Involvement of reactive oxygen species in the microsomal S-oxidation of thiobenzamide

Superoxide dismutase, catalase and methional proved capable of inhibiting the microsomal oxidation of thiobenzamide, which is most probably catalyzed by the flavin-containing monooxygenase. This indicates that excited oxygen species (e.g. X O-2,H2O2, X OH) are involved in the catalytic cycle of this enzymatic reaction. CO, which inhibits the cytochrome P-450-dependent oxygen radical formation, had no effect on the oxidation reaction, suggesting that the source of the reactive oxygen species is not the microsomal mixed-function oxidase.     

Involvement of reactive oxygen species in the microsomal S-oxidation of thiobenzamide

Summary Superoxide dismutase, catalase and methional proved capable of inhibiting the microsomal oxidation of thiobenzamide, which is most probably catalyzed by the flavin-containing monooxygenase. This indicates that excited oxygen species (e. g.·O ₂ ^– , H₂O₂, ·OH) are involved in the catalytic cycle of this enzymatic reaction. CO, which inhibits the cytochrome P-450-dependent oxygen radical formation, had no effect on the oxidation reaction, suggesting that the source of the reactive oxygen species is not the microsomal mixed-function oxidase.     

Influence of reactive oxygen species production by monoamine oxidase activity on aluminum-induced mitochondrial permeability transition

Treatment of Ca2+-loaded mitochondria with both aluminum and tyramine results in a swelling of higher amplitude than with aluminum alone, while tyramine alone is ineffective. The phenomenon is accompanied by H2O2 production and thiol and pyridine nucleotide oxidation. Cyclosporin A, N-ethylmaleimide or dithioerythritol completely prevent these effects, while catalase exhibits a lower inhibition, pointing to the induction of the permeability transition (MPT) by an oxidative stress. Reactive oxygen species are generated by the interaction of aluminum with the inner membrane and the oxidation of tyramine by monoamine oxidase on the outer membrane. This different localization determines the oxidation of critical thiol groups located on both internal and external sides of pore-forming structures, resulting in MPT induction. The reduced effect by aluminum or the inefficacy by tyramine, when implied alone, can be attributable to the oxidation of thiol groups located only on the internal or external side, respectively. Ultrastructural observations show that aluminum plus tyramine induce the typical configuration of mitochondria that have undergone the MPT. Instead, with aluminum alone, the sensitive subpopulation, although swollen, preserves the outer membrane and shows an apparently orthodox configuration.     

Highly reactive oxygen species: detection, formation, and possible functions

The so-called reactive oxygen species (ROS) are defined as oxygen-containing species that are more reactive than O(2) itself, which include hydrogen peroxide and superoxide. Although these are quite stable, they may be converted in the presence of transition metal ions, such as Fe(II), to the highly reactive oxygen species (hROS). hROS may exist as free hydroxyl radicals (HO·), as bound ("crypto") radicals or as Fe(IV)-oxo (ferryl) species and the somewhat less reactive, non-radical species, singlet oxygen. This review outlines the processes by which hROS may be formed, their damaging potential, and the evidence that they might have signaling functions. Since our understanding of the formation and actions of hROS depends on reliable procedures for their detection, particular attention is given to procedures for hROS detection and quantitation and their applicability to in vivo studies.     

Two axes in platelet-derived growth factor signaling: tyrosine phosphorylation and reactive oxygen species

The tyrosine phosphorylation cascade is a hallmark of platelet-derived growth factor (PDGF)- induced signal transduction. The amplitude and propagation of the tyrosine phosphorylation signal relies on the balance between tyrosine kinase and tyrosine phosphatase. The tyrosine kinase is latent in the absence of stimulation, whereas the tyrosine phosphatase is highly and constitutively active. Therefore, the kinase activation should be accompanied by temporal and spatial inactivation of tyrosine phosphatase to achieve the robust amplification of tyrosine phosphorylation. For the past decade, reactive oxygen species have been receiving a great deal of attention with regard to their ability to shut down tyrosine phosphatase activities in a reversible manner. In this article, the crosstalk between tyrosine phosphorylation and reactive oxygen species in PDGF signaling is discussed. Received 2 October 2006; received after revision 13 November 2006; accepted 27 November 2006     

