Showing papers in "International Review of Neurobiology in 2002"

Polyol pathway and diabetic peripheral neuropathy

Abstract: This chapter critically examines the concept of the polyol pathway and how it relates to the pathogenesis of diabetic peripheral neuropathy. The two enzymes of the polyol pathway, aldose reductase and sorbitol dehydrogenase, are reviewed. The structure, biochemistry, physiological role, tissue distribution, and localization in peripheral nerve of each enzyme are summarized, along with current information about the location and structure of their genes, their alleles, and the possible links of each enzymes and its alleles to diabetic neuropathy. Inhibitors of pathway enzymes and results obtained to date with pathway inhibitors in experimental models and human neuropathy trials are updated and discussed. Experimental and clinical data are analyzed in the context of a newly developed metabolic model of the in vivo relationship between nerve sorbitol concentration and metabolic flux through aldose reductase. Overall, the data will be interpreted as supporting the hypothesis that metabolic flux through the polyol pathway, rather than nerve concentration of sorbitol, is the predominant polyol pathway-linked pathogenic factor in diabetic peripheral nerve. Finally, key questions and future directions for basic and clinical research in this area are considered. It is concluded that robust inhibition of metabolic flux through the polyol pathway in peripheral nerve will likely result in substantial clinical benefit in treating and preventing the currently intractable condition of diabetic peripheral neuropathy. To accomplish this, it is imperative to develop and test a new generation of “super-potent” polyol pathway inhibitors.

Nerve growth factor for the treatment of diabetic neuropathy: what went wrong, what went right, and what does the future hold?

Abstract: Since their discovery in the 1950s, neurotrophic factors have raised expectations that their clinical application to neurodegenerative diseases might provide an effective therapy for what are now untreatable conditions Nerve growth factor (NGF) was the first neurotrophic factor to be discovered and was one of the earliest to proceed to clinical trials NGF, which is selectively trophic for small fiber sensory and sympathetic neurons, was selected as a potential therapy for diabetic polyneuropathy because of the serious consequences associated with degeneration of those neuronal populations in this condition In addition, evidence shows that reduced availability of NGF may contribute to the pathogenesis of diabetic neuropathy, and animal models of neuropathy respond to the exogenous administration of NGF Two sets of phase II clinical trials suggested that recombinant human NGF (rhNGF) administration was effective at ameliorating the symptoms associated with both diabetic polyneuropathy and HIV related neuropathy These early studies, however, revealed that painful side effects were dose limiting for NGF A large-scale phase III clinical trial of 1019 patients randomized to receive either rhNGF or placebo for 48 weeks failed to confirm the earlier indications of efficacy Among the explanations offered for the discrepancy between the two sets of trials was a robust placebo effect, inadequate dosage, different study populations, and changes to the formation of rhNGF for the phase III trial As a result of the phase II outcome, Genentech has decided no to proceed with further development of rhNGF

Stress and secretory immunity

Abstract: Publisher Summary This chapter focuses on the relationship between stress and saliva secretory immunity in humans. Salivary gland function is largely under autonomic control; the parasympathetic nerves mainly govern salivary fluid secretion, whereas the sympathetic nerves regulate protein secretion. The primary salivary centers in the brain stem receive inhibitory and excitatory inputs from neural structures in the forebrain and brain stem. As well as governing typical salivary functions, these structures are also involved in generating bodily changes associated with stress. It is, therefore, reasonable to assume that salivary changes during stress are an integral part of a centrally coordinated stress response that encompasses many other bodily functions. The autonomic receptors in the salivary glands can be divided into two main groups: the classic autonomic receptor types, which respond to either noradrenaline or acetylcholine, and the nonadrenergic–noncholinergic (NANC) receptors that respond to other autonomic messenger substances, such as peptides, nitric oxide, and purines. Differential activation of these receptor types can cause additive, synergistic, or antagonistic intracellular responses, ultimately resulting in a protein release that is capable of being differentially regulated among glands.

Glycation in diabetic neuropathy: characteristics, consequences, causes, and therapeutic options.

Abstract: Glycation is the nonenzymatic reaction of glucose, alpha-oxoaldehydes, and other saccharide derivatives with proteins, nucleotides, and lipids. Early glycation adducts (fructosamines) and advanced glycation adducts (AGEs) are formed. "Glycoxidation" is a term used for glycation processes involving oxidation. Sural, peroneal, and saphenous nerves of human diabetic subjects contained AGEs in the perineurium, endothelial cells, and pericytes of endoneurial microvessels and in myelinated and unmyelinated fibres localized to irregular aggregates in the cytoplasm and interstitial collagen and basement membranes. Pentosidine content was increased in cytoskeletal and myelin protein extracts of the sural nerve of human subjects and cytoskeletal proteins of the sciatic nerve of streptozotocin-induced diabetic rats. AGEs in the sciatic nerve of diabetic rats were decreased by islet transplantation. Improved glycemic control of diabetic patients may be expected to decrease protein glycation in the nerve. Protein glycation may decrease cytoskeletal assembly, induce protein aggregation, and provide ligands for cells surface receptors. The receptor for advanced glycation and products (RAGE) was expressed in peripheral neurons. It is probable that high intracellular glucose concentration is an important trigger for increased glycation, leading to increased formation of methylglyoxal, glyoxal, and 3-deoxyglucosone that glycate proteins to form AGEs intracellularly and extracellularly. Oxidative stress enhances these processes and is, in turn, enhanced by AGE/RAGE interactions. An established therapeutic strategy to prevent glycation is the use of alpha-oxoaldehyde scavengers. Available therapeutic options for trial are high-dose nicotinamide and thiamine therapies to prevent methylglyoxal formation. Future possible therapeutic strategies are RAGE antagonists and inducers of the enzymatic antiglycation defense. More research is required to understand the role of glycation in the development of diabetic neuropathy.

