Current Neurovascular Research, Volume 1, Number 1, 2004
Contents
Introduction from the Editor-in-Chief
Kenneth Maiese
[Abstract]
Mossy Fiber Sprouting as a Potential Therapeutic Target
for Epilepsy Pp. 3-10
Ryuta Koyama and Yuji Ikegaya
[Abstract] [Full text article]
Endogenous Facilitation: From Molecular Mechanisms to
Persistent Pain Pp. 11-20
Daphne A. Robinson, Amelita A. Calejesan, Feng Wei,
Gerald F. Gebhart and Min Zhuo
[Abstract] [Full text article]
Protective Effect of Heat Shock Proteins in the Nervous
System Pp. 21-27
David S. Latchman
[Abstract] [Full text article]
Cell Biological Consequences of Mitochondrial NADH: Ubiquinone
Oxidoreductase Deficiency Pp. 29-40
Jan A.M. Smeitink, Lambert W.P.J. van den Heuvel, Werner
J.H. Koopman, Leo G.J. Nijtmans, Cristina Ugalde and Peter H.G.M. Willems
[Abstract] [Full text article]
Apoptosis: A Potential Therapeutic Target for Retinal
Degenerations Pp. 41-53
Francesca Doonan and Thomas G. Cotter
[Abstract] [Full text article]
Role of the Hippocampus and Amygdala in the Extinction of
Fear- Motivated Learning Pp. 55-60
Monica R. Vianna, Adriana S. Coitinho and Ivan Izquierdo
[Abstract] [Full text article]
Molecular Targets to Promote Central Nervous System
Regeneration Pp. 61-75
Gino B. Ferraro, Yazan Z. Alabed and Alyson E. Fournier
[Abstract]
Brain Hyperthermia During Physiological and Pathological
Conditions: Causes, Mechanisms, and Functional Implications Pp. 77-90
Eugene A. Kiyatkin
[Back to top] Introduction
from the Editor-in-Chief
Kenneth Maiese
In the 17th century, the human body began to be viewed as a system of subunits and independent compartments. This eventually led to the first human anatomical descriptions that mapped the body into different organs and tissues. What followed was a series of significant advances in the understanding of human biology. One of the greatest achievements in physiology during the 17th century was William Harvey's documentation that blood within the human body was under continuous circulation. Yet, much of the initial credit for the recognition of the ultimate dependence of the vital organs on the circulatory system dates back to the 2nd century AD with Galen. The doctrines of Galenic physiology outlined that blood was produced in the liver, flowed to the heart to obtain "vital spirits," and subsequently bathed the brain to gain "animal spirits." The "vital spirits" described by Galen were later discovered independently by Schiele in Sweden and by Priestly in England to consist of the element oxygen that was a critical component to sustain the body and brain. Oxygen, also termed "acid-former", obtained its current name from Antoine Lavoisier of France. Lavoisier made essential medical discoveries concerning the role oxygen in respiration and its necessity to sustain life. He determined that oxygen comprises about one-fifth of the volume of atmospheric air and is the only gas in air that sustains combustion and respiration.
These investigators, who were at the vanguard of science during their time, are considered to be some of the earliest researchers who attempted to bridge the gap between basic science and clinical medicine. The initial work by these investigators helped provide direction for modern clinical science and the treatment of disease, especially concerning disorders of the nervous system. Incredibly, our understanding of human disease continues to grow at an exponential rate. At times, the accumulation of knowledge of the cellular and molecular components of clinical disease exceeds all prior expectations held just a few years ago, such as evidenced by the recent cloning of the human genome, the growth of proteomics for drug discovery, and the realization of inherent plasticity of the central nervous system during injury or neurodegenerative disorders.
Despite theses advances, both basic investigators and clinicians sometimes are unable to identify the vital link between basic science discovery and the development of effective therapies for clinical disease. Even more critical to this process is the initiative to foster novel ideas that may be contrary to "accepted dogmas" of the scientific community. Multiple anecdotes by both Noble laureates and visionary investigators describe the persistent resistance to their theories and work that eventually gave way with the maturation of scientific discovery. In particular, if one focuses upon the nervous system, greater understanding of the mechanisms that determine neuronal and vascular survival do not on the surface always appear to integrate well with prior beliefs.
