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

Authors: Manev, Hari | Costa, Erminio | Flaherty, Joseph A.

Article Type: Other

Citation: Restorative Neurology and Neuroscience, vol. 12, no. 2-3, pp. 57-58, 1998

Authors: Richter, Christoph

Article Type: Research Article

Abstract: This article emphasizes the importance of mitochondria, the cellular ATP level, and the liberation of certain mitochondrial proteins for the execution phase of apoptosis. Destabilization of mitochondria results in release of these proteins. Oxidative stress and altered cellular Ca2+ homeostatis, considered to be mediators of apoptosis, synergistically decrease the mitochondrial membrane potential and lower the cellular ATP level. Conversely, stabilization of the mitochondrial membrane potential, e.g., by the protooncogene bcl-2, prevents cell …death. An important process underlying mitochondrial destabilization is oxidant-induced mitochondrial Ca2+ release followed by re-uptake ("Ca2+ cycling"). Tumor necrosis factor-a induces oxygen radicals in mitochondria through ceramides, and the recently discovered mitochondrial nitric oxide synthase profoundly stimulates Ca2+ release from mitochondria through formation of nitrogen monoxide and peroxynitrite. Show more

Keywords: Ca2+, ceramides, cytochrome c, membrane potential, reactive nitrogen, reactive oxyogen

Citation: Restorative Neurology and Neuroscience, vol. 12, no. 2-3, pp. 59-62, 1998

Authors: Kong, Ah-Ng Tony | Yu, Rong | Lei, Wei | Mandlekar, Sandhya | Tan, Tse-Hua | Ucker, David S.

Article Type: Research Article

Abstract: Chemical-induced oxidative stress to a cell can signal many cellular responses which include proliferation, differentiation, hemeostasis, apoptosis or necrosis. To better understand the underlying molecular mechanisms after exposure to chemicals, we investigated the signal transduction pathways, in particular the mitogen-activated protein kinase (MAPK) pathway and the ICE/Ced-3 protease (caspase) pathway, activated by different agents. Butylated hydroxyanisol (BHA) and its metabolite, t-butyl-hydroquinone (tBHQ), both are well known phenolic antioxidants used in food preservatives, …strongly activated c-Jun N-terminal kinase 1 (JNK1) and/or extracellular signal-regulated protein kinase 2 (ERK2) in a dose- and time-dependent fashion. Pretreatment with free radical scavengers N-acetyl-L-cysteine (NAC), glutathione (GSH), or vitamin E, inhibited ERK2 activation and, to a much lesser extent, JNK 1 activation by BHA and tBHQ, implicating the role of oxidative stress. Under conditions where JNK1 and ERK2 were activated, BHA also activated transcription factors nuclear factor kappa B (NF-?B), activated-protein-1 (AP-1), and anti-oxidant response element (ARE), leading to induction of genes such as c-jun, and c-fos. At relatively high concentrations, BHA and tBHQ stimulated proteolytic activity of ICE/Ced3 cysteine proteases, and caused apoptosis, which was blocked by pretreatment with NAC. Further increase in concentrations lead to rapid cell death predominantly occurred via necrosis. Some naturally occurring phytochemicals, such as phenylethyl isothiocyanate (PEITC), green tea polyphenols (GTP), and sulfarophane, which have been shown to be potent inducers of Phase II enzymes, also differentially regulated the activities of JNK, ERK, or CPP-32, in a time- and dose-dependent manner. Our data, together with the work of others, enable us to propose a model in which low concentrations of these chemicals (e.g., BHA, PEITC) activate MAPKs leading to induction of gene expression (e.g., c-jun, c-fos, GSI) which may protect the cells against toxic insults and enhance cell survival. At relatively high concentrations, these agents activated both MAPKS, and the ICE/Ced-3 caspase pathway, leading to apoptosis. The exact mechanisms by which MAPK and caspases are activated by these agents are currently unknown, but may involve oxidative modification of glutathione (GSH) and/or protein thiols, and/or generation of secondary messengers, ceramide and calcium, which further activate downstream events. Taken together, our results suggest that chemicals including phenolic antioxidants activate MAPK pathways which may lead to the induction of genes producing protection and survival mechanisms, as well as the ICE/Ced-3 protease pathway, leading to apoptosis. The balancing amongst these pathways may dictate the fate of the cells upon exposure to chemicals. Show more