Potential mechanisms of neuropathic pain in diabetes

Abstract: Abnormal sensations and pain are features of approximately 10% of all cases of diabetic neuropathy and can cause marked diminution in the quality of life for these patients. The quality and distribution of pain are variable, although descriptions of burning pain in the hands and feet are commonly reported. Like other neuropathic pain states, painful diabetic neuropathy has an unknown pathogenesis and, in many cases, is not alleviated by nonsteroidal anti-inflammatory drugs or opiates. In the last decade, a number of behavioral and physiologic studies have revealed indices of sensory dysfunction in animal models of diabetes. These include hyperalgesia to mechanical and noxious chemical stimuli and allodynia to light touch. Animal models of painful diabetic neuropathy have been used to investigate the therapeutic potential of a range of experimental agents and also to explore potential etiologic mechanisms. There is relatively little evidence to suggest that the peripheral sensory nerves of diabetic rodents exhibit spontaneous activity or increased responsiveness to peripheral stimuli. Indeed, the weight of evidence suggests that sensory input to the spinal cord is decreased rather than increased in diabetic rodents. Aberrant spinal or supraspinal modulation of sensory processing may therefore be involved in generating allodynia and hyperalgesia in these models. Studies have supported a role for spinally mediated hyperalgesia in diabetic rats that may reflect either a response to diminished peripheral input or a consequence of hyperglycemia on local or descending modulatory systems. Elucidating the effects of diabetes on spinal sensory processing may assist development of novel therapeutic strategies for preventing and alleviating painful diabetic neuropathy.

Energy metabolism in the brain.

Abstract: Publisher Summary The studies of glucose metabolism in the brain reflect a dichotomy because the complex integrating functions of the brain can only be studied in the intact, functioning brain in the conscious individual (human or animal). On the other hand, the properties of brain cells, cell-cell interactions, and mechanisms are most readily evaluated in vitro under controlled conditions using brain slices, subcellular fractions, or purified, isolated cells of different types. A variety of in vitro methods has been used to assess metabolic activities in different brain cell types and in subcellular structures. Nevertheless, by combining different methodologies and continuously maintaining the in vivo situation as the general standard to which results obtained with different cellular and subcellular techniques must be compared, a picture of cellular interactions in glucose metabolism has emerged, and information has been obtained about the identity of energy-requiring and energy-yielding processes. Perhaps even more importantly, these studies have triggered the development of in vivo methods, primarily utilizing nuclear magnetic resonance imaging and spectroscopy, which have confirmed and further expanded many observations made in vitro . This chapter discusses the pathways and regulation of glucose metabolism in the functioning brain in the conscious human or animal during rest and during stimulation and describes the mechanisms, which increase glucose metabolism in vitro . A combination of these two approaches allows a tentative determination of not only the quantitative contributions to glucose metabolism by some of the major cell types, but also identification of mechanisms creating a demand for metabolically generated energy and their relationships to functional activation and neurotransmission.

Role of the Schwann cell in diabetic neuropathy.

Abstract: The relationships among Schwann cells, axons, and the perineurial barrier emphasize the key role Schwann cells play in normal functions of the nerve. Schwann cells are responsible for action potential velocity through insulation of axons, maintenance of axonal caliber, and correct localization of Na+ channels; immunological and funcitonal integrity of the nerve through the perineurial blood-nerve-barrier; and effective nerve regeneration. In diabetic neuropathy, many of these facets of nerve function are defective. Hypoxia, hyerglycemia, and increased oxidative stress contribute directly and indirectly to Schwann cell dysfunction. The results include impaired paranodal barrier function, damaged myelin, reduced antioxidative capacity, and decreased neurotrophic support for axons. This chapter discusses the role of the Schwann cell in the normal or regenerating nerve nad in the altered metabolic conditons of diabetes.

Mitochondria in Alzheimer's disease

Abstract: Publisher Summary Mitochondrial abnormalities are characteristic of Alzheimer's Disease (AD) and might be etiologically involved in the brain degenerative process. Data detailing AD mitochondrial pathology are described in the chapter, especially those involving the enzyme cytochrome oxidase, as most mitochondrial studies in AD have involved investigation of this enzyme. In future studies, examination of large numbers of patients with AD will probably reveal a modest overall reduction of brain cytochrome-oxidase activity. However, high scatter between the range of AD and control values will indicate that the change is not a robust defining feature of the disorder and therefore unlikely to be etiologically important for at least many patients with AD. The strength of a particular AD paradigm should be determined by its ability to explain all aspects of the disease. Comprehensive hypotheses of AD pathogenesis must take into account cerebral and extracerebral mitochondrial dysfunction.

