Current Neurovascular Research - Volume 1, Issue 4, 2004

Our objective for Current Neurovascular Research is to consistently provide a broad platform for leading scientific inquiry of both neuronal and vascular origins in neuroscience. To this end, our current issue is no exception to this rule and offers the opinions and hypotheses of scientific leaders from a broad spectrum of investigative fields. In this issue, the initial article by Lehmann et al. outlines the function of cellular water-selective channels in the central nervous system, termed aquaporins, and the unique role that these channels play in water transport during disorders such as cerebral ischemia, trauma, and neoplasms. Subsequently, the next series of articles in this issue highlight novel therapeutic strategies for a variety of nervous system disorders. Sakamaki presents the molecular mechanisms that can determine vascular endothelial cell injury in conjunction with the cellular and environmental factors that can repair damaged vascular cells and foster new endothelial cell growth during angiogenesis. In another article by Panchal et al., cellular mediators of abnormal peptide metabolism are identified in Alzheimer's disease. Employing current knowledge of the pathways involved in β-amyloid catabolism, potential treatment strategies that would pursue prevention of toxic β-amyloid generation, improve β-amyloid clearance from the brain, and target the modulation of peptidases to degrade β-amyloid in the brain are examined. Further work by Mouzaki et al., Greco and Minghetti, and Ekshyyan and Aw complements such novel therapeutic strategies and describe the use of cytokine modulation and peptide analogs of myelin epitopes for the treatment of demyelinating disease, the biological tracking of cellular oxidative stress through the use of isoprostanes, and the elucidation of molecular programs that lead to cellular suicide in an effort to develop new therapeutic avenues for a host of neurodegenerative disorders. Kuwabara and Misawa extend this work with their discussion of the ionic disturbances and altered membrane excitability that precipitate peripheral neuropathies and motor neuron degeneration. Interestingly, in the manuscript by Holthoff, similar ionic cellular mechanisms that involve membrane excitability also are responsible for regenerative dendrites spikes that may be necessary for the generation of longterm synaptic plasticity. Taken to another level, Brosh and Barkai further describe the sequence of events necessary for learning paradigms that begin with enhanced neuronal excitability and ultimately culminate with enhanced spine density and synaptic connectivity. With this series of articles, we share a glimpse into the varied, but intimately linked cellular mechanisms in the nervous system that can bring apparently diverse topics such as aquaporins and apoptosis to a more common ground.

Aquaporins (AQPs) are a family of water-selective channels that provide a major pathway for osmotically driven water transport through cell membranes. Some members of the aquaporin family have been identified in the central nervous system (CNS). The water channel aquaporin 1 (AQP1) is restricted to the apical domain of the choroid plexus epithelial cells. The AQP4 is abundantly expressed in astrocyte foot processes and ependymocytes facing capillaries and brain-cerebrospinal fluid (CSF) interfaces, whereas AQP9 is localized in tanycytes and astrocytes processes. The mRNA for other aquaporin homologs (i.e., AQP3, 5, and 8) have been recently found in cultured astrocytes. Based on their subcellular localization and data obtained from functional studies, it is assumed that aquaporins are implicated in water movements in nervous tissue and may play a role in central osmoreception, K+ siphoning, and cerebrospinal fluid formation. There have been recent reports describing different aquaporin-responses under pathologic states leading to brain edema. The data available provide a better understanding of the mechanisms responsible for brain edema and indicate that aquaporins are potential targets for drug development.

In multicellular organisms, apoptosis, also known as programmed cell death, is an important physiological response to eliminate unnecessary, excess, or harmful cells. Apoptosis occurs during embryonic development and is important in maintaining homeostasis during adulthood. Apoptosis also plays critical roles in angiogenesis and vessel regression. During these processes, activation of the apoptotic signaling pathway in endothelial cells mediates cell death. Several molecules, including growth factors and cytokines, produced by endothelial cells and other cells, regulate endothelial cell survival and apoptosis. Understanding the regulation of apoptosis is of great importance for determining the physiological role of endothelial cells and for developing novel therapeutic strategies. This review highlights the rapidly accumulating knowledge regarding endothelial cell death and provides insight into the molecular mechanisms regulating apoptosis and survival of endothelial cells.