Kinesins in the nervous system

Both the development and the maintenance of neurons require a great deal of active cytoplasmic transport. Much of this transport is driven by microtubule motor proteins. Membranous organelles and other macromolecular assemblies bind motor proteins that then use cycles of adenosine 5'-triphosphate hydrolysis to move these 'cargoes' along microtubules. Different sets of cargoes are transported to distinct locations in the cell. The resulting differential distribution of materials almost certainly plays an important part in generating polarized neuronal morphologies and in maintaining their vectorial signalling activities. A number of different microtubule motor proteins function in neurons; presumably they are specialized for accomplishing different transport tasks. Questions about specific motor functions and the functional relationships between different motors present a great challenge. The answers will provide a much deeper understanding of fundamental transport mechanisms, as well as how these mechanisms are used to generate and sustain cellular asymmetries.     

Heat shock response in the central nervous system

The heat shock response is induced in nervous tissue in a variety of clinically significant experimental models including ischemic brain injury (stroke), trauma, thermal stress and status epilepticus. Excessive excitatory neurotransmission or the inability to metabolically support normal levels of excitatory neurotransmission may contribute to neuronal death in the nervous system in many of the same pathophysiologic circumstances. We demonstrated that in vitro glutamate-neurotransmitter induced excitotoxicity is attenuated by the prior induction of the heat shock response. A short thermal stress induced a pattern of protein synthesis characteristic of the highly conserved heat shock response and increased the expression of heat shock protein (HSP) mRNA. Protein synthesis was necessary for the neuroprotective effect. The study of the mechanisms of heat shock mediated protection may lead to important clues as to the basic mechanisms underlying the molecular actions of the HSP and the factors important for excitotoxic neuronal injury. The clinical relevance of these findings in vitro is suggested by experiments performed by others in vivo demonstrating that pretreatment of animals with a submaximal thermal or ischemis stress confers protection from a subsequent ischemic insult.     

Multitasking with neurotensin in the central nervous system

The 13-amino acid peptide neurotensin (NT) was discovered over 30 years ago and has been implicated in a wide variety of neurotransmitter and endocrine functions. This review focuses on four areas where there has been substantial recent progress in understanding NT signaling and several functions of the endogenous peptide. The first area concerns the functional activation of the high-affinity NT receptor, NTR-1, including the delineation of the NT binding pocket and receptor domains involved in functional coupling to intracellular signaling pathways. The development of NT receptor antagonists and the application of genetic and molecular genetic approaches have accelerated progress in understanding NT function in several areas, including the involvement of NT in antipsychotic drug actions, psychostimulant sensitization and the modulation of pain, and these are reviewed in that order. There is now substantial evidence indicating that NT is required for certain antipsychotic drug actions and that the peptide plays a key role in stress-induced analgesia.Received 18 March 2005; received after revision 9 May 2005; accepted 23 May 2005     

Collagens in the developing and diseased nervous system

Collagens are extracellular proteins characterized by a structure in triple helices. There are 28 collagen types which differ in size, structure and function. Their architectural and functional roles in connective tissues have been widely assessed. In the nervous system, collagens are rare in the vicinity of the neuronal soma, occupying mostly a “marginal” position, such as the meninges, the basement membranes and the sensory end organs. In neural development, however, where various ECM molecules are known to be determinant, recent studies indicate that collagens are no exception, participating in axonal guidance, synaptogenesis and Schwann cell differentiation. Insights on collagens function in the brain have also been derived from neural pathophysiological conditions. This review summarizes the significant advances which underscore the function and importance of collagens in the nervous system. Received 09 September 2008; received after revision 24 October 2008; accepted 28 October 2008     