How does glucose generate oxidative stress in peripheral nerve

Abstract: Diabetes-associated oxidative stress is clearly manifest in peripheral nerve, dorsal root, and sympathetic ganglia of the peripheral nervous system and endothelial cells and is implicated in nerve blood flow and conduction deficits, impaired neurotrophic support, changes in signal transduction and metabolism, and morphological abnormalities characteristic of peripheral diabetic neuropathy (diabetic peripheral neuropathy). Hyperglycemia has a key role in oxidative stress in diabetic nerve, whereas the contribution of other factors, such as endoneurial hypoxia, transition metal imbalance, and hyperlipidemia, has not been rigorously proven. It has been suggested that oxidative stress, particularly mitochondrial superoxide production, is responsible for sorbitol pathway hyperactivity, nonenzymatic glycation/glycooxidation, and activation of protein kinase C. However, this concept is not supported by in vivo studies demonstrating the lack of any inhibition of the sorbitol pathway activity in peripheral nerve, retina, and lens by antioxidants, including potent superoxide scavengers. It has been also hypothesized that aldose reductase (AR) detoxifies lipid peroxidation products, and therefore, the enzyme inhibition in diabetes is detrimental rather than beneficial. However, the role for AR in lipid peroxidation product metabolism has never been demonstrated in vivo , and the effects of aldose reductase inhibitors and antioxidants on diabetic peripheral neuropathy are unidirectional, i.e., both classes of agents prevent and correct functional, metabolic, neuropathic, and morphological changes in diabetic nerve. Growing evidence indicates that AR has a key role in oxidative stress in the peripheral nerve and contributes to superoxide production by the vascular endothelium. The potential mechanism of this phenomenon are discussed.

Neuropathology and pathogenesis of diabetic autonomic neuropathy.

Abstract: Autonomic neuropathy is a significant complication of diabetes resulting in increased patient morbidity and mortality. A number of studies, which have shown correspondence between neuropathologic findings in experimental animals and human subjects, have demonstrated that axonal and dendritic pathology in sympathetic ganglia in the absence of significant neuron loss represents a neuropathologic hallmark of diabetic autonomic neuropathy. A recurring theme in sympathetic ganglia, as well as in the pot-ganglionic autonomic innervation of various end organs, is the involvement of distal portions of axons and nerve terminals by degenerative or dystrophic changes. In both animals and humans, there is a surprising selectivity of the diabetic process for subpopulations of autonomic ganglia, nerve terminals within sympathetic ganglia and end organs, from end organ to end organ, and between vascular and other targets within individual end organs. Although the involvement or autonomic axons in somatic nerves may reflect an ischemic pathogenesis, the selectivity of the diabetic process confounds simple global explanations of diabetic autonomic neuropathy as the result of diminished blood flow with resultant tissue hypoxia. A single unifying pathogenetic hypothesis has not yet emerged from clinical and experimental animal studies, and it is likely that diabetic autonomic neuropathy will be shown to have multiple causative mechanisms, which will interact to result in the variety of presentations of autonomic injury in diabetes. Some of these mechanisms will be shared with aging changes in the autonomic nervous system. The role of various neurotrophic substances and the polyol pathway in the pathogenesis and treatment of diabetic neuropathy likely represents a two-edged sword with both salutary and exacerbating effects. The basic neurobiologic process underlying the diabetes-induced development of neuroaxonal dystrophy, synaptic dysplasia, defective axonal regeneration, and alterations in neurotrophic substance may be mechanistically related.

Brain-immune interactions in sleep.

Abstract: This chapter discusses various levels of interactions between the brain and the immune system in sleep. Sleep-wake behavior and the architecture of sleep are influenced by microbial products and cytokines. On the other hand, sleep processes, and perhaps also specific sleep states, appear to promote the production and/or release of certain cytokines. The effects of immune factors such as endotoxin and cytokines on sleep reveal species specificity and usually strong dependence on parameters such as substance concentration, time relative to administration or infection with microbial products, and phase relation to sleep and/or the light-dark cycle. For instance, endotoxin increased SWS and EEG SWA in humans only at very low concentrations, whereas higher concentrations increased sleep stage 2 only, but not SWS. In animals, increases in NREM sleep and SWA were more consistent over a wide range of endotoxin doses. Also, administration of pro-inflammatory cytokines such as IL-6 and IFN-alpha in humans acutely disturbed sleep while in rats such cytokines enhanced SWS and sleep. Overall, the findings in humans indicate that strong nonspecific immune responses are acutely linked to an arousing effect. Although subjects feel subjectively tired, their sleep flattens. However, some observations indicate a delayed enhancing effect on sleep which could be related to the induction of secondary, perhaps T-cell-related factors. This would also fit with results in animals in which the T-cell-derived cytokine IL-2 enhanced sleep while cytokines with immunosuppressive functions like IL-4 and L-10 suppressed sleep. The most straightforward similarity in the cascade of events inducing sleep in both animals and humans is the enhancing effect of GHRH on SWS, and possibly the involvement of the pro-inflammatory cytokine systems of IL-1 beta and TNF-alpha. The precise mechanisms through which administered cytokines influence the central nervous system sleep processes are still unclear, although extensive research has identified the involvement of various molecular intermediates, neuropeptides, and neurotransmitters (cp. Fig. 5, Section III.B). Cytokines are not only released and found in peripheral blood mononuclear cells, but also in peripheral nerves and the brain (e.g., Hansen and Krueger, 1997; Marz et al., 1998). Cytokines are thereby able to influence the central nervous system sleep processes through different routes. In addition, neuronal and glial sources have been reported for various cytokines as well as for their soluble receptors (e.g., Kubota et al., 2001a). Links between the immune and endocrine systems represent a further important route through which cytokines influence sleep and, vice versa, sleep-associated processes, including variations in neurotransmitter and neuronal activity may influence cytokine levels. The ability of sleep to enhance the release and/or production of certain cytokines was also discussed. Most consistent results were found for IL-2, which may indicate a sleep-associated increase in activity of the specific immune system. Furthermore, in humans the primary response to antigens following viral challenge is enhanced by sleep. In animals results are less consistent and have focused on the secondary response. The sleep-associated modulation in cytokine levels may be mediated by endocrine parameters. Patterns of endocrine activity during sleep are probably essential for the enhancement of IL-2 and T-cell diurnal functions seen in humans: Whereas prolactin and GH release stimulate Th1-derived cytokines such as IL-2, cortisol which is decreased during the beginning of nocturnal sleep inhibits Th1-derived cytokines. The immunological function of neurotrophins, in particular NGF and BDNF, has received great interest. Effects of sleep and sleep deprivation on this cytokine family are particularly relevant in view of the effects these endogenous neurotrophins can have not only on specific immune functions and the development of immunological memories, but also on synaptic reorganization and neuronal memory formation.