As a result, publication of novel work that bridges the gap between basic science research and clinical discovery becomes critical for the development of new therapeutic regimens. To foster this process, a new neuroscience journal, Current Neurovascular Research, is making its debut. Current Neurovascular Research provides a cross platform for the publication of scientifically rigorous research that addresses disease mechanisms of both neuronal and vascular origins in neuroscience. The journal serves as an international forum for pioneering original work as well as timely neuroscience research reviews in the disciplines of cell developmental disorders, plasticity, and degeneration and emphasizes the elucidation of disease mechanisms that can impact the development of therapeutic strategies for neuronal and vascular disorders.
In this inaugural issue, Current Neurovascular Research covers a wide breadth of research topics for an expanding audience of both basic scientists and physicians that maintain interest in the nervous system. From respected leaders in the field, topics examine potential cellular and molecular targets that modulate neuronal and vascular function for translation into therapeutic strategies, such as the role of mossy fiber sprouting during epileptogenesis, apoptotic protease pathways during retinal degeneration, heat shock proteins and cellular plasticity, mechanisms that drive human complex I deficiency, and inhibitory pathways that involve myelin-associated proteins such as Nogo. Investigations that translate cellular injury into more broad impairments that involve altered synaptic transmission and nervous system dysfunction outline the cellular and molecular mechanisms that determine endogenous facilitation of pain, the extinction of fear motivated learning, and the physiological and pathological mediators of brain hyperthermia.
Even prior to its launch, Current Neurovascular Research has garnered the support of well recognized investigators and boasts a highly respected editorial board. As a result, we believe that the journal promises to become one of the essential resources for new and exciting developments in the neuroscience field. It is our goal that both basic scientists and physicians will glean further insight into the methods of translating investigative work into viable therapeutics for diseases of the nervous system. With this objective, we hope to continue in the forefront of science with the same vision and intuition as evidenced by not only many of our contemporaries, but also by the early pioneers who preceded us such as Galen, Harvey, and Lavoisier.
[Back to
top] Mossy Fiber Sprouting as a Potential
Therapeutic Target for Epilepsy
Ryuta Koyama and Yuji Ikegaya
Hippocampal mossy fibers, axons of dentate granule cells, converge in the dentate hilus and run through a narrow area called the stratum lucidum to synapse with hilar and CA3 neurons. In the hippocampal formation of temporal lobe epilepsy patients, however, this stereotyped pattern of projection is often collapsed; the mossy fibers branch out of the dentate hilus and abnormally innervate the dentate inner molecular layer, a phenomenon that is termed mossy fiber sprouting. Experimental studies have replicated this sprouting in animal models of temporal lobe epilepsy, including kindling and pharmacological treatment with convulsants. Because these axon collaterals form recurrent excitatory inputs into dendrites of granule cells, the circuit reorganization is assumed to cause epileptiform activity in the hippocampus, whereas some recent studies indicate that the sprouting is not necessarily associated with early-life seizures. Here we review the mechanisms of mossy fiber sprouting and consider its potential contribution to epileptogenesis. Based on recent findings, we propose that the sprouting can be regarded as a result of disruption of the molecular mechanisms underlying the axon guidance. We finally focus on the possibility that prevention of the abnormal sprouting might be a new strategy for medical treatment with temporal lobe epilepsy.
[Back to top]
Endogenous Facilitation: From Molecular Mechanisms to Persistent Pain
Daphne A. Robinson, Amelita A. Calejesan, Feng Wei, Gerald F. Gebhart and Min Zhuo
It is well documented that sensory transmission, including pain, is subject to endogenous inhibitory modulatory influences at dorsal horn of the spinal cord. Recent results, from behavioral to molecular studies, demonstrate that endogenous modulatory systems are bi-phasic, including inhibitory as well as new facilitatory systems. In this review, we propose the existence of endogenous facilitatory systems in the brain, and review evidence supporting the hypothesis. We believe that understanding molecular and cellular mechanisms of endogenous facilitatory systems hold the hope for better future treatment of patients with chronic pain.