Developmental and pathological angiogenesis in the central nervous system

Angiogenesis, the formation of new blood vessels from pre-existing vessels, in the central nervous system (CNS) is seen both as a normal physiological response as well as a pathological step in disease progression. Formation of the blood–brain barrier (BBB) is an essential step in physiological CNS angiogenesis. The BBB is regulated by a neurovascular unit (NVU) consisting of endothelial and perivascular cells as well as vascular astrocytes. The NVU plays a critical role in preventing entry of neurotoxic substances and regulation of blood flow in the CNS. In recent years, research on numerous acquired and hereditary disorders of the CNS has increasingly emphasized the role of angiogenesis in disease pathophysiology. Here, we discuss molecular mechanisms of CNS angiogenesis during embryogenesis as well as various pathological states including brain tumor formation, ischemic stroke, arteriovenous malformations, and neurodegenerative diseases.     

Neurotrophins and neuronal differentiation in the central nervous system

The central nervous system requires the proper formation of exquisitely precise circuits to function properly. These neuronal circuits are assembled during development by the formation of synaptic connections between hundreds of thousands of differentiating neurons. For these circuits to form correctly, neurons must elaborate precisely patterned axonal and dendritic arbors. Although the cellular and molecular mechanisms that guide neuronal differentiation and formation of connections remain mostly unknown, the neurotrophins have emerged recently as attractive candidates for regulating neuronal differentiation in the developing brain. The experiments reviewed here provide strong support for a bifunctional role for the neurotrophins in axonal and dendritic growth and are consistent with the exciting possibility that the neurotrophins might mediate activity-dependent synaptic plasticity.     

Lead distribution in the nervous system of 8-month-old rats intoxicated since birth by lead

Lead levels in the nervous system of rats intoxicated for 8 months by lead acetate (0.2% in drinking water) varied according to the region: the lowest levels were observed in sciatic nerve and the highest in hippocampus and cerebral neocortex, while intermediate levels were observed in pons medulla, cerebellum, midbrain, hypothalamus and striatum.     

Role of active oxygen species in diethyldithiocarbamate-induced gastric ulcer in the rat

Summary Diethyldithiocarbamate, an inhibitor of Cu,Zn-superoxide dismutase, was recently found to be ulcerogenic in the rat stomach, and active oxygen species were found to be responsible for its ulcerogenicity. To clarify which active oxygen species play a role in ulcerogenesis, the effects of various scavengers and iron-chelators were studied. As superoxide dismutase and catalase reduced the ulcerogenesis induced by diethyldithiocarbamate, the superoxide radical and hydrogen peroxide were considered to play a pathogenic role in this ulcer model.     

Central nervous system and hibernation

Conclusions The role of the nervous system in the mechanism of hibernation is extremely important. The special properties of the brain of hibernators permits them wonderfully to resist to hypoxia and hypothermia, such as this state ofneural hibernation, a reversible hypothermia whichBullard, David andNichols ⁶⁰ have obtained in the thirteen-lined ground squirrel (Citellus tridecimlineatus) by hypoxia at a low temperature.The study of the glycolysis of the brain of hibernators has revealed that the brain of hibernators (European hamster) uses more glucose and produces more lactic acid than the brain of homoiotherms (albino rat). One finds, therefore, in hibernators two metabolic manifestations which are known to increase the resistance to hypoxia and hypothermia.The study of ATP synthesis by isolated mitochondriae of the brain of hibernators shows that this synthesis is more intense in them than in homiotherms.The recording of cerebral waves indicates that during hibernation the cortex of hibernators remains excitable and manifests, either after external disturbances or without any apparent cause, periods of electrogenesis.The role of the nervous system as an integrator of the arousal mechanism has clearly appeared in the researches on the electric activity of the various subcortical systems.Hibernation appears as a metabolic regulation at a minimum level (Wyss ⁶¹), a regulation in which the role of central nervous system is capital: its functional suppression, e.g. by anesthesia, leads to fatal hypothermias (Benedict andLee ⁶²,Kayser ⁶³,Strumwasser ⁴⁰).