The steady-state level of peptide hormones represents a balance between their biosynthesis and proteolytic processing by convertases and their catabolism by proteolytic enzymes. Low levels of neuropeptide Y, somatostatin and corticotropin-releasing factor, described in Alzheimer disease (AD), were related to a defect in proteolytic processing of their protein precursors. In contrast the abundance of β-amyloid peptides, the major protein constituents of senile plaques is likely related to inefficient catabolism. Therefore, attention is mainly focused on convertases that generate active peptides and counter-regulatory proteases that are involved in their catabolism. Some well-described proteases such as NEP are thought to be involved in β-amyloid catabolism. The search of other possible candidates represents a primary effort in the field. A variety of vascular risk factors such as diabetes, hypertension and arteriosclerosis suggest that the functional vascular defect contributes to AD pathology. It has also been described that β-amyloid peptides potentiate endothelin-1 induced vasoconstriction. In this review, we will critically evaluate evidence relating proteases implicated in amyloid protein precursor proteolytic processing and β-amyloid catabolism.

Multiple Sclerosis (MS) is a chronic inflammatory degenerative disease of the central nervous system (CNS), first described over 100 years ago. MS is a clinically heterogeneous disease with an increasing incidence over time, and a population prevalence that increases with distance from the equator. It is postulated that environmental factors such as diet and population-specific genetics, influence the distribution of MS. Diagnosis is based on established clinical criteria, aided by magnetic resonance imaging, evoked potential recordings and cerebrospinal fluid examination. Whichever the type of clinical manifestation, MS is considered an organ-specific autoimmune disease, characterized by T-cell and macrophage infiltrates, triggered by CNS-specific CD4 T-cells. The prominent autoimmune etiology of MS is considered to be the aberrant activation of IFN-γ-producing Th1 cells that recognize self-peptides of the myelin sheath, such as myelin basic protein (MBP) and proteolipid protein (PLP). Current treatments for MS aim primarily to suppress T-cell-mediated immune responses, albeit non-specifically. Experimental approaches towards the therapeutic management of MS involve the use of peptide analogs of disease-associated myelin epitopes or vaccines, to help shift T helper cell responses from Type-1 (secreting pro-inflammatory cytokines) to Type-2 (secreting anti-inflammatory cytokines) or induce peripheral Tcell tolerance. Animal models of MS have been useful to dissect disease mechanisms and evaluate new therapies. Experimental clinical trials, although few, are valuable to assess new treatment regimens and clarify possible conceptual mistakes about the disease. This review attempts to link the current knowledge of MS pathogenesis with clinical and experimental protocols of immunotherapy for MS.

Isoprostanes are a family of prostaglandin-like compounds that are generated in vivo by free radical attack of esterified arachidonic acid and then released in free form in biological fluids. Since their discovery in 1990, they have been extensively used as biomarkers of lipid peroxidation and oxidative damage in an increasing number of human diseases. Few members of the isoprostane family are biologically active and could contribute to the functional consequences of oxidant injury. The present review summarises the current knowledge on formation and biological activities of these lipid peroxidation products, focusing on their role as valuable biomarkers to investigate the involvement of oxidative stress in the pathogenesis of infant and adult central nervous system diseases. In addition to isoprostanes, a new class of free radical-mediated peroxidation products, named neuroprostanes, is discussed. Neuroprostanes derive from peroxidation of docosahexaenoic acid, a polyunsatured fatty acid particularly abundant in neurons, and may represent a more selective index of brain oxidant injury than isoprostanes. In spite of some discrepancies in the results reported in different studies, isoprostane and neuroprostane levels in human biological fluids, as well as in experimental models of brain diseases, appear to be valuable indicators not only to monitor the occurrence and the causal role of oxidative stress in brain pathologies, but also for critical selection and evaluation of appropriate antioxidant therapies.

