CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 6, Issue 5, 2007

Correct diagnosis and effective treatment of diseases are two essential tasks for a clinical doctor. With advancing technology, the early and correct diagnosis of diseases is getting easier; however, the treatment of most diseases remains one of the biggest challenges for clinical medicine in 21st century. Broadly speaking, the causes of human diseases can be classified into two categories: abnormal cell death and abnormal cell proliferation. Examples of the former are Alzheimer disease and stroke, both of which cause cell death in the brain. Cell death in different locations produces different diseases. For example, Parkinson disease prdouces death of cells in the substantia nigra, whereas Alzheimer disease prominently affects the hippocampus and cerebral cortex. Abnormal cell proliferation is a feature of cancer. Recent studies show that cancer is initiated from cancer stem cells. In theory, if we can find an approach to kill cancer stem cells, we can cure cancer, and if we can induce stem cells to differentiate into mature cells such as neurons, we will be able to replace damaged neurons for therapy of neurodegenerative diseases. Hence, stem cells are important medically both because of the risk they pose in carcinogenesis, and for the potential they offer for tissue regeneration or replacement. Stem cells can be classified into embryonic stem cells (ESCs), derived from blastocysts, and adult stem cells, which are found in adult tissues. Both have two important characteristics that distinguish them from other types of cells. First, they are unspecialized cells that are able to renew themselves through mitotic cell division. The second is that under certain conditions, they can differentiate into a diverse range of specialized cell types. Pluripotent ESCs can form cells of all tissues of the adult organism and adult stem cells have generally been regarded as having the capacity to form only the cell types of the organ in which they are found; however some adult stem cells may exhibit multipotency. Although human ESCs, which were first generated from human embryos in 1998, hold immense potential for therapeutic use in cell therapy, they also have disadvantages. This is evident in the proposed use of such cells to treat neurological diseases by intracerebral transplantation. First, surgical transplantation may result in local tissue damage or stroke. Second, the use of human ESCs is ethically and politically controversial. Third, neural degeneration in some CNS diseases is extensive, multifocal or even global, which may require widespread replacement beyond the capabilities of surgical transplantation. Finally, intracerebral transplantation may be associated with adverse effects related to the unregulated function of ectopic tissue. It was thought for some time that the brains of adult mammals do not generate new neurons, although Altman first observed the proliferative potential of adult rodent brain in the 1960s. After years of debate, it is now accepted that neural stem cells are present in the rostral subventricular zone (SVZ) surrounding the lateral ventricles and the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) in adult mouse, rat, non-human primate and human brain. Newly generated cells in the SGZ can differentiate into mature, functional neurons and integrate into the DG as granule cells, which are involved in memory formation in normal brain. More interestingly, endogenous neural stem cells in these discrete regions proliferate in response to brain injuries such as stroke and neurodegerative diseases such as Huntington's diseases. These disease-induced newborn cells can migrate into damaged brain regions, where they differentiate into mature neuronal cells. Therefore, it might be possible for damaged cells to be replaced from endogenous neural stem cell pools. However, the innate capacity for brain repair appears to be limited......

The function of neurogenesis in the adult brain is still unknown. Interventions such as environmental enrichment and exercise impinge on neurogenesis, suggesting that the process is regulated by experience. Conversely, a role for neurogenesis in learning has been proposed through ‘cellular plasticity’, a process akin to synaptic plasticity but operating at the network level. Although neurogenesis is stimulated by acute injury, and possibly by neurodegenerative processes such as Alzheimer's disease (AD), it does not suffice to restore function. While the role and direction of change in the neurogenic response at different stages of AD is still a matter of debate, it is possible that a deficit in neurogenesis may contribute to AD pathogenesis since at least one of the two regions ostensibly neurogenic in the adult human brain (the subgranular zone of the dentage gyrus and the ventriculo-olfactory neurogenic system) support high-level functions affected in early AD (associative memory and olfaction respectively). The age of onset and the rate of progression of sporadic forms of AD are highly variable. Sporadic AD may have a component of insufficient neurogenic replacement or insufficient neurogenic stimulation that is correlated with traits of personal history; the rate of neurogenesis and the survival of replicating progenitors is strongly modified by behavioral interventions known to impinge on the rate of neurogenesis and the probability of survival of newly born neurons - exercise, enriched experience, and learning. This view is consistent with epidemiological data suggesting that higher education and increased participation in intellectual, social and physical aspects of daily life are associated with slower cognitive decline in healthy elderly (“cognitive reserve”) and may reduce the risk of AD. Although neurogenesis can be modulated exogenously by growth factors, stimulation of neurogenesis as a mean to treat neurodegeneration is still for the most part speculative. Moreover, it is possible that different roles of neurogenesis during the course of AD are dictated by the degree of permissibility of the environment in which the process is taking place. A unique opportunity may exist in which the therapeutic stimulation of neurogenesis might contribute to functional ‘repair’ of the adult diseased brain, before damage to whole neuronal networks has ensued. In spite of the considerable gaps in our knowledge of neurogenesis, and of the considerable limitations that will need to be overcome before we can intervene in the process, that new neurons are added continuously to the adult mammalian brain is a discovery that has already changed the way we think about neurobiology, and may soon change the way we understand and approach neurodegenerative diseases such as AD.

