of derived cells in transplants, and the inability to predict with confidence how the cells will behave after transplantation are discussed. Finally, we suggest the need for further elucidation of the biology of Schwann cell differentiation and the signals for their derivation from MSC, in order to resolve these obstacles and to enable transplantation of MSC-derived Schwann cells as a therapeutic strategy in CNS injury.

Parkinson's disease (PD) is a common neurodegenerative disease, characterized by a selective loss of midbrain dopaminergic (DA) neurons. To address this problem, various types of stem cells that have potential to differentiate into DA neurons are being investigated as cellular therapies for PD, including cells derived from embryonic or adult donor tissue, and embryonic stem cells. These cell sources, however. have raised certain questions with regard to ethical and rejection issues. Recent progress in adult stems has further proved that the cells derived from adult tissue could be expanded and differentiated into DA precursor cells in vitro, and cell therapy with adult stem cells could produce a clear improvement for PD models. Using adult stem cells for clinic application may not only overcome the ethical problem inherent in using human fetal tissue or embryonic stem cells, but also open the possibility for autologous transplantation. The patient-specific adult stem cell is therefore a potential and prospective candidate for PD treatment.

Parkinson's disease (PD) is a severe deliberating neurological disease caused by progressive degenerative death of dopaminergic neurons in the substantia nigra of midbrain. While cell replacement strategy by transplantation of neural stem cells and inducement of dopaminergic neurons is recommended for the treatment of PD, understanding the differentiation mechanism and controlled proliferation of grafted stem cells remain major concerns in their clinical application. Here we review recent studies on molecular signaling pathways in regulation of dopaminergic differentiation and proliferation of stem cells, particularly Wnt/β-catenin signaling in stimulating formation of the dopaminergic phenotype, Notch signaling in inhibiting stem cell differentiation, and Sonic hedgehog functioning in neural stem cell proliferation and neuronal cell production. Activation of oncogenes involved in uncontrolled proliferation or tumorigenicity of stem cells is also discussed. It is proposed that a selective molecular manipulation targeting strategy will greatly benefit cell replacement therapy for PD by effectively promoting dopaminergic neuronal cell generation and reducing risk of tumorigenicity of in vivo stem cell applications.