Acth treatment of infantile spasms: mechanisms of its effects in modulation of neuronal excitability

Abstract: The efficacy of ACTH, particularly in high doses, for rapid and complete elimination of infantile spasms (IS) has been demonstrated in prospective controlled studies However, the mechanisms for this efficacy remain unknown ACTH promotes the release of adrenal steroids (glucocorticoids), and most ACTH effects on the central nervous system have been attributed to activation of glucocorticoid receptors The manner in which activation of these receptors improves IS and the basis for the enhanced therapeutic effects of ACTH--compared with steroids--for this disorder are the focus of this chapter First, a possible "common excitatory pathway," which is consistent with the many etiologies of IS and explains the confinement of this disorder to infancy, is proposed This notion is based on the fact that all of the entities provoking IS activate the native "stress system" of the brain This involves increased synthesis and release of the stress-activated neuropeptide, corticotropin-releasing hormone (CRH), in limbic, seizure-prone brain regions CRH causes severe seizures in developing experimental animals, as well as limbic neuronal injury Steroids, given as therapy or secreted from the adrenal gland upon treatment with ACTH, decrease the production and release of CRH in certain brain regions Second, the hypothesis that ACTH directly influences limbic neurons via the recently characterized melanocortin receptors is considered, focusing on the effects of ACTH on the expression of CRH Experimental data showing that ACTH potently reduces CRH expression in amygdala neurons is presented This downregulation was not abolished by experimental elimination of steroids or by blocking their receptors and was reproduced by a centrally administered ACTH fragment that does not promote steroid release Importantly, selective blocking of melanocortin receptors prevented ACTH-induced downregulation of CRH expression, providing direct evidence for the involvement of these receptors in the mechanisms by which ACTH exerts this effect Thus, ACTH may reduce neuronal excitability in IS by two mechanisms of action: (1) by inducing steroid release and (2) by a direct, steroid-independent action on melanocortin receptors These combined effects may explain the robust established clinical effects of ACTH in the therapy of IS

Cortical and subcortical generators of normal and abnormal rhythmicity.

Abstract: The cerebral cortex and thalamus can both generate cyclical oscillations of neuronal activity. Within the thalamus, sleep spindles are generated as a recurrent interaction between thalamocortical and thalamic reticular cells. Abnormally strong activation of the inhibitory thalamic reticular neurons can result in the transformation of this normal rhythm into one that resembles that underlying absence seizures. The cerebral cortex can generate periodic activity at < 1 Hz through recurrent excitation that is controlled by inhibition. Again, loss of inhibitory control allows this normal activity to become epileptiform. Together, the cerebral cortex and thalamus can form cyclical loops of activity that may contribute to some forms of epileptic seizures. It is proposed that hypsarrhythmic activity that is characteristic of children with infantile spasms may be generated through abnormal, locally synchronized bursts of activity within the cerebral cortex.

Role of subcortical structures in the pathogenesis of infantile spasms: What are possible subcortical mediators?

Abstract: Infantile spasms present a constellation of symptoms and laboratory findings that suggest a role of subcortical circuits in the pathogenesis of this illness. The clinical features of spasms and the influence of subcortical circuits in the regulation of the electroencephologram, along with frequent abnormalities in subcortical structure and functional anatomy, brain stem electrophysiology, sleep regulation, and subcortical neurotransmitter levels, point to the importance of subcortical circuits in the generation of spasms. Furthermore, laboratory evidence shows that modulation of subcortical nuclei may attenuate and ameliorate seizures. We review clinical evidence indicating abnormal function in subcortical circuits and present a hypothesis that the development of infantile spasms requires dysfunction in both cortical and subcortical circuits. The confluence of evidence suggesting a role of subcortical structures in the origin of spasms and laboratory data indicating an anticonvulsant role on some subcortical nuclei raise the possibility of novel approaches to the treatment of infantile spasms.

