Restorative Neurology and Neuroscience - Volume 12, issue 2-3

Authors: Behl, Christian | Lezoualc'h, Frank

Article Type: Research Article

Abstract: Oxidative stress-induced neurodegeneration has been implicated in a variety of neuropsychiatric disorders including Alzheimer's disease (AD). Therefore, neuroprotection is of central interest in basic and preclinical neuroscience. Recently, we reported that the AD-associated amyliod B protein can induce neuronal cell death via the generation of free radicals, oxidative stress and lipid peroxidation. The depletion of the intracellular pool of glutathione (GSH), an important intracellular oxidant, can also induce oxidative events. Various lipophilic …antioxidants, including the female sex hormone estrogen, can protect neurons against oxidative cell death. Here, we report that estrogens prevent oxidative cell death induced by GSH depletion in murine clonal hippocampal HT22 cells and in cells of the sympathetic precursor-like cell line PC12. Estrogens act as free radical scavengers and inhibit the intracellular accumulation of peroxides caused by GSH depletion and, ultimately, prevent neuronal cell death. This protective activity is independent of the presence or activation of estrogen receptors but is dependent on the presence of an intact hydroxyl group in the steroid ring A of the estrogen molecule. The modification or the absence of this group led to a loss of the neuroprotective activity. These data further support the important role of antioxidants in neuroprotection and may help in the design of novel antioxidant drugs. Show more

Keywords: oxidative stress, Alzheimer's disease, neurodegeneration, glutathione, antioxidants, neuroprotection, estrogen, PC12 cells

Citation: Restorative Neurology and Neuroscience, vol. 12, no. 2-3, pp. 127-134, 1998

Authors: Reiter, Russel J. | Garcia, Joaquin J. | Pie, Juan

Article Type: Research Article

Abstract: In this brief review the antioxidative actions of melatonin are summarized and they are discussed relative to several models of oxidative neurotoxicity. Melatonin is a ubiquitously acting antioxidant. It has been shown to scavenge the hydroxyl radical, peroxyl radical, singlet oxygen and the peroxynitrite anion; secondarily, it also scavenges the superoxide anion radical. In addition, melatonin reportedly stimulates a number of antioxidative enzymes including glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase. On …the other hand, melatonin inhibits the pro-oxidative enzyme nitric oxide synthase. Besides these actions which help to resist oxidative damage, melatonin prevents membrane rigidity, reduces polymorphonuclear cell infiltration into damaged tissue, limits the adhesion of leucocytes to endothelial cells, thereby increasing blood flow and reducing edema. Some or all of these actions may have been operative in the experimental models of oxidative neurotoxicity that were improved by melatonin treatment. In brief, melatonin has been found to protect the CNS from B-amyloid toxicity, experimental models of Parkinsonism, excitotoxicity, nitric oxide toxicity, aminolevulinic acid, lipopolysaccharide, hyperbaric hyperoxia, L-cysteine, cyanide and ischemia/reperfusion injury. Show more

Keywords: melatonin, free radicals, neurotoxicity, lipid peroxidation, antioxidant, Alzheimer's disease, ischemia/reperfusion

Citation: Restorative Neurology and Neuroscience, vol. 12, no. 2-3, pp. 135-142, 1998

Authors: Wiesenberg, Irmgard | Missbach, Martin | Carlberg, Carsten

Article Type: Research Article

Abstract: The pineal gland hormone melatonin is well known as a regulator of circadian rhythmicity, but has also other functions in the central nervous system as well as in the periphery including the maturation of neurons and the regulation of cellular growth and differentiation. Three mechanisms of the hormone's action are currently discussed: a membrane signaling pathway, a nuclear signaling pathway and a receptor-independent radical scavenging function. Melatonin membrane receptors are seven transmembrane receptors and …mediate their functions through a G-protein-coupled second messenger pathway. Nuclear melatonin signaling seems to be mediated via the transcription factor RZR/ROR, which is an orphan member of the nuclear receptor superfamily. The widespread distribution of the a-subtype of RZR/ROR suggests that this receptor may be an important mediator of those effects of melatonin that can not be explained by membrane receptors or radical scavenging. Interestingly, natural RZR/RORa "knock-out" mice (staggerer) show severe defects in the development of cerebellar Purkinje cells, a reduced body weight and immunological defects. RZR/ROR binds as a monomer to DNA, but also forms homodimers on appropriate binding sites. Natural RZR/ROR binding sites have been identified in the regulatory regions of many genes. 5-lipoxygenase, p21WAF1/CIP1, apolipoprotein A-1, N-myc and Purkinje cell protein 2 may be functionally important target genes. On some of these binding sites RZR/ROR competes with other members of the nuclear receptor superfamily (e.g., COUP-TF, RAR and Rev-ErbA) indicating a cross-talk between these transcription factors RZR/ROR often shows in transient transfection assays a high constitutive, i.e. ligand-independent activity. However, under conditions of low constitutive activity a significant and specific stimulation of RZR/ROR by low nanomolar concentrations of melatonin and structurally novel class of thiazolidinediones (lead structure: CGP52608) has been observed. Taken together, the effects of melatonin on transcriptional regulation clearly depend on the expression fo RZR/ROR and support the concept that the receptor is a mediator of nuclear melatonin signaling. Show more