Keywords: oxidative stess, apoptosis, caspase, MAPK, ERK, JNK, BHA

Citation: Restorative Neurology and Neuroscience, vol. 12, no. 2-3, pp. 63-70, 1998

Authors: Kiedrowski, Lech

Article Type: Research Article

Abstract: The hypothesis that a destabilization of mitochondrial function during neuronal exposure to excitatory amino acids may be involved in the mechanism of neuronal death was examined. The mitochondrial membrane potential (??m) and the cytoplasmic Ca2+ concentration ([Ca2+]c) were monitored simultaneously in single cultured rat cerebellar granule cells (CGCs) loaded with tetramethylrhodamine methyl ester (TMR) and fura-2; CGCs were depolarized with K+, or exposed to excitotoxic doses of glutamate or kainate, and viability of the same neurons was studied for 24-30 h. This approach made it possible to single out the neurons that died, and to describe the changes in ??m …and [Ca2+]c that were characteristic for these neurons. Exposure to glutamate caused an increase in [Ca2+]c that was associated with a decrease in the mitochondrial TMR fluorescence, which indicates a decrease in ??m. The neurons that failed to restore ??m following glutamate withdrawal, also failed to restore low [Ca2+]c, and later died. Although a similar number of neurons died following kainate exposure as did after glutamate exposure, the kainate-elicited neuronal death resulted not from the collapse of ??m but from an excessive neuronal swelling, which led to rupture of the plasma membrane. Depolarzation with K+ was not neurotoxic and caused only a minor decrease in TMR fluorescence. These results indicate that in vitro glutamate and kainate destroy neurons by different mechanisms: glutamate by a failure to restore ??m following the exposure, and kainate by an osmotic lesion of the plasma membrane. Show more

Keywords: glutamte, kainate, NMDA, mitochondria, membrane potential, depolarization, calcium, sodium, neurons, excitotxicity, apoptosis, neuronal death

Citation: Restorative Neurology and Neuroscience, vol. 12, no. 2-3, pp. 71-79, 1998

Authors: Manev, H. | Uz, T. | Qu, T.

Article Type: Research Article

Abstract: 5-Lipoxygenase (5-LO; arachidonate:oxygen 5-oxidoreductase, EC 1.13.11.34) is the enzyme responsible for the first step in the formation of inflammatory leukotrienes from arachidonic acid. 5-LO is expressed in hippocampal neurons. Increased formation of leukotrienes was found in the hippocampus of rats in which seizures were induced by a glutamate receptor agonist, kainate. Expression of the 5-LO gene can be stimulated by vitamin D3 and suppressed by the pineal hormone melatonin. Here we hypothesize that …kainate also stimulates 5-LO expression in the hippocampus. Kainate was injected intraperitoneally (10 mg/kg). Rats were sacrificed 3 hr later and their hippocampi were dissected and total RNA was extracted and processed for quantitative reverse transcription/polymerase chain reaction (RT-PCR) assay of 5-LO and cyclophilin (cyc) mRNAs. Mutated primers were used as internal standards to assay attomol quantities of these two specific mRNAs per microgram of total RNA. Fixed hippocampal slices were processed for 5-LO immunostaining and Nissl staining (assay of cell damage). Kainate induced about a 2.5-fold increase in 5-LO mRNA and triggered a redistribution of 5-LO like immunoreactivity from the pyramidal cell bodies into the dendrites of these neurons, particularly in the CA3 area. The results suggest that glutamate receptor-mediated signaling may modify the expression of neuronal 5-LO and that this enzyme might be involved in glutamte receptor-mediated neuronal plasticity and/or degeneration. Show more

Keywords: leukotriene, kainate, 5-lipoxygenase, inflammation, melatonin, eicosanoids, glutamate, hippocampus

Citation: Restorative Neurology and Neuroscience, vol. 12, no. 2-3, pp. 81-85, 1998

Authors: Hanbauer, Ingeborg | Galdzicki, Zygmunt | Rapoport, Stanley I. | Scortegagna, Marzia