Expression, regulation, and functional role of glucose transporters (GLUTs) in brain.

Abstract: Publisher Summary Glucose is the primary source of energy for the mammalian brain. As in most other tissues, glucose transport in the central nervous system (CNS) is mediated by facilitative glucose transporter proteins, glucose transporters (GLUTs). However, to date a thorough understanding of the mechanisms regulating glucose transport in the brain lags behind what is known in the “periphery.” The objective of this chapter is to expand the working knowledge of brain glucose uptake and utilization in the context of recent advances in the transport field. As a starting point, current molecular models of the GLUT protein structure are presented and compared with the known structures of other related transporters. The various structures may provide insights into the mechanisms by which glucose is transported across cell membranes. Data regarding the different GLUT isoforms found in brain and their regional distribution are summarized. There has been a virtual explosion within the past two years resulting in a doubling of the members of the family of facilitative glucose transporters. This chapter classifies the new members of this family as mammalian glucose transporters and shows their specific neural locations and functions in the CNS.

Sympathetic nervous system interaction with the immune system.

Abstract: Publisher Summary Both T cells and B cells express the β 2 -adrenergic receptor (AR) and bind norepinephrine that is released within lymphoid organs. Norepinephrine plays a role in modulating the activity of CD 4 + T cells and B cells participating in an immune response against antigen. This role of norepinephrine in regulating T and B cell activity needs to be fully understood because antibodies preserve well-being by defending against bacteria, viruses, and allergens and cytokines provide help to B cells, allowing the B cell to differentiate and thus secrete antibodies of particular isotypes. Given the importance to the host of having T cells and B cells that function optimally, it is likely that the mechanisms regulating and modulating these functions are varied and interrelated. For example, it is necessary to understand how products released from the hypothalamic-pituitary-adrenal axis, at the same time norepinephrine is released by sympathetic nerve terminals within lymphoid organs, affect immune cell function. An understanding of the mechanism by which the sympathetic nervous system (SNS) modulates the level of cytokines and antibody produced enables the development of therapeutic approaches for treating and preventing changes in the immunocompetent state of persons experiencing any disease that involves an alteration in either the nervous or the immune system function.

Diabetes, the brain, and behavior: is there a biological mechanism underlying the association between diabetes and depression?

Abstract: In summary, our review of the literature suggests that diabetes, especially type 1 diabetes, may place patients at risk for a depressive disorder through a biological mechanism linking the metabolic changes of diabetes to changes in brain structure and function. Further studies are warranted examining these relationships in order to better understand the impact of diabetes on brain functioning and structure as well as one potential manifestation of such changes--affective disorder. Moreover, such studies could play a useful role in better understanding mechanisms that commonly underlie the development of depression in individuals without diabetes but with other medical problems or conditions.

Protein kinase C changes in diabetes: is the concept relevant to neuropathy?

Abstract: Protein kinase C (PKC) comprises a superfamily of isoenzymes, many of which are activated by 1,2-diacylglycerol (DAG) in the presence of phosphatidylserine. In order to be capable of DAG activation, PKC must first undergo a series of phosphorylations at three conserved sites. PKC isoforms phosphorylate a wide variety of intracellular target proteins and have multiple functions in signal transduction-mediated cellular regulation. An elevation in DAG levels and an increase in composite PKC activity and/or certain isoforms occurs in several nonneural tissues from diabetic animals, including the vasculature. The ability of isoform-specific PKC inhibitors to antagonize diabetes-induced abnormalities has implicated altered PKCβ activity in the onset of several diabetic complications. In contrast to many other tissues, DAG levels fall in diabetic nerve and a consistent pattern of change in PKC activity has not been observed. Treatments that alter PKC activity affect nerve Na + ,K + -ATPase activity, but the mechanism involved is not well understood. Inhibition of PKCβ in diabetic rats appears to correct reduced nerve blood flow and decreased nerve conduction velocity. These and other findings indicate that changes in the neurovasculature exert adverse effects during the pathogenesis of diabetic neuropathy. Still unresolved is a clear-cut role of PKC in the development of abnormalities in neural cell metabolism. Further progress will depend on a more complete understanding of the functions of individual PKC isoforms in nerve. Future investigation could focus profitably on biochemical processes in nerve cells that modulate PKC activity and that are altered in diabetes, such as vascular endothelial growth factor levels and production of reactive oxygen species arising from oxidative stress.

Electrophysiologic measures of diabetic neuropathy: mechanism and meaning.

Abstract: Whole nerve electrophysiologic procedures afford a battery of measures that can provide a noninvasive and objective index of the onset and progression of diabetic polyneuropathy (DPN). Advances in physiologic procedures, digital hardware, and mathematical models have allowed assessment of activity in slower conducting fibers, as well as measures that reflect changes in refractory periods and threshold excitability. These expanded options can augment standard measures of maximal conduction velocity and compound amplitude and greatly enhance the sensitivity of whole nerve measures to both structural (e.g., demyelination) and “nonstructural” (e.g., redistribution of ion channels) deficits associated with DPN. The mechanisms underlying the physiologic events in DPN are multifactorial and their sequence is complex, with different mechanisms contributing to change at overlapping, but distinct points in the progression. Factors influencing early change in velocity may differ from those contributing to chronic deficits and these mechanisms may also differ in their response to various putative therapies. This review attempts to summarize the pattern of whole nerve electrophysiologic change associated with DPN, outlines the strengths and limitations of the various measures that are feasible, and discusses the specific impact of known pathophysiologic mechanisms on these end points.