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Résumé Le sommeil hivernal est une régulation métabolique à minimum (Wyss ⁶¹). Cette régulation exige une température optimale de l'ambiance audessus et au-dessous de laquelle les échanges respiratoires de l'hibernant sont augmentés.Le système nerveux central est responsable de cette régulation: si l'on supprime l'activité des centres nerveux de l'hibernant par des anesthésiques on supprime sa faculté de régler ses échanges et l'hibernant meurt en hypothermie (Benedict etLee ⁶²).Les centres nerveux de l'hibernant en sommeil hivernal restent excitables en dépit de la profonde hypothermie. L'hibernant partage cette faculté avec les homéothermes nouveau-nés, incomplètement développés. La résistance des centres nerveux à l'hypothermie se trouve associée dans les deux cas à une résistance accrue à l'hypoxie.L'étude du métabolisme cellulaire de la substance nerveuse des hibernants et des mammifères nouveaunés révèle une consommation de glucose et une production d'acide lactique accrues. Vu que le blocage de la consommation de glucose et de la glycolyse supprime la résistance à l'hypoxie, il est naturel d'attribuer la résistance spéciale du système nerveux des hibernants et des jeunes mammifères à cette particularité métabolique.L'intensité de la formation de l'acide adényl-triphosphorique par les mitochondries des cellules nerveuses des hibernants est aussi plus marquée que chez les homéothermes de même taille pris comme témoins. Cette seconde manifestation semble aussi correspondre à une adaptation particulière de l'activité des centres nerveux des hibernants à des conditions de fonctionnement spéciales.Le sommeil hivernal ne s'explique pas uniquement par les particularités fonctionnelles du système nerveux des hibernants. Le sommeil hivernal est une manifestation saisonnière liée à des facteurs externes (température, lumière, nourriture) et à des facteurs internes (cycle saisonnier des glandes endocrines;Kayser ⁵⁹). Mais seules les particularités fonct onnelles du système nerveux des hibernants autorisent une adaptation de l'hibernant aux conditions de vie en hypothermie. C'est la raison pour laquelleBullard et al.⁶⁰ ont pu réaliser chez un Spermophile américain ce qu'ils ont appelé le «Neural state of hibernation». C'est la même raison qui permet la survie de 30 jours en hypothermie du Lérot à jeun vivant à +5°C en été (Kayser ²³), avec une dépense d'énergie qui ne diffère à peu près pas de celle du Lérot en hibernation en plein hiver.

     

Role of active oxygen species in diethyldithiocarbamate-induced gastric ulcer in the rat

Diethyldithiocarbamate, an inhibitor of Cu,Zn-superoxide dismutase, was recently found to be ulcerogenic in the rat stomach, and active oxygen species were found to be responsible for its ulcerogenicity. To clarify which active oxygen species play a role in ulcerogenesis, the effects of various scavengers and iron-chelators were studied. As superoxide dismutase and catalase reduced the ulcerogenesis induced by diethyldithiocarbamate, the superoxide radical and hydrogen peroxide were considered to play a pathogenic role in this ulcer model.     

Receptor and nonreceptor protein tyrosine phosphatases in the nervous system

Protein tyrosine phosphatases (PTPs) have emerged as a new class of signaling molecules that play important roles in the development and function of the central nervous system. They include both tyrosine-specific and dual-specific phosphatases. Based on their cellular localization they are also classified as receptor-like or intracellular PTP. However, the intracellular mechanisms by which these PTPs regulate cellular signaling pathways are not well understood. Evidence gathered to date provides some insight into the physiological function of these PTPs in the nervous system. In this review, we outline what is currently known about the functional role of PTPs expressed in the brain.Received 31 March 2003; received after revision 7 May 2003; accepted 22 May 2003