Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We attempted to ascertain the neuroprotective effects and mechanisms of minocycline in inflammatory-mediated neurotoxicity using primary neuron/glia co-cultures treated with lipopolysaccharide (LPS). Neuronal cell death was induced by treatment with LPS for 48 h, and the cell damage was assessed using lactate dehydrogenase (LDH) assays and by counting microtubule-associated protein-2 (MAP-2) positive cells. Through terminal transferase deoxyuridine triphosphate-biotin nick end labeling (TUNEL)-staining and by measuring caspase-3 activity, we found that LPS-induced neuronal cell death was mediated by apoptosis. We determined that pre-treatment with minocycline significantly inhibited LPS-induced neuronal cell death. In addition, LPS induced inducible nitric oxide synthase (iNOS) expression significantly, resulting in nitric oxide (NO) production within glial cells, but not in neurons. Both nitric oxide synthase (NOS) inhibitors (N(G)-monomethyl-L-arginine monoacetate (L-NMMA) and S-methylisothiourea sulfate (SMT)) and minocycline inhibited iNOS expression and NO release, and increased neuronal survival in neuron/glia co-cultures. Pre-treatment with minocycline significantly inhibited the rapid and extensive production of tumor necrosis factor-alpha (TNF-alpha) mediated by LPS in glial cells. We also determined that the signaling cascade of LPS-mediated iNOS induction and NO production was mediated by TNF-alpha by using neutralizing antibodies to TNF-alpha. Consequently, our results show that the neuroprotective effect of minocycline is associated with inhibition of iNOS induction and NO production in glial cells, which is mediated by the LPS-induced production of TNF-alpha.
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PMID:Minocycline inhibits apoptotic cell death via attenuation of TNF-alpha expression following iNOS/NO induction by lipopolysaccharide in neuron/glia co-cultures. 1548 88

Neuronal loss has been observed in post mortem brains of patients with human immunodeficiency virus type 1 (HIV-1). Experimental evidence has implicated HIV-1-derived envelope glycoprotein 120 (gp120) in the neuronal cell death observed in these patients. However, the intrinsic mechanisms by which gp120 causes neurotoxicity are still unknown. We have recently shown that the neurotoxic effect of gp120 in vitro is reduced by brain-derived neurotrophic factor (BDNF). We therefore tested the hypothesis that low levels of BDNF render neurons more sensitive to gp120. Gp120 was injected acutely into the striatum of BDNF heterozygous mice and wild-type littermates. BDNF heterozygous mice exhibited more apoptotic neurons in the striatum than wild-type mice, suggesting that BDNF is neuroprotective also in vivo. Because several neurodegenerative disorders are characterized by lack of trophic support, we tested the hypothesis that gp120 may cause apoptosis by reducing BDNF expression. Gp120 was injected acutely in the rat striatum and BDNF levels determined by a two-site immunoassay at various times after the injection. Gp120 elicited a dramatic decrease in BDNF protein levels by 24 h. Reduced BDNF levels were still present at 4 days. Cellular localization of BDNF immunoreactivity revealed that gp120 decreases BDNF immunoreactivity mainly in neuronal processes. This effect of gp120 precedes the peak of caspase-3 activation and neuronal cell death. We propose that one of the mechanisms whereby gp120 causes neurotoxicity is a reduction of the neurotrophic factor environment crucial for cell survival.
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PMID:Human immunodeficiency virus type 1 glycoprotein gp120 reduces the levels of brain-derived neurotrophic factor in vivo: potential implication for neuronal cell death. 1557 39

