Current Drug Targets-CNS & Neurological Disorders - Volume 4, Issue 4, 2005

In the past ten years, the neuron-glia interaction has been one of the most fast-growing and sustained research themes in neuroscience. The functional cross-talk between neurons, astrocytes and microglia in normal brain function, in brain diseases and age-related disorders has been a central element in the understanding some of the most relevant responses of the nervous tissue to injury. The new developments of this research field have had a major impact in the elucidation of the mechanisms involved in the neuro-inflammatory response, neurogenesis, neuroprotection and neuronal replacement. In the present special issue we reviewed the most recent breakthrough publications about basic mechanisms of neuroimmunity, neurogenesis and neuroprotection in brain repair associated with several brain disorders with a major social and economic impact. In two commentaries and eight review articles dedicated to “Synaptic modulators and neuroprotection”, “Major brain diseases” and “New models and therapeutic strategies”, the authors review basic concepts and highlight potential new research and therapeutic strategies in brain dysfunction. The major role of key synaptic modulators including, nitric oxide, adenosine, neuropeptide Y and cytokines in modulating neurotransmitter release and neuroprotection is highlighted in the first papers by Araujo and Carvalho, Ribeiro and by Silva et al. The neuroprotective properties of the above indicated neuromodulators and also the fine tune control of neuronal death, neurogenesis and brain inflammation in major neurological diseases is a common theme in the review articles dedicated to Epilepsy, Huntington's disease, Alzheimer's disease, Parkinson's disease and Diabetic Retinopathy. The contributions by Bernardino et al., Rego and Almeida, Pereira et al., Cardoso et al. and Leal et al., respectively, are a review of the state of the art in the basic mechanisms of disease. Moreover, these reviews critically identify new research fields for the future development of new therapeutic strategies. The final two review papers are dedicated to organotypic brain slice cultures as a highlighted research model in neuroscience and to the use of liposomal and viral vectors as research tools for gene therapy. The popularity of organotypic brain slice cultures is mostly due to the partial preservation of natural interaction between brain cells and neuronal circuits, allowing the use of this tool to fill the gap between monolayer cultures and in vivo experiments. These characteristics contribute to the increasing popularity of this model in pharmacological research, making it a preferred research tool for the development of new therapeutic strategies of brain diseases. Moreover, the last review article of the current special issue of CDT-CNSND is a source of inspiration for the neuroscientist dedicated to brain disease. The development of new formulations, and the in vivo application, of liposomal and viral vector for gene therapy is a promising interdisciplinary research field, with a major potential impact in the future of therapeutic strategies of brain repair.

Dysregulation of intracellular calcium homeostasis is a common hallmark of degenerating neurons, at some point in the cell death cascade. It is also a feature of many neurological disorders, including stroke, epilepsy, trauma and several neurodegenerative diseases, commonly associated with the phenomenon of excitotoxicity. Nitric oxide (NO) is a signaling gaseous molecule formed in the brain as a part of the normal intracellular calcium signalling, playing highly diversified roles in cellular physiology. For the past 20 years, numerous studies have demonstrated that NO can acts as a neurotoxin in several disorders of the nervous system. More recent evidence shows that NO can also act as a neuroprotective agent. Calcium-dependent proteases, like calpains, were also shown to be activated in several conditions of the nervous system that involve excitotoxic neurodegeneration, and have been receiving increasing attention as therapeutical targets in recent years. In this review, we bring together the recent literature concerning the involvement of NO and calpains in neuronal survival and death. The biological pathways involved with NO and calpains may be good drug targets to alter neurodegenerative diseases.

The possibility of repairing brain lesions is a crucial issue. Knowing how regeneration occurs allows novel concepts in the process of protecting the nervous system, in other words to induce and to develop neuroprotection. Brain insults cause irreversible tissue damage by at least three mechanisms: First, through consequences of mechanical disruption of neurons or their projections; secondly, through biochemical or metabolic changes that are initiated by the insult; and finally, through inflammatory reactions or gliotic changes. The cellular elements and the chemical neuro-mediators involved in brain injury act via interconnections between the cellular elements and their secretions; the immune system and the nervous system are highly regulated in normal physiology, which benefits the organism. When these cells suffer insults in the central nervous system (CNS), the connections between the systems are altered; these systems act together to strangulate the tissue, depriving it of the local control over microcirculation and necessary oxygen, rendering membrane potentials useless to modulate neuronal function. Surgical interventions during the stages of brain injury continue to progress as do biochemical and bioelectric therapeutics during the chronic and rehabilitation stages. There is some hope, too, for effective neuropharmacological intervention. The fact that chemical mediators are already part of normal physiology, whether during development or adulthood, means that their activity can be modified by specific agonists and antagonists to restore homeostasis or to promote the safe pathways that can lead to regeneration. This is the orientation of much of current basic and clinical research. During the past decade considerable experimental and clinical data have been accumulated regarding cellular and biochemical events associated with brain repair.

