Induced Neuronal Death (induced + neuronal_death)

Distribution by Scientific Domains

Selected Abstracts

Routes of zinc entry in mouse cortical neurons: role in zinc-induced neurotoxicity

Philippe Marin
Abstract Exposure of central neurons to Zn2+ triggers neuronal death. The routes of Zn2+ entry were investigated in living cortical neurons from the mouse using the specific Zn2+ fluorescent dye N-(6-methoxy-8-quinolyl)-p-toluene sulphonamide (TSQ), which preferentially detects membrane-bound Zn2+. Exposure of cortical neurons to increasing concentrations of Zn2+ (1,100 ,m) induced a progressive increase in the fluorescence of TSQ. This fluorescence signal was not attenuated by the permeation of plasma membrane with digitonin. Accordingly, the major part of TSQ fluorescence (two-thirds) was associated to the particulate fraction of cortical neurons exposed to Zn2+. These results suggest that Zn2+ detected with TSQ in neurons is mainly bound to membranes. TSQ fluorescence measured in neurons exposed to 3 ,m Zn2+ was enhanced by Na+ -pyrithione, a Zn2+ ionophore, ,-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), N-methyl- d -aspartate (NMDA) or KCl-induced depolarization. However, in the absence of any treatment, TSQ labelling of neurons exposed to 3 ,m Zn2+ was only decreased by NMDA receptor antagonists, whereas it remained unaltered in the presence of antagonists of AMPA receptors or L-type voltage-gated Ca2+ channels. Zn2+ entry through NMDA receptors did not contribute to Zn2+ -induced neuronal death, as it was prevented by antagonists of NMDA receptors only when they were added after the Zn2+ exposure. Finally, Zn2+ induced a delayed accumulation of extracellular glutamate which might be responsible for the delayed NMDA receptor activation that leads to neuronal death. [source]

Neuroprotective role of bradykinin because of the attenuation of pro-inflammatory cytokine release from activated microglia

Mami Noda
Abstract Bradykinin (BK) has been reported to be a mediator of brain damage in acute insults. Receptors for BK have been identified on microglia, the pathologic sensors of the brain. Here, we report that BK attenuated lipopolysaccharide (LPS)-induced release of tumor necrosis factor-alpha (TNF-,) and interleukin-1, from microglial cells, thus acting as an anti-inflammatory mediator in the brain. This effect was mimicked by raising intracellular cAMP or stimulating the prostanoid receptors EP2 and EP4, while it was abolished by a cAMP antagonist, a prostanoid receptor antagonist, or by an inhibitor of the inducible cyclooxygenase (cyclooxygenase-2). BK also enhanced formation of prostaglandin E2 and expression of microsomal prostaglandin E synthase. Expression of BK receptors and EP2/EP4 receptors were also enhanced. Using physiological techniques, we identified functional BK receptors not only in culture, but also in microglia from acute brain slices. BK reduced LPS-induced neuronal death in neuron,microglia co-cultures. This was probably mediated via microglia as it did not affect TNF-,-induced neuronal death in pure neuronal cultures. Our data imply that BK has anti-inflammatory and neuroprotective effects in the central nervous system by modulating microglial function. [source]

Integrins mediate ,-amyloid-induced cell-cycle activation and neuronal death

Giuseppina Frasca
Abstract Early intracellular events responsible for cell-cycle induction by ,-amyloid (A,) in neurons have not been identified yet. Extracellular signal,regulated kinases 1/2 (ERK1/2) have been identified in this pathway, and inhibition of ERK activity prevents cell-cycle activation and reduces neuronal death induced by A,. To identify upstream events responsible for ERK activation, attention has been focused on integrins. Treatment of SH-SY5Y cells, differentiated by long-term exposure to 10 ,M retinoic acid with a neutralizing anti-,1-integrin antibody significantly reduced A,-induced neuronal death. However, cell-cycle analysis showed that treatment with anti-,1-integrin per se produced changes in the distribution of cell populations, thus hampering any effect on A,-induced cell-cycle activation. 4-Amino-5-(4-chlorophenyl)-7(t-butyl)pyrazol(3,4- D)pyramide, an inhibitor of src protein kinases that colocalizes with focal adhesion kinase (FAK) and is involved in integrin signaling, was effective in reducing activation of the cell cycle and preventing induction of neuronal death by A, while inhibiting ERK1/2 phosphorylation. Similar results were obtained when FAK expression was down-regulated by siRNA silencing. The present study identifies a sequence of early events in the toxic effect of A, in neuronal cultures that involves interaction with integrins, activation of FAK/src, enhanced phosphorylation of ERK1/2, and induction of the cell cycle, all leading to neuronal death. 2007 Wiley-Liss, Inc. [source]

Protective effect of Toki-shakuyaku-san on amyloid ,25,35 -induced neuronal damage in cultured rat cortical neurons

Nobuaki Egashira
Abstract Amyloid , protein (A,) is the major component of senile plaques, the pathological hallmark of the neurodegeneration associated with Alzheimer's disease (AD). This study investigated the effect of Toki-shakuyaku-san (TSS), a traditional medicine, on A,25,35 -induced neuronal death and lipid peroxidation assessed by measuring lactate dehydrogenase (LDH) and malondialdehyde (MDA), respectively. A,25,35 at 10 M induced neuronal damage and increased the LDH and MDA. TSS at concentrations of 100 and 300 g/mL significantly reduced the A,25,35 -induced neuronal death and the lipid peroxidation. These results suggest that TSS has a protective effect against A,25,35 -induced neuronal damage. TSS may be beneficial for the treatment of AD. Copyright 2005 John Wiley & Sons, Ltd. [source]

Promotion of axonal maturation and prevention of memory loss in mice by extracts of Astragalus mongholicus

C Tohda
Background and purpose: Neurons with atrophic neurites may remain alive and therefore may have the potential to regenerate even when neuronal death has occurred in some parts of the brain. This study aimed to explore effects of drugs that can facilitate the regeneration of neurites and the reconstruction of synapses even in severely damaged neurons. Experimental approach: We investigated the effects of extracts of Astragalus mongholicus on the cognitive defect in mice caused by injection with the amyloid peptide A,(25-35). We also examined the effect of the extract on the regeneration of neurites and the reconstruction of synapses in cultured neurons damaged by A,(25-35). Key results: A. mongholicus extract (1 g kg,1 day,1 for 15 days, p.o.) reversed A,(25-35)-induced memory loss and prevented the loss of axons and synapses in the cerebral cortex and hippocampus in mice. Treatment with A,(25-35) (10 ,M) induced axonal atrophy and synaptic loss in cultured rat cortical neurons. Subsequent treatment with A. mongholicus extract (100 ,g/ml) resulted in significant axonal regeneration, reconstruction of neuronal synapses, and prevention of A,(25-35)-induced neuronal death. Similar extracts of A. membranaceus had no effect on axonal atrophy, synaptic loss, or neuronal death. The major known components of the extracts (astragalosides I, II, and IV) reduced neurodegeneration, but the activity of the extracts did not correlate with their content of these three astragalosides. Conclusion and implications: A. mongholicus is an important candidate for the treatment of memory disorders and the main active constituents may not be the known astragalosides. British Journal of Pharmacology (2006) 149, 532,541. doi:10.1038/sj.bjp.0706865 [source]