Intestinal inflammatory conditions are associated with structural and functional alterations of the enteric nervous system (ENS). While injury to the enteric nervous system is well described, the mechanisms of neuronal injury and neuronal cell loss remain unclear. The aim of the present study was to examine the neural consequences of distal colitis and to assess the role of neutrophil granulocytes in mediating these changes. Colitis was induced in C3H/HEN female mice with dinitrobenzene sulfonic acid. The mice were then sacrificed at 0.5, 1, 1.5, 2, 3, 4, 6, 12, 24, 120 h post instillation of dinitrobenzene sulfonic acid. The inflammatory response was assessed by macroscopic damage score, myeloperoxidase activity and histology. HuC/D and PGP 9.5 immunostaining was used to examine myenteric plexus density and structure, neural cell body numbers and distribution in cross-section and whole mount preparations. Apoptosis was investigated in whole mount preparations double stained with HuC/D and activated caspase-3 or cleaved poly (ADP-ribose) polymerase (PARP). Dinitrobenzene sulfonic acid-induced colitis was associated with a rapid and significant loss of HuC/D immunoreactive myenteric plexus neuronal cell bodies (42% decrease relative to control) that remained unchanged between 6 and 120 h. No change in myenteric plexus density was observed with PGP 9.5 immunostaining. Neuronal apoptosis was evident between 0.5 and 3 h. PARP immunoreactive neurons ranged between 1% and 2.5%. Colitis was associated with significant impairment in colonic propulsive function. Pre-treatment of mice with anti-neutrophil serum attenuated the inflammatory response and partially reduced the extent of myenteric plexus neuronal cell loss. Taken together, these data suggest that acute colitis is associated with loss of myenteric plexus neurons that is partly mediated by neutrophil granulocyte infiltration and is accompanied by impairment of colonic motility.
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PMID:Myenteric plexus injury and apoptosis in experimental colitis. 1562 May 69

The relationships between astrocytic apoptosis and both senile plaques and neurofibrillary tangles (NFT) in gray matter lesions were examined quantitatively in Alzheimer's disease (AD) brains. Seven cortical regions were examined in seven AD brains by terminal dUTP nick end-labeling and immunolabeling with antibodies to glial fibrillary acidic protein, phosphorylated tau protein (AT180), apoptosis-related proteins (caspase-3, bcl-2, and CD95), and beta amyloid protein. Senile plaques showed the lowest density in the cornu ammonis. The density of apoptotic astrocytes was significantly correlated with the density of uncored and cored senile plaques. Neuronal caspase-3 and CD95 expression levels were too low to allow statistical assessment, but Bcl-2 was expressed strongly in the astrocytes and neurons with and without NFT. The correlation of the density of apoptotic astrocytes with apoptotic neurons and NFT was not statistically significant. The density of Bcl2-positive neurons correlated significantly with those of NFT and cored senile plaques, but Bcl2-positive astrocyte density showed no correlation with density of senile plaques or apoptotic astrocytes. These observations suggest that senile plaques may be a cause of astrocytic apoptosis in the gray matter, and that Bcl-2 protein is associated with NFT formation.
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PMID:Correlation between astrocyte apoptosis and Alzheimer changes in gray matter lesions in Alzheimer's disease. 1566 2

Oxygen free radicals and nitric oxide (NO) participate in the pathogenesis of acute central nervous system (CNS) injury by forming peroxynitrite, which promotes oxidative damage and tyrosine nitration. Neuronal nitration is associated with cell death, but little is known of the characteristics and cell fate of nitrated astrocytes. In this study, we have used a postnatal excitotoxic lesion model (intracortical NMDA injection) and our aims were (i) to evaluate the temporal and spatial pattern of astroglial nitration in correlation with the neuropathological process and the sources of NO; and (ii) to establish, if any, the correlation among astrocyte nitration and other events such as expression of cytoskeletal proteins, antioxidant enzymes, and cell death markers to cope with nitration and/or undergo cell death. Our results show that after postnatal excitotoxic damage two distinct waves of nitration were observed in relation to astrocytes. At 24 h post-lesion, early-nitrated astrocytes were found within the neurodegenerating area, coinciding with the time of maximal cell death. These early-nitrated astrocytes are highly ramified protoplasmic cells, showing diffuse glial fibrillary acidic protein (GFAP) content and expressing inducible NOS. At later time-points, when astrogliosis is morphologically evident, nitrated hypertrophied reactive astrocytes are observed in the penumbra and the neurodegenerated area, displaying increased expression of GFAP and vimentin cytoskeletal proteins and of metallothionein I-II and Cu/Zn superoxide dismutase antioxidant proteins. Moreover, despite revealing activated caspase-3, they do not show TUNEL labeling. In summary, we show that nitrated astrocytes in vivo constitute a subpopulation of highly reactive astrocytes which display high resistance towards oxidative stress induced cell death.
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PMID:Astroglial nitration after postnatal excitotoxic damage: correlation with nitric oxide sources, cytoskeletal, apoptotic and antioxidant proteins. 1566 12