Keywords: melatonin, nuclear signaling, nuclear receptor RZR/ROR, natural responding genes, thaizolidinediones, regulation of transcription, interference with membrane receptors

Citation: Restorative Neurology and Neuroscience, vol. 12, no. 2-3, pp. 143-150, 1998

Authors: Claustrat, Bruno | Brun, Jocelyne | Geoffriau, Martine | Chazot, Guy

Article Type: Research Article

Abstract: Melatonin (MLT) is a methoxyindole secreted principally by the pineal gland. It is synthesized at night under normal environmental conditions. The endogenous rhythm of secretion is generated by the suprachiasmatic nuclei and entrained by the light/dark cycle. Light is able to both suppress or synchronize melatonin production according to the light schedule. The nycthohemeral rhythm of this hormone is determined by repeated measurement of plasma of saliva MLT or urine sulfatoxymelatonin, the main hepatic metabolite. …Melatonin can be considered as the output (the hand) of the endogenous clock. Since the regulating system follows central and sympathetic nervous pathways, an abnormality at any level unspecifically modifies the melatonin secretion, especially in patients with sympathalgia or dysautonomia. Melatonin plays the role of an endogenous zeitgeber on sleep-wake cycle or core temperature. Exogenous melatonin is able to influence the endogenous secretion of the hormone according to a phase response curve. There are therapeutic implications for this property in situations when biological rhythms are disturbed (jet-lag syndrome, delayed sleep phase syndrome, insomnia in blind or elderly people, shift-work). Improvement of pharmaceutical forms studied in controlled trials under the responsibility of the medical community or development of melatonin analogs could lead to decisive progress in this field. Show more

Keywords: melatonin, biological rhythms, circadian, clock, humans, chronobiotics

Citation: Restorative Neurology and Neuroscience, vol. 12, no. 2-3, pp. 151-157, 1998

Authors: Alho, H. | Leinonen, J.S. | Erhola, M. | Lönnrot, K. | Aejmelaeus, R.

Article Type: Research Article

Abstract: Oxidative damage to DNA and other macromolecules accumulates with age and has been postulated to be one of the major forms of endogenous damage leading to aging and has been implicated also in initiation of cancer and over a hundred other diseases. The human body has developed an antioxidant (AOX) defense system which contains enzymatic, metal chelating, and free radical scavenging properties. Thus, it is essential to consider the concentration of all AOXs in plasma and …CSF when investigating the relationship between diet, oxidative stress, and disease. In the present study a luminometric TRAP-method (total peroxyl radical-trapping potential) was used to determine the activity of all chain breaking AOXs in several clinical states. We have measured TRAP of plasma, cerebrospinal fluid (CSF) and of low density lipoprotein (LDL, TRAPLDL), and the concentrations of main AOX-components (uric acid, protein SH-groups, a-tocopherol, ascorbic acid, ubiquinone and the fraction of unknown antioxidants) to study the effect of: 1) aging, 2) acute infection, 3) diabetes, 4) immobilization and 5) cancer. TRAP of CSF is five times lower than of plasma, mainly due to the low urate concentration in CSF. We have observed that plasma antioxidant defenses respond to the basic metabolic rate and the challenges caused by physiological or pathological stress: i) in a healthy normal population TRAP and TRAPLDL change with age and a substantial proportion of TRAP cannot be attributed to any known AOXs thus indicating the existence of unmeasured an unidentified antioxidant(s); ii) during acute infection and immobilization the exogenous AOXs (vitamin C and E) remained unchanged, whereas the activity of unidentified AOXs of plasma declined sharply; iii) in those NIDDM patients with coronary heart disease plasma TRAP is reduced. In conclusion, TRAP has revealed important information for evaluating the AOX status of human plasma, CSF and LDL. According to our studies, important, possibly endogenous AOXs still remain to be identified. Show more

Keywords: antioxidants, total peroxyl radical-trapping potential, aging, cancer, chemiluminescence

Citation: Restorative Neurology and Neuroscience, vol. 12, no. 2-3, pp. 159-165, 1998

Authors: Yan, Shi Du | Stern, David | Kane, Michael D. | Kuo, Yu-Min | Lampert, Heather C. | Roher, Alex E.