Article Type: Research Article

Abstract: In the trisomy 16 mouse the increased gene dosage of SOD-1 increases H2O2 production that results in increased oxidative stress. We report here that in hippocampal primary cultures, metallothionein (MT)-I/II immunoreactivity was present mainly in glial fibrillary acidic protein-immunolabeled cells. Western blot analysis showed a two-fold higher level of MT-I/II in trisomy 16 mice then in euploid littermates. In contrast, the immunoreactivity of glutamine synthetase, another glia-expressed protein, was similar in hippocampal …cultures of trisomy 16 mouse and euploid littermates. Oxyblot analysis of hippocampal cultures showed that the carbonyl content in several protein bands was higher in trisomy 16 mice than in euploid littermates giving evidence for increased oxidative stress in trisomy 16 mouse cultures. To evaluate the responsiveness of MT-I/II to agents that increase the level of reactive oxygen species in cells we measured the effect of H2O2, kainic acid, (±) ACPD, and B-amyloid peptide 1-42. Western blot analysis documented that in hippocampal cultures of euploid littermates MT-I/II was maximally increased by 50 µM H2O2, 100 µM kainic acid, 10 µM (±)ACPD, or 1.0 mM B-amyloid peptide 1-42, whereas in those of trisomy 16 mice no furter increase above the elevated level was observed. Our data suggest that in the trisomy 16 mouse the production of reactive oxygen species may have shifted the intracellular redox environment that could have alerted the susceptibility of MT-I/II transcription. The possibilty that transcription factors whose activation may be essential to initiate MT-I/II transcription get oxidized has yet to be examined. Show more

Keywords: trisomy 16 mouse, oxidative stress, metallothionein, antioxidant response, hydrogen peroxide, ionotropic, metabotropic glutamate receptor

Citation: Restorative Neurology and Neuroscience, vol. 12, no. 2-3, pp. 87-93, 1998

Authors: Scortegagna, Marzia | Chikhale, Elsbeth | Hanbauer, Ingeborg

Article Type: Research Article

Abstract: E14 mesencephalic cultures grown 6 days in Neurobasal Medium containing 10% horse serum consist of differentiated neurons and astroglia. In these cultures, glutathione and metallothionein-I/II are enriched in astrocytes and play an important role in heavy metal scavenging and oxidative stress response. A 24 h exposure to 25 µM Pb, in serum-containing medium, elevated the glutathione content by more than twofold and increased the metallothionein I/II-immunolabeled protein band. In contrast, exposure to 3 to 25 µM …Pb is serum-free medium increased Pb uptake by cells 2 to 4-times above the levels found in 10% serum-containing medium, reduced the glutathione level and obliterated the metallothionein-I/II protein band. The rapid decrease of metallothionein-I/II and glutathione levels in serum-free medium implies that their regulation may depend on a serum factor operative in inducing immediate early genes. Exposure to 6 µM Pb in serum-free or in B27-supplemented medium increased the carbonyl content of several protein bands above control levels indicating that under conditions that curtail metallothionein induction Pb exposure causes increased oxidative stress. Show more

Keywords: primary cultures, lead, glutathione, metallothionein, serum deprivation, oxidative stress

Citation: Restorative Neurology and Neuroscience, vol. 12, no. 2-3, pp. 95-101, 1998

Authors: Ebadi, M. | Ramana Kumari, M.V. | Hiramatsu, M. | Hao, R. | Pfeiffer, R.F. | Rojas, P.

Article Type: Research Article

Abstract: The finding that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) elicits parkinsonism in human beings suggests that endogenous or xenobiotic neurotoxic compounds may be involved in the etiology of Parkinson's disease (PD). We have shown that cerebrospinal fluid (CSF) of newly diagnosed and drug untreated patients with PD contains a low molecular weight substance(s) which inhibits the growth and function of dopaminergic neurons in culture. In addition, selegiline in a dosage below the level that inhibits monoamine …oxidase B (MAO-B), protects dopaminergic neurons in culture against toxic factor(s) present in the CSF of patients with PD, and the said effect is mediated via elaboration of brain-derived neurotrophic factor (BDNF). In view of the fact that 6-hydroxydopamine (6-OHDA) or MPTP causes parkinsonism by generating free radicals, and inducers of metallothionein (MT) isoforms avert the said neurotoxicity, we intended to learn whether MT isoforms were capable of scavenging free radicals. By employing electron spin resonance spectroscopy (ESR), we examined for the first time the free radical scavenging effects of MT-I and MT-II isoforms on four types of free radicals. Solutions of 0.15 mM of MT-I and 0.3 mM of MT-II scavenged the 1,1-diphenyl-2-picrylhydrazyl radicals completely. Furthermore, they were able to scavenge hydroxyl radicals generated in a Fenton reaction. Moreover, MT-I scavenged almost 90% of the superoxide generated by the hypoxanthine and xanthine oxidase system, while MT-II could only scavenge 40%. By using 2,2,6,6-tetramethyl-4-piperidone as a "spin-trap" for the reactive oxygen species (containing singlet oxygen, superoxide and hydroxyl radicals) generated by photosensitized oxidation of riboflavin, and measuring the relative signal intensities of the resulting stable nitroxide adduct, 2,2,6,6-tetramethyl-4-piperidone-1-oxyl, we observed that MT-II could scavenge 92%, while MT-I could completely scavenge all the reactive species generated. The results of this investigation are interpreted to suggest that selegiline by preventing the generation of free radicals, MT isoforms by scavenging free radicals, and neurotrophins by rescuing dopaminergic neurons are capable of attenuating oxidative stress and of providing neuro-protection in PD. Show more