Systemic stress-induced Th2 shift and its clinical implications

Abstract: Publisher Summary This chapter discusses systemic stress-induced T helper-2 (Th2) shift and its clinical implications. Stress hormones selectively suppress T helper-1 (Th1) responses and cause a Th2 shift rather than generalized immunosuppression. The stress hormone–induced Th2 shift may have both beneficial and detrimental consequences. Although interest in the Th2 response is initially directed at its protective role in helminthic infections and its pathogenic role in allergy, this response may have important regulatory functions in countering the tissue-damaging effects of macrophages and Th1 cells. Thus, an excessive immune response, through activation of the stress system, may trigger a mechanism that inhibits Th1 but potentiates Th2 responses. This important feedback mechanism may protect the organism from overshooting by type 1/pro-inflammatory cytokines and other products of activated macrophages with tissue-damaging potential. The substantial Th2-driving force, however, of endogenous glucocorticoids and catecholamines (CAs) can be amplified to a great extent during certain conditions such as severe acute or chronic stress, excessive exercise, or pregnancy. An abnormal stress-system activity, therefore, in either direction, might contribute to the pathophysiology of common human diseases, where a selection of Th1 (type 1) versus Th2 (type 2) responses plays a significant role. These include several intracellular infections, major injury and its complications, allergic (atopic) reactions, autoimmune/inflammatory diseases, and tumor growth.

Immunity and schizophrenia: autoimmunity, cytokines, and immune responses.

Abstract: As is evident from the present account, there is no single or persuasive argument that signals emanating from the immune system are directly involved in the etiology of schizophrenia. We do not even know if we are dealing with a single disorder with a single causality; almost certainly we are not. The precise etiology of schizophrenia, as with so many neurological disorders, remains obscure. However, there is abundant evidence in schizophrenia of mutual dysregulation of neuronal function and immune system activity. Although this evidence is not always consistent, a pattern emerges suggesting aspects of immune activity being involved in the pathology of neuronal development that characterizes schizophrenia. Exposure to infective agents, HLA associations, autoimmune associations, disturbances in lymphocyte populations, and cytokine imbalances with a skew toward Th2 activity are supportive of this view. That the evidence is not always consistent is a testament to the complexity and heterogeneity of the disorder, to confounding by antipsychotics that themselves are immunomodulatory, and to the multifaceted nature, with all its checks and balances, of the immune system itself.

CNS sensing and regulation of peripheral glucose levels

Abstract: Publisher Summary It is clear that the brain has evolved a mechanism for sensing the levels of ambient glucose. Teleologically, this is likely to be a function of its requirement for glucose as a primary metabolic substrate. There is no question that the brain can sense and mount a counterregulatory response to restore very low levels of plasma and brain glucose. However, it is less clear that the changes in glucose associated with normal diurnal rhythms and feeding cycles are sufficient to influence either ingestive behavior or the physiologic responses involved in regulating plasma glucose levels. Glucosensing neurons are clearly a distinct class of metabolic sensors with the capacity to respond to a variety of intero- and exteroceptive stimuli. This makes it likely that these glucosensing neurons do participate in physiologically relevant homeostatic mechanisms involving energy balance and the regulation of peripheral glucose levels. It is our challenge to identify the mechanisms by which these neurons sense and respond to these metabolic cues. This chapter focuses on the glucosensing role of these neurons. The chapter also states that glucosensing neurons represent a distinct and unique type of neuron, which has evolved specifically to sense, and regulate energy homeostasis in the body.

In situ hybridization with oligonucleotide probes.

Abstract: Publisher Summary In situ hybridization (ISH) is an important method for tracing the regional and cellular sites of gene expression (mRNA distribution) within a tissue. This method comes into its own when applied to the intermingled cell types of the brain. ISH allows the particular cell type in which the mRNA is contained to be marked out from others. The technique is simple—a nucleic-acid probe, tagged with either radiolabeled nucleotides or molecules allowing calorimetric/light detection, is applied to a tissue section. The probe searches out and finds (hybridizes to) its corresponding mRNA in the cells and forms a probe-mRNA double helix. After the excess probe has been washed away, the section is either exposed for autoradiography or processed histochemically to reveal the sites on the section targeted by the probe. ISH with oligonucleotides needs less hands-on time than other ISH methods. Large numbers of oligonucleotides (e.g., up to 20 at one time) and sections (e.g., 100) can be handled at once. The method is well suited to large-scale studies that, for example, compare the expression of all members of a gene family or map the expression of novel gene sets.

Insulin-like growth factor-1 promotes neuronal glucose utilization during brain development and repair processes.