Apoptosis is an important process in the development of the nervous system. Typically, ∼50% of the neurons apoptose during neurogenesis before the nervous system matures. However, recent paradigms implicate premature apoptosis and / or aberrations in the fine control of neuronal apoptosis in the pathogenesis of a variety of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal muscular atrophy, stroke, brain trauma, spinal cord injury, and diabetic neuropathy. This review will focus on the current concepts salient to understanding the apoptosis death program, the mediators and control of cellular apoptosis, and the relationship between aberrant apoptosis and genesis of neurodegenerative disorders. The discussion will also highlight current advances in methodology, such as utilization of neuronal cell lines and mutant animal models, in investigations of neuronal apoptotic death. The knowledge of apoptosis mechanisms could underpin the basis for development of novel therapeutic strategies and treatment modalities that are directed at control of the neuronal apoptotic death program.

Testing the excitability of axons can provide insights into the ionic mechanisms underlying the pathophysiology of axonal dysfunction in human neuropathies and motor neuron diseases. Threshold tracking, which was developed in the 1990's, non-invasively measures a number of axonal excitability indices, which depend on membrane potential and on the Na+ and K+ conductances. This paper reviews recent advances in ionic-pathophysiological studies in human subjects in vivo. Membrane potential of human axons can be estimated, because most of the ion channels expressed on the axolemma are voltage-dependent, and patterns of changes in multiple excitability indices can suggest whether axons are depolarized or hyperpolarized. This has been clearly demonstrated in a single patient with acute hypokalemia (hyperpolarization) and patients with chronic renal failure (depolarization due to hyperkalemia). Muscle cramps / fasciculations arise from hyperexcitability of the motor axons. The enhanced excitability can result from altered ion channel function; an increase in persistent Na+ conductance, a decrease in accommodative K+ conductance, and focal membrane depolarization, all of which increase excitability, have been demonstrated in amyotrophic lateral sclerosis or other disorders affecting lower motor neurons. Patients with demyelinating neuropathy often complain of muscle fatigue. During voluntary contraction, the activation of the electrogenic Na+-K+ pump and resulting membrane hyperpolarization can cause activity-dependent conduction block when the safety factor for impulse transmission is critically reduced. Studies of ion-channel pathophysiology in human subjects have recently begun. Investigating ionic mechanisms is of clinical relevance, because once a specific ionic conductance is identified, blocking or activating it may provide a new therapeutic option for a variety of neuromuscular diseases.

During the last decade, our vision of the neuronal dendritic tree has changed from a simple input device conducting afferent input as a passive cable to the cell soma to a series of independent and actively operating processing units. Different voltage- and ligand-gated ion channels located in the dendritic tree not only participate in processing afferent inputs but also enable the dendritic tree to initiate regenerative spikes, traditionally considered to be exclusively restricted to axonal structures. Recent results suggest that these local dendritic spikes may act as a means to initiate longterm synaptic plasticity. Different from Hebbian synaptic plasticity this type of induction does not need axonal action potential firing and backpropagation into the dendrite. This new proximity learning rule, first postulated by neural network theorists, may have large significance for the information processing in the brain.

The idea that memory is manifested at the cellular level by enhancement of synaptic connections between simultaneously activated neurons has been suggested half a century ago by Hebb, and is widely accepted since. Much effort is done to describe such enhancement and reveal the underlying mechanisms. Learning-induced synaptic modifications were studied in the last decade with in-vitro brain slices preparations. Several forms of long-term enhancement of synaptic connections between layer II pyramidal neurons in the piriform cortex accompany olfactory learning. Such modifications were described also in other brain areas, following other training paradigms. Post-synaptic enhancement of synaptic transmission is indicated by reduced rise time of (post synaptic potentials) PSPs and formation of new synaptic connections is indicated by increased spine density along dendrites of these neurons. Enhanced synaptic release is indicated by reduced paired-pulse facilitation. In slices from trained rats predisposition for long-term potentiation is decreased and predisposition for long-term depression is increased. These modifications are attributed to olfactory-discrimination rule learning, rather than to memories for specific odors, and may be subsequent to intrinsic modifications in pyramidal neurons that create favorable conditions for activity-dependent synaptic enhancement.