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Apoptotic Neuronal Death (apoptotic + neuronal_death)
Selected AbstractsA role for synGAP in regulating neuronal apoptosisEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2005Irene Knuesel Abstract The brain-specific Ras/Rap GTPase-activating protein synGAP is a major component of the postsynaptic density at glutamatergic synapses. It is a target for phosphorylation by Ca2+/calmodulin-dependent protein kinase II, which up-regulates its GTPase-activating activity. Thus, SynGAP may play an important role in coupling N -methyl- d -aspartate-type glutamate receptor activation to signaling pathways downstream of Ras or Rap. Homozygous deletion of synGAP is lethal within the first few days after birth. Therefore, to study the functions of synGAP, we used the cre/loxP recombination system to produce conditional mice mutants in which gradual loss of synGAP begins at ,,1 week, and usually becomes maximal by 3 weeks, after birth. The resulting phenotypes fall into two groups. In a small group, the level of synGAP protein is reduced to 20,25% of wild type, and they die at 2,3 weeks of age. In a larger group, the levels remain higher than ,,40% of wild type, and they survive and remain healthy. In all mutants, however, an abnormally high number of neurons in the hippocampus and cortex undergo apoptosis, as detected by caspase-3 activation. The effect is cell autonomous, occurring only in neuronal types in which the synGAP gene is eliminated. The level of caspase-3 activation in neurons correlates inversely with the level of synGAP protein measured at 2 and 8 weeks after birth, indicating that neuronal apoptosis is enhanced by reduction of synGAP. These data show that synGAP plays a role in regulation of the onset of apoptotic neuronal death. [source] Cell death mechanisms in neurodegenerationJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 1 2001K. A. Jellinger Abstract Progressive cell loss in specific neuronal populations often associated with typical cytoskeletal protein aggregations is a pathological hallmark of neurodegenerative disorders, but the nature, time course and molecular causes of cell death and their relation to cytoskeletal pathologies are still unresolved. Apoptosis or alternative pathways of cell death have been discussed in Alzheimer's disease and other neurodegenerative disorders. Apoptotic DNA fragmentation in human brain as a sign of neuronal injury is found too frequent as to account for continous neuron loss in these slowly progressive processes. Morphological studies revealed extremely rare apoptotic neuronal death in Alzheimer's disease but yielded mixed results for Parkinson's disease and other neurodegenerative disorders. Based on recent data in human brain, as well as in animal and cell culture models, a picture is beginning to emerge suggesting that, in addition to apoptosis, other forms of programmed cell death may participate in neurodegeneration. Better understanding of the molecular players will further elucidate the mechanisms of cell death in these disorders and their relations to cytoskeletal abnormalities. Susceptible cell populations in a proapoptotic environment show increased vulnerability towards multiple noxious factors discussed in the pathogenesis of neurodegeneration. In conclusion, although many in vivo and in vitro data are in favor of apoptosis involvement in neurodegenerative processes, there is considerable evidence that very complex events may contribute to neuronal death with possible repair mechanisms, the elucidation of which may prove useful for future prevention and therapy of neurodegenerative disorders. [source] The mitochondrial uncoupler 2,4-dinitrophenol attenuates tissue damage and improves mitochondrial homeostasis following transient focal cerebral ischemiaJOURNAL OF NEUROCHEMISTRY, Issue 6 2005Amit S. Korde Abstract Ischemic stroke is caused by acute neuronal degeneration provoked by interruption of cerebral blood flow. Although the mechanisms contributing to ischemic neuronal degeneration are myriad, mitochondrial dysfunction is now recognized as a pivotal event that can lead to either necrotic or apoptotic neuronal death. Lack of suitable ,upstream' targets to prevent loss of mitochondrial homeostasis has, so far, restricted the development of mechanistically based interventions to promote neuronal survival. Here, we show that the uncoupling agent 2,4 dinitrophenol (DNP) reduces infarct volume approximately 40% in a model of focal ischemia,reperfusion injury in the rat brain. The mechanism of protection involves an early decrease in mitochondrial reactive oxygen species formation and calcium uptake leading to improved mitochondrial function and a reduction in the release of cytochrome c into the cytoplasm. The observed effects of DNP were not associated with enhanced cerebral perfusion. These findings indicate that compounds with uncoupling properties may confer neuroprotection through a mechanism involving stabilization of mitochondrial function. [source] Neuroprotective effect of luteolin on amyloid , protein (25,35)-induced toxicity in cultured rat cortical neuronsPHYTOTHERAPY RESEARCH, Issue S1 2010Hao-Yuan Cheng Abstract The present study was carried out to investigate the neuroprotective effect of luteolin on amyloid , (A,) (25,35)-induced neurotoxicity using cultured rat cortical neurons. After exposure of primary cultures of rat cortical cells to 10 ,M A, (25,35) for 48 h, cortical cell cultures exhibited marked apoptotic death. Pretreatment with luteolin (1, 10 ,M) significantly protected cortical cell cultures against A, (25,35)-induced toxicity. Luteolin (1, 10 ,M) showed a concentration-dependent inhibition on 10 ,M A, (25,35)-induced apoptotic neuronal death, as assessed by MTT assay. Furthermore, luteolin reduced apoptotic characteristics by DAPI staining. For Western blot analysis, the results showed that the protective effect of luteolin on A, (25,35)-induced neurotoxicity was mediated by preventing of ERK-p, JNK, JNK-p, P38-p and caspase 3 activations in rat primary cortical cultures. Taken together, the results suggest that luteolin prevents A, (25,35)-induced apoptotic neuronal death through inhibiting the protein level of JNK, ERK and p38 MAP kinases and caspase 3 activations. Copyright © 2009 John Wiley & Sons, Ltd. [source] | |||||||||||||