[Back to top] Protective Effect
of Heat Shock Proteins in the Nervous System
David S. Latchman
The heat shock proteins (hsps) are expressed in normal cells but their expression is enhanced by a number of different stresses including heat and ischemia. They play important roles in chaperoning the folding of other proteins and in protein degradation. In the brain, a number of studies have shown that prior induction of the hsps by a mild stress has a protective effect against a more severe stress. Moreover, over-expression of an individual hsp in neuronal cells in culture and in the intact brain either of transgenic animals or using virus vectors also produces a protective effect, directly demonstrating the ability of the hsps to produce protection. These findings indicate the potential importance of developing procedures for elevating hsp expression in a safe and efficient manner in human individuals either using pharmacological or gene therapy procedures.
[Back
to top] Cell Biological Consequences of Mitochondrial
NADH: Ubiquinone Oxidoreductase Deficiency
Jan A.M. Smeitink, Lambert W.P.J. van den Heuvel, Werner
J.H. Koopman, Leo G.J. Nijtmans, Cristina Ugalde and Peter H.G.M. Willems
Human complex I (NADH:ubiquinone oxidoreductase; EC 1.6.5.3) is the first and largest multi-protein assembly of the mitochondrial oxidative phosphorylation (OXPHOS) system; the final biochemical cascade of events leading to the production of ATP. The complex consists of 46 subunits, 7 encoded by the mitochondrial DNA and the remainder by the nuclear genome. In recent years, numerous gene mutations leading to an isolated complex I deficiency have been characterized in both genomes. Disorders associated with complex I deficiency (OMIM 252010) mostly lead to multi-system disorders affecting brain, skeletal muscle and the heart. Of these, Leigh syndrome, a progressive fatal encephalopathy symmetrically affecting specific areas of the brain, brainstem and myelin, is the most frequently observed phenotype. Here, we review the current understanding of the cell biological consequences of isolated complex I deficiencies and propose further directions the field needs to take in order to develop rational treatment strategies for these devastating disorders.
[Back to top]
Apoptosis: A Potential Therapeutic Target for Retinal Degenerations
Francesca Doonan and Thomas G. Cotter
Many retinal degenerations both inherited and induced are characterized by a loss of vision that is associated with death of photoreceptors. Inherited retinal diseases, which include Retinitis Pigmentosa (RP), form the largest single cause of blindness in the developed world. The genetics of RP is complex and approximately 48 genes have been implicated in the pathology of this disorder, in addition to the numerous mutations that exist within each gene (e.g. rhodopsin has <100). An attempt to overcome each individual mutation provides an overwhelming challenge. However targeting apoptosis, which represents a highly controlled, final common pathway to photoreceptor cell death, may provide a more practical approach. Caspases have been considered the primary executioners of apoptosis in many systems, however it is now apparent that other proteases such as calpains and cathepsins are affiliated with apoptosis. Conflicting data regarding the role of caspases in the execution of apoptosis in retinal degenerations will be critically discussed in light of reports demonstrating that key components of this pathway are downregulated during retinal development. This may control susceptibility to apoptosis in the developing retina and indeed during the maturation of other post-mitotic cells such as neurons and heart and skeletal muscle. Mitochondria function as central regulators of the intrinsic pathway of apoptosis through their role in energy production, calcium homeostasis and compartmentalization of cell death activators. The potential to control release of these apoptogenic proteins from mitochondria will also be examined with particular emphasis on the role of Bcl-2 family proteins and the regulators of calcium influx.