Abstract: We have reviewed several lines of evidence suggesting that IGF-1 augments neuronal glucose utilization during brain development. To briefly recapitulate, brain glucose utilization parallels IGF-1 receptor expression during brain development. In normal murine brain development, IGF-1 is produced in greatest abundance by growing cerebellar and sensory projection neurons during the time of dendrite elaboration and synaptogenesis. Glucose utilization is significantly reduced in developing IGF1 -/-brain, particularly in those sites where IGF-1 expression is normally most abundant. The defect in glucose utilization in IGF1 -/-brains is demonstrable at the terminal level in vitro , and is reversed by IGF-1. It appears that IGF-1 promotes glucose allocation to growing neurons in an autocrine manner, enabling the extraordinary elaboration of processes characterizing these complex information-processing systems. These sensory processing centers continue to exhibit high-level glucose utilization in the mature brain, after IGF-1 expression has receded, reflecting the extraordinary dendritic complexity and synaptic density achieved by these structures. IGF-1 is not likely to play a major role in the rapid, neural activity-based glucose utilization in the mature brain, as discussed in Section IV. It will be interesting to determine whether IGF-1 is involved in activity-induced synaptic remodelling, as a number of studies suggest ( Torres-Aleman, 2000 ). IGF-1 is highly expressed by reactive (GFAP-positive) astrocytes in various injury models ( Komoly et al. , 1992 ; Lee et al. , 1992 ; Lee and Bondy, 1993 ; Gehrmann et al. , 1994 ; Yao et al. , 1995 ; Walter et al. , 1997 ; Beilharz et al. , 1998 ; Li et al. , 1998 ). We have found that astrocytic IGF-1 expression several days after MCAO is closely correlated with increased glucose utilization in the injury site, as shown in Fig. 7 ( Lee et al. , 1992 ). The significance of this local increase in glucose utilization is unclear, but it may be attributed to increased anabolic activity by astrocytes synthesizing and secreting collagen and other extracellular proteins involved in scar formation. PKB/Akt and GSK3β appear to be central players in IGF signaling to the brain (Fig. 13). PKB/Akt phosphorylation in IGF-1-expressing neurons is associated with increased GLUT4 expression and translocation from intracellular to the plasma membrane. IGF1's apparent link with this “insulin-sensitive” transporter may represent a specific anabolic pathway, distinct from the glucose transport pathways involving GLUTs 1 and 3. PKB/Akt phosphorylation also leads to the inhibition of GSK3β in IGF-1-expressing neurons (Figs. 11 and 13). This inhibition is expected to facilitate glycogen and protein synthesis, as GSK3β normally inhibits both glycogen synthase and eIF2B (Fig. 13). As a result, there is accumulation of glycogen in IGF-1-expressing neurons ( Cheng et al. , 2000 ), which may serve to create a relative “sink” for G-6-P, promoting further glucose transport into the neuron. GSK3β also phosphorylates the microtubule-associated protein tau. Tau is hyper-phosphorylated in the IGF1 null brain, as expected if IGF-1 normally inhibits this multifunctional enzyme. Tau hyperphosphorylation is the mechanisms governing normal cell- and developmental stage-specific regulation of IGF-1 expression, and to attempt to restore normal patterns of expression in conditions such as fetal alcohol exposure and malnutrition, and possibly in other forms of mental retardation.

Nerve and ganglion blood flow in diabetes: an appraisal.

Abstract: Vasa nervorum, the vascular supply to peripheral nerve trunks, and their associated cell bodies in ganglia have unique anatomical and physiological characteristics. Several different experimental approaches toward understanding the changes in vase nervorum following injury and disease have been used. Quantative techniques most widely employed have been microelectrode hydrogen clearance palarography and [14C]iodoantipyrine autoradiographic distribution, whereas estimates of red blood cell flux using a fiber-optic laser Doppler probe offer real time data at different sites along the nerve trunk. There are important caveats about the use of these techniques, their advantages, and their limitations. Reports of nerve blood flow require careful documentation of physiological variables, including mean arterial pressure and nerve temperature during the recordings. Several ischemic models of the peripheral nerve trunk have addressed the ischemic threshold below which axonal degeneration ensues (< 5ml/100 g/min). Following injury, rises in local blood flow reflect acitons of vasoactive peptides, nitric oxide, and the development of angiogenesis. In experimental diabetes, a large number of studies have documented reductions in nerve blood flow and tandem corrections of nerve blood flow and conduction slowing. A significant proportions, however, of the work can be criticized on the basis of methodology and interpretation. Similarly, not all work has confirmed that reductions of nerve blood flow are an invariable feature of experimental or human diabetic polyneuropathy. Therefore, while there is disagreement as to whether early declines in nerve blood flow "account" for diabetic polyneuropathy, there is unquestioned eveidence of early microangiopathy. Abnormalities of vase nervorum and micorvessels supplying ganglia at the very least develop parallel to and together with changes in neurons, Schwann cells, and axons.

Glucose, stress, and hippocampal neuronal vulnerability.

Abstract: Publisher Summary The hippocampus has been recognized to be an important integration center for learning and memory. A number of underlying neurochemical systems within the hippocampus contribute to cognitive function, as well as hippocampal glucoregulatory activities. Metabolic disorders that disrupt the interactions of these systems may compromise hippocampal neuronal homeostasis and contribute to cognitive impairments. The dysregulation of glucose utilization that is observed in diabetes mellitus or Alzheimer disease may represent an important component of the cognitive impairments observed in these disease states. The hippocampus is one of the major target areas for glucocorticoids (GCs) in the central nervous system (CNS). While basal levels of glucocorticoids are essential for neuronal maintenance, exposure to the stress levels of GCs can reduce hippocampal glucose utilization and produce morphological changes that are accompanied by cognitive impairments. Diabetic subjects exhibit increased circulating levels of GCs, suggesting that neuronal allostatic load may be increased in the hippocampus by the combined actions of hyperglycemia and GCs. The aim of this chapter is to review and update the understanding of the effects of stress and disease states that are associated with metabolic disturbances, such as diabetes mellitus, upon hippocampal glucoregulatory activities.