Neuropeptide Y (NPY) is one of the most abundant and widely distributed neuropeptides in the mammalian central nervous system (CNS). An overview of the distribution of the G-protein coupled NPY receptor family (Y1, Y2, Y4, Y5 receptors) in the brain is described. The coexistence of NPY with other neurotransmitters and its wide distribution in several brain areas predict the high importance of NPY as a neuromodulator. Thus, the effect of NPY on the release of several neurotransmitters such as glutamate, gammaaminobutyric acid (GABA), norepinephrine (NE), dopamine, somastotatin (SOM), serotonin (5-HT), nitric oxide (NO), growth hormone (GH) and corticotropin releasing factor (CRF) is reviewed. A neuroprotective role for NPY under physiological conditions and during hyperactivity such as epileptic-seizures has been suggested. We have shown previously that NPY inhibits glutamate release evoked from hippocampal nerve terminals and has a neuroprotective effect in rat organotypic hippocampal cultures exposed to an excitotoxic insult. Moreover, changes in NPY levels have been observed in different pathological conditions such as brain ischemia and neurodegenerative diseases (Huntington's, Alzheimer's and Parkinson's diseases). Taken together, these studies suggest that NPY and NPY receptors may represent pharmacological targets in different pathophysiological conditions in the CNS.

The aim of the present review is to discuss the evidence supporting the hypothesis that inflammation and neurogenesis play an important role in temporal lobe epilepsy (TLE) and to examine whether possible strategies that involve the pharmacological manipulation of inflammation/neurogenesis can lead to the development of novel approaches for the treatment of epilepsy. Since it is not yet clear whether the neuron-glia response obtained in this pathology is a secondary effect of an aggressive inflammation or if it is somehow related to the cause of the epileptic condition, with the present review we guide the readers through the complex and ambiguous crosstalk between neuroimmunology and epilepsy.

This article provides an overview of the molecular mechanisms associated with striatal neuronal degeneration in Huntington's disease (HD), the most studied of the diseases caused by polyglutamine expansion. We discuss the current status of research in cellular and animal models of HD, in which protein aggregation, excitotoxicity, mitochondrial dysfunction, transcription deregulation, trophic factor starvation and the disruption of axonal transport appear to be key features for selective striatal neurodegeneration. We further emphasize some of the most promising current strategies in HD treatment. We delineate the molecular and cellular rationale underlying the development of new pharmaceutical interventions that offer new hope of future treatment for HD patients worldwide.

The characteristic hallmarks of Alzheimer's disease (AD), the most common form of dementia in the elderly, include senile plaques, mainly composed of beta-amyloid (Aβ) peptide, neurofibrillary tangles and selective synaptic and neuronal loss in brain regions involved in learning and memory. Genetic studies, together with the demonstration of Aβ neurotoxicity, led to the development of the amyloid cascade hypothesis to explain the AD-associated neurodegenerative process. However, a modified version of this hypothesis has emerged, the Aβ cascade hypothesis, which takes into account the fact that soluble oligomeric forms and protofibrils of Aβ and its intraneuronal accumulation also play a key role in the pathogenesis of the disease. Recent evidence posit that synaptic dysfunction triggered by non fibrillar Aβ species is an early event involved in memory decline in AD. The current understanding of the molecular mechanisms responsible for impaired synaptic function and cognitive deficits is outlined in this review, focusing on oxidative stress and disturbed metal ion homeostasis, Ca2+ dysregulation, mitochondria and endoplasmic reticulum dysfunction, cholesterol dyshomeostasis and impaired neurotransmission. The activation of apoptotic cell death as a mechanism of neuronal loss in AD, and the prominent role of neuroinflammation in this neurodegenerative disorder, are also reviewed herein. Furthermore, we will focus on the more relevant therapeutical strategies currently used, namely those involving antioxidants, drugs for neurotransmission improvement, hormonal replacement, γ- and β- secretase inhibitors, Aβ clearance agents (Aβ immunization, disruption of Aβ fibrils, modulation of the cholesterol-mediated Aβ transport), nonsteroidal anti-inflammatory drugs (NSAIDs), microtubules stabilizing drugs and kinase inhibitors.

