Neuroscience
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Oxidative/nitrosative stress is involved in NMDA receptor-mediated excitotoxic brain damage produced by the glutamate analog quinolinic acid. The purpose of this work was to study a possible role of peroxynitrite, a reactive oxygen/nitrogen species, in the course of excitotoxic events evoked by quinolinic acid in the brain. The effects of Fe(TPPS) (5,10,15,20-tetrakis (4-sulfonatophenyl)porphyrinate iron (III)), an iron porphyrinate and putative peroxynitrite decomposition catalyst, were tested on lipid peroxidation and mitochondrial function in brain synaptic vesicles exposed to quinolinic acid, as well as on peroxynitrite formation, nitric oxide synthase and superoxide dismutase activities, lipid peroxidation, caspase-3-like activation, DNA fragmentation, and GABA levels in striatal tissue from rats lesioned by quinolinic acid. ⋯ The porphyrinate-mediated reduction in DNA fragmentation simultaneous to the decrease in caspase-3-like activation from quinolinic acid-lesioned rats suggests a prevention in the risk of peroxynitrite-mediated apoptotic events during the course of excitotoxic damage in the striatum. In summary, the protective effects that Fe(TPPS) exhibited both under in vitro and in vivo conditions support an active role of peroxynitrite and its precursors in the pattern of brain damage elicited by excitotoxic events in the experimental model of Huntington's disease. The neuroprotective mechanisms of Fe(TPPS) are discussed.
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Cholinergic neurons degenerate in Alzheimer's disease and dementia and neuroprotective substances are of high interest to counteract this cell death. The aim of the present study was to test the effect of urea and the nitric oxide synthetase inhibitor l-thiocitrulline on the survival of cholinergic neurons. Organotypic brain slices of the basal nucleus of Meynert were cultured for 2 weeks in the presence of 1-100 microM urea with or without NGF or other growth factors or with or without 1-10 microM of the NOS inhibitor L-thiocitrulline. ⋯ NGF as well as urea did not stimulate expression of the enzyme choline acetyltransferase pointing to survival promoting effects. Urea did not modulate the NGF binding in PC12 cells indicating that this effect was indirect. It is concluded that urea may play a role as an indirect survival promoting molecule possibly involving the nitric oxide pathway.
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Comparative Study
Evidence that peripheral rather than intracranial thermal signals induce thermoregulation.
Numerous effector mechanisms have been discovered, which change body temperature and thus serve to maintain the thermal integrity of homeothermic animals. These mechanisms are driven by thermal signals that are processed by neurons in the hypothalamic preoptic area. To keep a tight control over body temperature, these neurons have to receive accurate thermal information. ⋯ Since the brain temperature did not decrease, it is unlikely that intracranial thermoreceptors are involved in the transmission of "cold" thermal signal to induce thermoregulation. At 30 min of cold exposure, neurons in all known thermoregulatory areas (like the ventrolateral part of the medial preoptic nucleus, the lateral retrochiasmatic area, the lateral parabrachial nucleus and the peritrigeminal nucleus) were already maximally activated. These observations clearly indicate that the activation of neurons in the preoptic and several other thermoregulatory nuclei is induced in vivo by thermal signals originating in the periphery, and not in the CNS.
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3-Hydroxyglutaric acid (3HGA) accumulates in the inherited neurometabolic disorder known as glutaryl-CoA dehydrogenase deficiency. The disease is clinically characterized by severe neurological symptoms, frontotemporal atrophy and striatum degeneration. Because of the pathophysiology of the brain damage in glutaryl-CoA dehydrogenase deficiency is not completed clear, we investigated the in vitro effect of 3HGA (0.01-5.0mM) on critical enzyme activities of energy metabolism, including the respiratory chain complexes I-V, creatine kinase isoforms and Na(+),K(+)-ATPase in cerebral cortex and striatum from 30-day-old rats. ⋯ Since 3HGA stimulated oxygen consumption in state IV and compromised ATP formation, it can be presumed that this organic acid might act as an endogenous uncoupler of mitochondria respiration. Finally, we observed that 3HGA changed C6 cell morphology from a round flat to a spindle-differentiated shape, but did not alter cell viability neither induced apoptosis. The data provide evidence that 3HGA provokes a moderate impairment of brain energy metabolism and do not support the view that 3HGA-induced energy failure would solely explain the characteristic brain degeneration observed in glutaryl-CoA dehydrogenase deficiency patients.
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Epilepsy may result from altered transmission of the principal inhibitory transmitter GABA in the brain. Using in situ hybridization in two animal models of epileptogenesis, we investigated changes in the expression of nine major GABA(A) receptor subunits (alpha1, alpha2, alpha4, alpha5, beta1-beta3, gamma2 and delta) and of the GABA(B) receptor species GABA(B)R1a, GABA(B)R1b and GABA(B)R2 in 1) hippocampal kindling and 2) epilepsy following electrically-induced status epilepticus (SE). Hippocampal kindling triggers a decrease in seizure threshold without producing spontaneous seizures and hippocampal damage, whereas the SE model is characterized by spontaneous seizures and hippocampal damage. ⋯ The observed changes suggest substantial and cell specific rearrangement of GABA receptors. Lasting downregulation of subunits delta and alpha5 in granule cells and transient decreases in subunit alpha2 and beta1-3 mRNA levels in cornu ammonis 3 pyramidal cells are suggestive of impaired GABA(A) receptor-mediated inhibition. Persistent upregulation of subunits beta1-3 and gamma2 of the GABA(A) receptor and of GABA(B)R2 mRNA in granule cells, however, may result in activation of compensatory anticonvulsant mechanisms.