Structural and morphological changes in limbic brain regions are associated with depression, chronic stress and antidepressant treatment, and increasing evidence supports the hypothesis that dysregulation of cell proliferation contributes to these effects. We review the morphological alterations observed in two brain regions implicated in mood disorders, the prefrontal cortex and hippocampus, and discuss the similarities and differences of the cellular consequences of chronic stress. We briefly discuss the proposed mechanisms implicated in neuroplasticity impairments that result from stress and that contribute to mood disorders, with a particular interest in adult neurogenesis and gliogenesis. This information has contributed to novel antidepressant medication development that utilizes adult neurogenesis and gliogenesis as preclinical cellular markers for predicting antidepressant properties of novel compounds.

Stroke stimulates neurogenesis in select regions of the adult brain, and the newborn neurons that result can migrate to areas of ischemic injury, where they may have the capacity to enhance brain recovery. These observations suggest that stroke-induced neurogenesis may contribute to endogenous brain repair after stroke, and that the mechanisms that underlie neurogenesis may represent potential therapeutic targets. Alternatively, transplantation of exogenously derived neural cells might also be an approach to the treatment of stroke.

Parkinson's disease is a neurodegenerative disorder characterized by a progressive neuronal loss affecting preferentially the dopaminergic neurons of the nigrostriatal projection. Transplantation of fetal dopaminergic precursor cells has provided the proof of principle that a cell replacement therapy can ameliorate clinical symptoms in affected patients. Recent years have provided evidence for the existence of neural stem cells with the potential to produce new neurons, particularly of a dopaminergic phenotype, in the adult mammalian brain. Such stem cells have been identified in so called neurogenic brain areas, where neurogenesis is constitutively ongoing, but also in primarily non-neurogenic areas, such as the midbrain and the striatum, where neurogenesis does not occur under normal physiological conditions. We review here presently published evidence to evaluate the concept that endogenous neural stem cells may have the potential to be instrumentalized for a non-invasive cell replacement therapy with autologous neurons to repair the damaged nigrostriatal dopaminergic projection in Parkinson's disease.

Neural stem cells are present throughout life and continuously give rise to new neurons and glia cells in the mammalian central nervous system. Accumulating evidence suggests essential roles of micro-environments, or niches, in supporting active neurogenesis from endogenous neural stem cells within restricted regions of the adult brain. These neurogenic niches also regulate different steps of adult neurogenesis in response to physiological and pathological stimulations. Recent studies have identified several cellular niche components, including endothelial cells, astroglia, ependymal cells, immature progeny of NSCs and mature neurons. In this review, we discuss identified niche signals from these cellular components in regulating different steps of adult neurogenesis. We also highlight some of the potential therapeutic targets to be manipulated within neurogenic niche for repair of the adult central nervous system.

The dentate gyrus, a region of the hippocampal formation, displays the highest level of plasticity in the brain and exhibits neurogenesis all through life. Dentate neurogenesis, believed to be essential for learning and memory function, responds to physiological stimuli as well as pathological situations. The role of dentate neurogenesis in the pathophysiology of temporal lobe epilepsy (TLE) has received increased attention lately because of its disparate response in the early and chronic stages of the disease. Acute seizures or status epilepticus immensely enhance dentate neurogenesis and lead to an aberrant migration of newly born neurons into the dentate hilus and the formation of epileptogenic circuitry in the injured hippocampus. Conversely, spontaneous recurrent seizures that arise during chronic TLE are associated with dramatically reduced dentate neurogenesis. In this review, we discuss the potential significance of enhanced but abnormal neurogenesis taking place shortly after brain injury or the status epilepticus towards the development of chronic epilepsy, and prospective implications of dramatically waned dentate neurogenesis occurring during chronic epilepsy for learning and memory function and depression in TLE. Furthermore, we confer whether hippocampal neurogenesis is a possible drug target for preventing TLE after brain injury or the status epilepticus, and for easing learning and memory impairments during chronic epileptic conditions. Additionally, we discuss some possible drugs and approaches that need to be evaluated in future in animal models of TLE to further understand the role of neurogenesis in the pathogenesis of TLE and whether modulation of neurogenesis is useful for treating TLE.

The evidence that new neuron addition takes place in the mammalian brain throughout adult life has dramatically altered our perspective of the potential for plasticity in the adult CNS. Although several recent reports suggest a latent neurogenic capacity in multiple brain regions, the two major neurogenic niches that retain the ability to generate substantial numbers of new neurons in adult life are the subventricular zone (SVZ) lining the lateral ventricles and the subgranular zone (SGZ) in the hippocampal formation. The discovery of adult neurogenesis has also unveiled a novel therapeutic target for the repair of damaged neuronal circuits. In this regard, understanding the endogenous mechanisms that regulate adult neurogenesis holds promise both for a deeper understanding of this form of structural plasticity, as well as the identification of pathways that can serve as therapeutic targets to manipulate adult neurogenesis. The purpose of the present review is to discuss the regulation of adult neurogenesis by neurotransmitters and to highlight the relevance of these endogenous regulators as targets to modulate adult neurogenesis in a clinical context.