[Back to top] Role
of the Hippocampus and Amygdala in the Extinction of Fear- Motivated Learning
Monica R. Vianna, Adriana S. Coitinho and Ivan Izquierdo
Fear-motivated learning is at the root of phobias, panic, generalized anxiety and the posttraumatic stress disorder. This makes the inhibition of fear-motivated behavior a therapeutic desideratum in these diseases. The simplest way to accomplish this is by extinction, a procedure by which a given association between a conditioned stimulus or context (CS) and a fearsome event is replaced by a new association between the CS and the lack of the fearsome stimulus. This is a new learning for the subject and, in rats, it requires gene expression and protein synthesis both in the hippocampus and the basolateral amygdala, alongside with the activation of various metabolic signaling pathways. These requirements are similar to, but not identical with those for consolidation of the original memory. In addition, some systems uninvolved in original consolidation appear to be involved in extinction, namely, the endocannabinoid system. Extinction can be enhanced by prolonging the exposure to the lack of fearsome stimulation; e.g., in rats, by increasing the time of permanence in the compartment where the animals no longer receive a footshock. Further research into the possibilities of enhancing extinction at the expense of the original fearsome learning is desirable.
[Back to top] Molecular
Targets to Promote Central Nervous System Regeneration
Gino B. Ferraro, Yazan Z. Alabed and Alyson E. Fournier
Trauma in the adult mammalian central nervous system (CNS) results in devastating clinical consequences due to the failure of injured axons to spontaneously regenerate. This regenerative failure can be attributed to both a lack of positive cues and to the presence of inhibitory cues that actively prevent regeneration. Substantial progress has been made in elucidating the molecular identity of negative cues present at the CNS injury site following injury. In the past several years, multiple myelin-associated inhibitors including Nogo, Myelin-associated glycoprotein and Oligodendrocyte-myelin glycoprotein have been characterized. Furthermore a neuronal receptor complex and several intracellular substrates leading to outgrowth inhibition have been identified. Rapid progress has also been made in identifying the role of neurotrophins and other positive cues in promoting axonal regrowth. The most recent advances in our understanding of positive stimuli for axon regeneration come from transplantation studies at the CNS lesion site. A number of artificial substrates, tissues, and cells including fetal cells, neural stem cells, Schwann cells and olfactory-ensheathing cells have been tested in animal models of CNS injury. Based on our expanded knowledge of inhibitory influences and on the positive characteristics of various transplants, a number of interventions have been tested to promote recovery in models of CNS trauma. These advances represent the first steps in developing a viable therapy to promote axon regeneration following CNS trauma.
[Back to top] Brain Hyperthermia
During Physiological and Pathological Conditions: Causes, Mechanisms, and
Functional Implications
Although brain metabolism consumes high amounts of energy and is accompanied by intense heat production, brain temperature is usually considered a stable, tightly regulated homeostatic parameter. Current animal research, however, has shown that different forms of functional neural activation are accompanied by relatively large brain hyperthermia (2-3°C), which has an intra-brain origin; cerebral circulation plays a crucial role in dissipating this potentially dangerous metabolic heat from brain tissue. Brain hyperthermia, therefore, reflects enhanced brain metabolism and is a normal physiological phenomenon that can be enhanced by interaction with common elements of an organism’s environment. There are, however, instances when brain hyperthermia becomes pathological. Both exposure to extreme environmental heat and intense physical activity in a hot, humid environment restrict heat dissipation from the brain and may push brain temperatures to the limits of physiological functions, resulting in acute life-threatening complications and destructive effects on neural cells and functions of the brain as a whole. Brain hyperthermia may also result from metabolic activation induced by various addictive drugs, such as heroin, cocaine, and meth-amphetamine (METH). In contrast to heroin and cocaine, whose stimulatory effects on brain metabolism invert with increases in dose, METH increases brain metabolism dose-dependently and diminishes heat dissipation because of peripheral vasoconstriction. The thermogenic effects of this drug, moreover, are enhanced during physiological activation, resulting in pathological brain hyperthermia. Since brain hyperthermia exacerbates drug-induced toxicity and is destructive to neural cells, uncontrollable use of amphetamine-like drugs under conditions restricting heat dissipation from the brain may result both in acute life-threatening complications and clinically latent but dangerous morphological and functional brain destruction.