Keywords: selegiline, 6-hydroxydopamine, dopamine, nerve growth factor, brain-derived neurotrophic factor, oxygen free radicals

Citation: Restorative Neurology and Neuroscience, vol. 12, no. 2-3, pp. 103-111, 1998

Authors: Yu, P.H. | Zhang, X. | Zuo, D.M. | Lai, C.T. | Tieu, K. | Davis, B.A. | Boulton, A.A.

Article Type: Research Article

Abstract: Several clinical investigations have indicated that R-deprenyl, a typical monoamine oxidas B inhibitor, delays the progression of Parkinson's and Alzheimer's disease. A number of aliphatic N-methylpropargylamines, such as R-2-hexyl-N-methylpropargylamines (R-2HxMP), have been found to be highly potent, irreversible, selective, MAO-B inhibitors both in vitro and in vivo. These aliphatic propargylamines do not affect noradrenaline of dopamine uptake and are chemically without an amphetamine moiety and therefore do not exhibit any amphetamine-like effects. …They are capable of protecting mouse striatal dopamine neurons against MPTP-induced toxicity in the caudate, against MK-801-induced apoptosis in the retrosplenial cortex and against DSP-4-induced depletion of naradrenergic axons. They rescue hippocampal neurons in rodents following kainate-induced neuronal damage. They block the expression of heat shock protein (HSP70) and delayed c-Fos expression in hippocampal CA1 region as elicited by kainate. Confocal microscopy also revealed prevention of neuronal damage in hippocampal slices under hypoxia-hypoglycemia conditions. Aliphatic N-methylpropargylamines may be useful in the treatment of neurodegenerative disorders. The mechanism and site of action of the neurorescue effect of these propargylamines, however, remains to be established. Show more

Keywords: MAO, neuroprotection, neurorescue

Citation: Restorative Neurology and Neuroscience, vol. 12, no. 2-3, pp. 113-118, 1998

Authors: Wood, J.P.M. | Pergande, G. | Osborne, N.N.

Article Type: Research Article

Abstract: We have recently reported that the non-opiate analgesic, flupirtine, counteracts apoptosis in cultures of human retinal pigmented epithelial (RPE) cells induced by deprivation of serum, oxygen and glucose (experimental ischaemia). In the present study, human RPE cells grown on coverslips were treated with buthionine sulphoxamine (BSO), a compound that inhibits glutathione biosynthesis. BSO caused a dose-dependent reduction in culture density and an increase in the number of cell nuclei that were positively …labelled by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) procedure. These data show that reduction of glutathione levels causes apoptosis in the RPE cultures. When flupirtine gluconate was co-incubated with BSO, it dose-dependently prevented the induction of apoptosis. The most effective concentration of flupitine found to inhibit cell death caused by BSO (1 µM - 1 mM) was 100 µM. The presence of serum (2% or 10%) in the culture medium did not have any effect on the outcome of apoptosis and overall cell death caused by BSO. Futhermore, melatonin, also known to reduce experimental ischaemia-induced overall cell death and apoptosis of cultured RPE cells had only a mild protective effect at 1 mM. The combined data suggest that flupirtine prevents apoptosis by increasing the cellular levels of reduced glutathione and/or protects the cells against the damaging effects of reactive oxygen species (ROS) that are produced subsequent to inhibition of glutathione production. Show more

Keywords: apoptosis, glutathione, buthionine sulphoxamine, retinal pigmented epithelium, flupirtine gluconate

Citation: Restorative Neurology and Neuroscience, vol. 12, no. 2-3, pp. 119-125, 1998

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