Parkinson's disease (PD), considered one of the major neurological disorders, is characterized by the loss of dopaminergic neurons in the pars compacta of the substantia nigra and by the presence of intraneuronal cytoplasmic inclusions called Lewy bodies. The causes for degeneration of PD neurons remain unclear, however, recent findings contributed to clarify this issue. This review will discuss the current understanding of the mechanisms underlying Parkinson's disease pathogenesis, focusing on the current and potential therapeutic strategies for human treatment.

Diabetic Retinopathy (DR) is a major complication of diabetes and is a leading cause of blindness in western countries. DR has been considered a microvascular disease, and the blood-retinal barrier breakdown is a hallmark of this disease. The available treatments are scarce and not very effective. Despite the attempts to control blood glucose levels and blood pressure, many diabetic patients are affected by DR, which progresses to more severe forms of disease, where laser photocoagulation therapy is needed. DR has a huge psychological impact in patients and tremendous economic and social costs. Taking this into account, the scientific community is committed to find a treatment to DR. Understanding the cellular and molecular mechanisms underlying the pathogenesis of DR will facilitate the development of strategies to prevent, or at least to delay the progression of the disease. The involvement of the polyol pathway, advanced glycation end products, protein kinase C and oxidative stress in the pathogenesis of DR is well-documented, and several clinical trials have been conducted to test the efficacy of various drugs. More recent findings also demonstrate that DR has characteristics of chronic inflammatory disease and neurodegenerative disease, which increases the opportunity of intervention at the pharmacological level. This review presents past and recent evidences demonstrating the involvement of different molecules and processes in DR, and how different approaches and pharmacological tools have been used to prevent retinal cell dysfunction.

Slices of developing brain tissue can be grown for several weeks as socalled organotypic slice cultures. Here we summarize and review studies using hippocampal slice cultures to investigate mechanisms and treatment strategies for the neurodegenerative disorders like stroke (cerebral ischemia), Alzheimer's disease (AD) and epilepsia. Studies of non-excitotoxic neurotoxic compounds and the experimental use of slice cultures in studies of HIV neurotoxicity, traumatic brain injury (TBI) and neurogenesis are included. For cerebral ischemia, experimental models with oxygen-glucose deprivation (OGD) and exposure to glutamate receptor agonists (excitotoxins) are reviewed. For epilepsia, focus is on induction of seizures with effects on neuronal loss, axonal sprouting and neurogenesis. For Alzheimer's disease, the review centers on the use of beta-amyloid (Abeta) in different models, while the section on repair is focused on neurogenesis and cell migration. The culturing techniques, set-up of models, and analytical tools, including markers for neurodegeneration, like the fluorescent dye propidium iodide (PI), are reviewed and discussed. Comparisons are made between hippocampal slice cultures and other in vitro models using dispersed cell cultures, experimental in vivo models, and in some instances, clinical trials. New techniques including slice culturing of hippocampal tissue from transgenic mice as well as more mature brain tissue, and slice cultures coupled to microelectrode arrays (MEAs), on-line biosensor monitoring, and time-lapse fluorescence microscopy are also presented.

Due to the presence of the blood-brain barrier, the central nervous system (CNS) is not easily accessible to systemically delivered macromolecules with therapeutic activity such as growth factors, cytokines or enzymes. Therefore, the expression of exogenously administered genes in the brain has been proposed for a wide variety of inherited and acquired diseases of the CNS, for which classical pharmacotherapy is unavailable or not easily applicable. Gene therapy to the CNS has been the target of a great number of studies aiming at finding a viable therapeutic strategy for the treatment of neurological disorders. This approach has already been used as a promising tool for brain protection and repair from neuronal insults and degeneration in several animal models, and is currently being applied in clinical trials. The choice of an appropriate vector system for transferring the desired gene into the affected brain area is an important issue for developing a safe and efficient gene therapy approach for the CNS. In this review, we focus on the various types of vectors that have been used for gene delivery into the CNS. Particular emphasis is given to their mode of preparation, biological activity, safety and in vivo behavior. Examples illustrating the potential of both viral and non-viral vectors in therapeutic applications to brain disorders are provided. In addition, the use of lentiviral vectors for in vivo modeling of genetic disorders of the CNS is discussed.