Cerebellar development is fully dependent on thyroid hormone (T3) levels. We have previously demonstrated a glia-mediated effect of T3 on cerebellar neurons. We have reported that cerebellar astrocytes treated with thyroid hormone secrete epidermal growth factor (EGF), which directly induces neuronal proliferation and, indirectly, by increasing synthesis of extracellular matrix proteins, induces neurite outgrowth in vitro. Here, by using a neuron-astrocyte coculture model, we investigated the involvement of cell contact on neuronal proliferation. Culturing of cerebellar neurons on T3-treated astrocyte carpets or conditioned medium derived from them (T3CM) yielded similar results, revealed by a 60% increase in cell population. However, the absolute number of neurons in coculture assays was greatly enhanced in comparison with that in CM assays (3.5-4-fold). Bromodeoxyuridine (BrdU) incorporation assays revealed that such an increase was due mainly to proliferation of precursors cells. BrdU incorporation was three times higher in cell carpet (31%) than in CM (13%). Treatment of astrocytes by T3 increased neuronal proliferation either by T3CM (2.5 times) or by contact with T3-treated astrocytes (1.5 times). Neuronal death was not affected by T3 treatment of astrocytes as revealed by either trypan blue viability assays or active caspase-3 labeling. Treatment of astrocytes by EGF mimicked T3 effects on neuronal proliferation. Addition of the EGF receptor tyrosine kinase inhibitor genistein and the protein kinase A (PKA) inhibitor KT5720 to cocultutres and T3CM completely reversed neuronal proliferation. Our results implicate EGF and the PKA pathway in the proliferation induced by T3-treated astrocytes. Furthermore, the fact that cocultures potentiate the effect of T3 on neuronal proliferation suggests that neuron-astrocyte contact may cooperate with astrocyte soluble factors to enhance neuronal population. Our data reveal an important role of astrocytes as mediators of T3-induced cerebellar development and partially elucidate the role of cell contact and soluble factors on this process.
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PMID:Proliferation of cerebellar neurons induced by astrocytes treated with thyroid hormone is mediated by a cooperation between cell contact and soluble factors and involves the epidermal growth factor-protein kinase a pathway. 1578 7

In this study we investigated the mechanisms of neuronal cell death induced by lipoteichoic acid (LTA) and muramyl dipeptide (MDP) from Gram-positive bacterial cell walls using primary cultures of rat cerebellum granule cells (CGCs) and rat cortical glial cells (astrocytes and microglia). LTA (+/- MDP) from Staphylococcus aureus induced a strong inflammatory response of both types of glial cells (release of interleukin-1beta, tumour necrosis factor-alpha and nitric oxide). The death of CGCs was caused by activated glia because in the absence of glia (treatment with 7.5 microm cytosine-d-arabinoside to inhibit non-neuronal cell proliferation) LTA + MDP did not cause significant cell death (less than 20%). In addition, staining with rhodamine-labelled LTA confirmed that LTA was bound only to microglia and astrocytes (not neurones). Neuronal cell death induced by LTA (+/- MDP)-activated glia was partially blocked by an inducible nitric oxide synthase inhibitor (1400 W; 100 microm), and completely blocked by a superoxide dismutase mimetic [manganese (III) tetrakis (4-benzoic acid)porphyrin chloride; 50 microm] and a peroxynitrite scavenger [5,10,15,20-tetrakis (4-sulfonatophenyl) porphyrinato iron (III); 100 microm] suggesting that nitric oxide and peroxynitrite contributed to LTA-induced cell death. Moreover, neuronal cell death was inhibited by selective inhibitors of caspase-3 (z-DEVD-fmk; 50 microm) and caspase-8 (z-Ile-Glu(O-Me)-Thr-Asp(O-Me) fluoromethyl ketone; 50 microm) indicating that they were involved in LTA-induced neuronal cell death.
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PMID:Inflammatory neurodegeneration induced by lipoteichoic acid from Staphylococcus aureus is mediated by glia activation, nitrosative and oxidative stress, and caspase activation. 1614 39