Mechanisms by which cytokines signal the brain.

Abstract: Publisher Summary Several different mechanisms exist for cytokines to signal the brain. The relevance of mechanisms depends on the cytokine and the response under consideration. The existing evidence almost exclusively relates to effects of interleukin-1 (IL-1). This is largely because the brain effects of IL-6 and tumor necrosis factor (TNF) and other cytokines are weaker and have been harder to demonstrate than those of IL-1. There are five principal known mechanisms for cytokine signaling of the brain. First, cytokines can be transported into the brain to a limited extent using selective uptake systems (transporters) that bypass the blood–brain barrier. Second, cytokines can act on brain tissue at sites where the blood–brain barrier is weak or nonexistent. Third, cytokines may act directly or indirectly on peripheral nerves that send afferent signals to the brain. Fourth, cytokines can act on peripheral tissues inducing the synthesis of molecules whose ability to penetrate the brain is not limited by the barrier. A major target appears to be endothelial cells that bear receptors for IL-1. Fifth, cytokines can be synthesized by immune cells that infiltrate the brain. Despite the evidence from clinical studies of the effects of the interferons, the responses to interferons in animals have proven to be inconsistent and/or difficult to study.

Infantile spasms: criteria for an animal model.

Abstract: Infantile spasms is an epilepsy syndrome with several distinctive features, including age specificity during infancy, characteristic semiology (epileptic spasms), specific electroencephalographic patterns (interictal hypsarrhythmia and ictal voltage suppression), and responsiveness to the adrenocorticotropic hormone (ACTH). There is no adequate animal model of infantile spasms, perhaps due to these clinically unique features, that is specific for the developing human brain. An informative animal model would provide insights into the pathophysiology of this syndrome and form the basis for the development of innovative therapies. This chapter considers criteria for an “ideal” animal model of infantile spasms, as well as “minimal” criteria that we consider essential to yield useful information. Two animal models of infantile spasms have been described in rodents: seizures induced by corticotropin-releasing factor and N -methyl- d -aspartic acid. Neither of these models conforms exactly to the human analog, but each possesses intriguing similarities that provide testable hypotheses for future investigations.

Treatment of infantile spasms: An evidence-based approach

Abstract: The object of this work was to subject established empirical medical treatment regimens for infantile spasms to evidence-based medicine analysis in order to determine the current best practice for the treatment of infantile spasms in children. Clinical studies of infantile spasms reported during the presteroid era were reviewed critically to define the natural history of the disorder. Treatment trials of infantile spasms conducted since 1958 were rigorously assessed using MEDLINE and hand searches of the English language literature. Inclusion criteria were the documented presence of infantile spasms and hypsarrhythmia. Outcome measures included complete cessation of spasms, resolution of hypsarrhythmia, relapse rate, developmental outcome, the presence or absence of epilepsy, and/or an epileptiform electroencephalogram. Evidence was defined as class I, II, or III, and practice parameter recommendations were made using the framework devised by the American Academy of Neurology. Class I and III evidence support a standard of practice recommendation for the use of vigabatrin in the treatment of infantile spasms in children with tuberous sclerosis. Class I and III evidence support a guidelines recommendation for the use of either ACTH or vigabatrin in infantile spasms in nontuberous sclerosis patients. There is no strong evidence that successful treatment of infantile spasms improves the long-term prognosis for cognitive outcome or decreases the incidence of later epilepsy. A practice option recommendation for the use of oral corticosteroids in the treatment of infantile spasms is supported by limited and inconclusive class I and III data. Based on the evidence, no recommendation can be made for the use of pyridoxine, benzodiazepines, or the newer antiepileptic drugs in the treatment of infantile spasms. ACTH and vigabatrin are the most effective agents in the treatment of infantile spasms, but concerns remain about the risk/benefit profiles of these drugs.

Neurosteroids and infantile spasms: the deoxycorticosterone hypothesis.

Abstract: Deoxycorticosterone (DOC) is a mineralocorticoid precursor that has anticonvulsant properties in animals and possibly also in humans. Studies indicate that the anticonvulsant activity of DOC requires its enzymatic conversion to 5 alpha,3 alpha-tetrahydrodeoxycorticosterone (THDOC), a neurosteroid that lacks classical hormonal properties but acts as a powerful positive allosteric modulator of GABAA receptors. DOC can be considered a stress hormone because its synthesis is under the control of ACTH. Therefore, stress-induced fluctuations in seizure susceptibility could in part result from alterations in DOC availability. Also, the therapeutic activity of ACTH in infantile spasms could partially relate to its stimulatory effects on the synthesis of DOC, which then undergoes biotransformation to neurosteroids. The recent demonstration that the synthetic neurosteroid analog ganaxolone reduces spasm frequency in children with intractable infantile spasms suggests that neurosteroid-related anticonvulsants may offer a potential new nonhormonal approach for the treatment of infantile spasms and other developmental epilepsies. In addition, it further confirms the utility of pharmacological enhancement of GABA-mediated inhibition in the control of infantile spasms.