Article Type: Research Article

Abstract: RAGE is a cell surface molecule primarily identified for its capacity to bind advanced glycation end-products and amphoterin. Immunocytochemical studies demonstrated that in Alzheimer's Disease (AD) the expression of RAGE is elevated in neurons close to neuritic plaque beta-amyloid (AB) deposits and in the cells of AB containing vessels. Cross-linking of surface bound AB 1-40 to endothelial cells, yielded a band of 50 kDa identified as RAGE. Using the soluble extracellular domain of recombinant human RAGE, …we found that AB binds to RAGE with a Kd = 57 ± 14 nM, a value close to those found for mouse brain endothelial cells and rat cortical neurons. The interaction of AB with RAGE in neuronal, endothelial, and RAGE-transfected COS-1 cells induced oxidative stress, as assessed by the TBARS and MTT assays. ELISA demonstrated a 2.5 times increase of RAGE in AD over control brains. Activated microglia also showed elevated expression of RAGE. In the BV-2 microglial cell line, RAGE bound AB in dose dependent manner with a Kd of 25 ± 9 nM. Soluble AB induced the migration of microglia along a concentration gradient, while immobilized AB arrested this migration. AB-RAGE interaction also activated NF-kB, resulting in neuronal up-regulation of macrophage-colony stimulating factor (M-CSF) which also induced microglial migration. Taken together, our data suggest that RAGE-AB interactions play an important role in the pathophysiology of Alzheimer's Disease. Show more

Citation: Restorative Neurology and Neuroscience, vol. 12, no. 2-3, pp. 167-173, 1998

Authors: Anderson, J.E. | O'Donnell, B.F. | McCarley, R.W. | Shenton, M.E.

Article Type: Research Article

Abstract: Schizophrenia is a disorder characterized by multiple symptoms, with a varied course and outcome. The etiology is yet unknown, but multiple pathological processes or, equally likely, a unique pathophysiological process, may be involved. Here, we review evidence for progressive changes in schizophrenia in order to understand further the pathophysiology of this disorder. We first present evidence for clinical and psycho-social changes over time, followed by evidence from structural brain studies that suggests that …schizophrenia is a brain disorder. We then review findings from the small number of longitudinal studies that have evaluated structural brain changes in schizophrenia, followed by a review of the evidence for neurophysiological changes, both cross-sectional and longitudinal. This is followed by a discussion of possible cellular mechanisms, including NMDA receptor abnormalities, that might account for structural and functional brain changes (temporal and frontal), and we discuss how these abnormalities might be related to not only the specific signs and symptoms of schizophrenia but also to the onset and course of the illness. Finally, we discuss neurodevelopment (static and perhaps non-static alterations) and neurodegenerative theories of schizophrenia. We propose that the two are not mutually exclusive, but instead likely reflect a "two-hit" model for some subtypes of schizophrenia. Show more

Keywords: schizophrenia, brain, neurodevelopmental, neurodegenerative, MRI, ERP, functional and structural changes

Citation: Restorative Neurology and Neuroscience, vol. 12, no. 2-3, pp. 175-184, 1998

Authors: Prince, Jonathan A. | Oreland, Lars

Article Type: Research Article

Abstract: The main contributors to the search for functional brain changes in schizophrenia in the past years have employed imaging techniques such as positron emission tomography (PET), single photon emmission computed tomography (SPECT), and magnetic resonance imaging (MRI). Our laboratory has applied a novel strategy involving the post-mortem measurement of the mitochondrial respiratory chain enzyme cytochrome-c-oxidase (COX) to address the question of regional metabolic changes in schizophrenia. This approach is based upon a …strong body of evidence which indicates that neuronal COX is highly regulated by the energy demands of the cell and as such represents an endogenous marker of cellular energy metabolism over time. Our original findings indicated that COX activity may be reduced in the striatum and frontal cortex consistent with the concept that a state reduced activity in cortico-striatal circuits may underlie schizophrenia. Subsequent studies from our laboratory on the effects of neuroleptics, PCP, and methamphetamine on animals, have provided additional evidence that a state of dopaminergic overactivity or glutamatergic underactivity produces a hypometabolic state similar to that which is evident in the brains of schizophrenics. Show more

Citation: Restorative Neurology and Neuroscience, vol. 12, no. 2-3, pp. 185-193, 1998

Authors: Leonard, Sherry | Gault, Judith | Adams, Catherine | Breese, Charles R. | Rollins, Yvonne | Adler, Lawrence E. | Olincy, Ann | Freedman, Robert

Article Type: Research Article

Abstract: Neuronal nicotinic acetylcholine receptor expresssion was examined in schizophrenia. The incidence of smoking in schizophrenia is remarkably high and nicotine has been found to normalize an auditory evoked potential deficit seen in most subjects who suffer from this disease. Antagonists and agonists of a specific subset of this receptor family, the a7 nicotinic receptor, were found to regulate the gating of filtering of auditory information in both humans and in an animal model. The a7 gene …has been cloned and a polymorphic dinucleotide repeat near the gene was used for linkage analysis, showing the a7 locus to be linked to the P50 deficit. Expression of the a7 receptor, which binds nicotine with low affinity, is reduced in the hippocampus of schizophrenics. [3H]-nicotine binding, a measure of the high affinity nicotinic receptors, was also decreased in schizophrenics and does not increase in response to tobacco use, as is seen in control subjects. The results of these studies suggest the presence of abnormal expression and function of the neuronal nicotinic receptor gene family in schizophrenia. Show more

Keywords: nicotine, smoking, schizophrenia, nicotinic receptor, auditory gating

Citation: Restorative Neurology and Neuroscience, vol. 12, no. 2-3, pp. 195-201, 1998