Serum and potassium deprivation-induced neuronal death on the primary culture of rat cerebellar granule neurons is being widely used as an in vitro model of neurodegeneration and neuronal apoptosis. In our experiments, serum and potassium deprivation for 12 h induced neuronal death in approximately 20% of cerebellar granule neurons as demonstrated by Trypan Blue assay. Neuronal death was accompanied by a transient increase in the intralysosomal cathepsin L activity, which preceded neuronal death. During this time, the lysosomal membrane integrity remained preserved and no leakage of cathepsin L into the cytosol was seen. Ultrastructural analysis revealed the appearance of multiple vacuoles and autophagosomes in the cytoplasmatic compartment of serum- and potassium-deprived granule neurons. Addition of selective cathepsin L inhibitors or of the autophagy inhibitor 3-methyladenine provided partial protection against serum and potassium deprivation-induced death. Our data also show that combining cathepsin L inhibitors and caspase-3 inhibitors leads to a synergistic neuroprotective effect against serum and potassium deprivation. The results of the current study suggest that activation of the autophagosomal--lysosomal compartment plays an important role in neuronal death induced by serum and potassium deprivation in cultured cerebellar granule cells.
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PMID:Up-regulation of lysosomal cathepsin L and autophagy during neuronal death induced by reduced serum and potassium. 1617 44

In traditional Chinese medicine, Ligusticum wallichii Franchat (Chuan Xiong) and its active ingredient tetramethylpyrazine (TMP) have been used to treat cardiovascular diseases and to relieve various neurological symptoms such as ischemic deficits. However, scientific evidence related to their effectiveness or precise modes of neuroprotective action is largely unclear. In the current study, we elicited the neuroprotective mechanisms of TMP after focal cerebral ischemic/reperfusion (I/R) by common carotid arteries and middle cerebral artery occlusion model in rats. TMP was administrated 60 min before occlusion via intraperitoneal injection. TMP concentration-dependently exhibited significant neuroprotective effect against ischemic deficits by reduction of behavioral disturbance. Neuronal loss and brain infarction in the ischemic side of rats were markedly lowered by treatment with TMP. Cerebral I/R-induced internucleosomal DNA fragmentation, caspase-8, caspase-9, and caspase-3 activation, and cytochrome c release were reduced by TMP treatment. Western blot analysis revealed the down-regulation of Bcl-2 and Bcl-xL and the up-regulation of Bax and Bad by cerebral I/R insult. Among them, only the alteration in Bcl-xL expression was reversed by TMP treatment. Moreover, the activation of microglia and/or recruitment of inflammatory cells within the ischemic side and the consequent production of monocyte chemoattractant protein 1 (MCP-1) were suppressed by TMP pre-treatment. Our findings suggest that TMP might provide neuroprotection against ischemic brain injury, in part, through suppression of inflammatory reaction, reduction of neuronal apoptosis, and prevention of neuronal loss.
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PMID:Neuroprotection by tetramethylpyrazine against ischemic brain injury in rats. 1631 8

The aim of our study is to evaluate the extent and distribution of grey matter demyelinating lesions in multiple sclerosis (MS), addressing also neuronal loss and synaptic loss. Whole coronal sections of 6 MS brains and 6 control brains were selected. Immunohistochemistry was performed for myelin basic protein, neurofilaments, synaptophysin, ubiquitin, and activated caspase-3. Neuronal density and optical density of synaptophysin staining were estimated in cortical lesions and compared with those observed in corresponding areas of normal (i.e. nondemyelinated) cortex in the same section. Demyelinating lesions were observed in the cerebral cortex, in the thalamus, basal ganglia, and in the hippocampus. The percentage of demyelinated cortex was remarkable in 2 cases of secondary progressive MS (48% and 25.5%, respectively). Neuronal density was significantly reduced in cortical lesions (18-23% reduction), if compared with adjacent normal cortex, in the 2 cases showing the higher extent of cortical demyelination; in the same cases, very rare apoptotic neurons expressing caspase-3 were observed in cortical lesions and not in adjacent normal cortex. No significant decrease in optical density of synaptophysin staining was observed in cortical lesions. Grey matter demyelination and neuronal loss could contribute to disability and cognitive dysfunctions in MS.
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PMID:Grey matter pathology in multiple sclerosis. 1631 20


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