Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The beta-carboline norharman is present in cooked food and tobacco smoke and show structural resemblance to the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. C57BL/6 mice were injected subcutaneously with norharman (3 and 10 mg/kg) twice per day for five consecutive days. Eighteen hours after the last dose an increased expression of glial fibrillary acidic protein and fluoro-jade staining were demonstrated whereas the number of tyrosine hydroxylase positive cells were unchanged in the substantia nigra. Two weeks after the last treatment a decreased motor activity was observed whereas cognitive functions remained intact. In cultured PC12 cells norharman treatment induced mitochondrial dysfunction and increased the number of caspase-3 and TUNEL-positive cells. The results demonstrate that norharman induced apoptosis in cultured cells as well as early neurodegeneration, glial activation and sustained motor deficits in mice and suggest that exposure to norharman may contribute to idiopathic Parkinson's disease.
 ...
PMID:Norharman-induced motoric impairment in mice: neurodegeneration and glial activation in substantia nigra. 1607 88

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in young people in industrialized countries. Although various anti-inflammatory and antiapoptotic modalities have shown neuroprotective effects in experimental models of TBI, to date, no specific pharmacological agent aimed at blocking the progression of secondary brain damage has been approved for clinical use. Erythropoietin (Epo) belongs to the cytokine superfamily and has traditionally been viewed as a hematopoiesis-regulating hormone. The newly discovered neuroprotective properties of Epo lead us to investigate its effect in TBI in a mouse model of closed head injury. Recombinant human erythropoietin (rhEpo) was injected at 1 and 24 h after TBI, and the effect on recovery of motor and cognitive functions, tissue inflammation, axonal degeneration, and apoptosis was evaluated up to 14 days. Motor deficits were lower, cognitive function was restored faster, and less apoptotic neurons and caspase-3 expression were found in rhEpo-treated as compared with vehicle-treated animals (P<0.05). Axons at the trauma area in rhEpo-treated mice were relatively well preserved compared with controls (shown by their density; P<0.01). Immunohistochemical analysis revealed a reduced activation of glial cells by staining for GFAP and complement receptor type 3 (CD11b/CD18) in the injured hemisphere of Epo- vs. vehicle-treated animals. We propose that further studies on Epo in TBI should be conducted in order to consider it as a novel therapy for TBI.
 ...
PMID:Erythropoietin is neuroprotective, improves functional recovery, and reduces neuronal apoptosis and inflammation in a rodent model of experimental closed head injury. 1609 48

Several evidences suggest that cell death after cerebral ischemia involves both necrosis and apoptosis. However, it is still unknown which is the relative contribution of both types of cell death. Exposing rat cortical cultures to oxygen-glucose deprivation (OGD), we show the simultaneous presence of necrotic and apoptotic cells. The relative contribution of necrosis and apoptosis was dependent on the duration of the OGD. OGD-mediated apoptotic cell death is caspase-dependent because the addition of a pan-caspase inhibitor specifically blocked the apoptotic component of the OGD-mediated cell death. Moreover, we observed the activation of caspase-3, -7, and -9 after OGD in neurons and microglial cells. No activation of these caspases was observed in GFAP positive cells. Our results also show that calpain is related to OGD-mediated proteolysis of caspase-3 and -9 but not of caspase-7. These data suggest that different pathways could be involved in OGD-mediated caspase activation.
 ...
PMID:Contribution of caspase-mediated apoptosis to the cell death caused by oxygen-glucose deprivation in cortical cell cultures. 1613 64

During pregnancy, infection or immune responses induce cytokine release, which might influence fetal neurodevelopment, leading to neurodegenerative disease in adulthood. Because the hippocampus is a key area for learning and memory, we evaluated 4- and 24-wk-old rats for the effects of early and late prenatal exposure to interleukin-6 (IL-6) on hippocampal morphology, expression of mRNA for IL-6, the gamma-aminobutyric acid receptor (GABA(Aalpha5)), the NR1 subunit of the N-methyl-D-aspartate receptor, and glial fibrillary acidic protein (GFAP), caspase-3 protein and mRNA levels, and learning abilities. Late exposure increased serum IL-6 and hippocampal expression of IL-6 mRNA at 4 and 24 wk. All adult rats showed neuronal loss in the hilus and astrogliosis; males had losses mainly in the CA2 and CA3 regions, and females in CA1. Expression of GABA(Aalpha5), NR1, and GFAP mRNA increased in late-exposed males and females at 4 and 24 wk. mRNA and protein levels of the apoptosis marker caspase-3 were increased in all late-exposed rats except males at 4 wk. Evaluation of hippocampus-dependent working memory in the Morris water maze at 20 wk of age showed increases in escape latency and time spent near the pool wall in all IL-6 adult rats, especially females. These findings suggest that fetal IL-6 exposure, especially in late pregnancy, leads to increased IL-6 levels in the circulation and hippocampus, abnormalities of hippocampal structural and morphology, and decreased learning during adulthood.
 ...
PMID:Prenatal exposure to interleukin-6 results in inflammatory neurodegeneration in hippocampus with NMDA/GABA(A) dysregulation and impaired spatial learning. 1635

Epidemiologic and experimental findings implicate maternal infection in the etiology of injury to brain white matter, which may lead to cerebral palsy in preterm newborns. In the present study, inflammation and brain damage in 1- and 7-d-old rats were investigated after maternal inflammation. Intraperitoneal injection of 300 microg/kg of Escherichia coli lipopolysaccharide was administered to pregnant Wistar rats at d 19 and 20 of gestation (LPS group). Control females received a saline injection. Proinflammatory cytokines IL-1beta, tumor necrosis factor-alpha, and IL-6 expression in the fetal brain were determined by reverse transcription quantitative polymerase chain reaction. Brain injury was examined in 16-mum coronal brain sections by GFAP, MBP, caspase-3 immunohistochemistry, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. Expression of IL-1beta was significantly increased 3 d after maternal administration (P1). A significant increase in cell death occurred at P1 and P7 in specific brain areas, i.e. in the subventricular striatal zone at P1, and in 1) the periventricular striatum, 2) the periventricular white matter, and 3) the germinative ventricular zone at P7. We also observed typical astrogliosis and strong hypomyelination in the external and internal capsule in the LPS group at P7. These results demonstrate that maternal LPS treatment induces persistent fetal inflammatory reactions associated with significant white matter injury in progeny at P1 and P7. This model should be relevant for the study of the pathophysiological mechanisms involved in cerebral white matter damage in preterm human newborns and in the development of therapeutic strategies.
 ...
PMID:Maternal exposure to LPS induces hypomyelination in the internal capsule and programmed cell death in the deep gray matter in newborn rats. 1649 84

Recent studies demonstrate roles for activation of caspases and cleavage of cellular proteins within neurons of the Alzheimer's disease (AD) brain. To determine whether a similar role for caspases also occurs within glial cells in AD, we designed a site-directed caspase-cleavage antibody specific to glial fibrillary acidic protein (GFAP), a cytoskeleton protein specifically expressed in astrocytes. In vitro characterization of this antibody using both a cell-free system and a cell model system of apoptosis demonstrated that the antibody (termed GFAP caspase-cleavage product antibody or GFAP-CCP Ab) immunolabeled the predicted caspase-cleavage fragment, but not full-length GFAP, by Western blot analysis. To determine whether caspases cleave GFAP in vivo, tissue sections from control and AD brains were examined by immunohistochemistry using the GFAP-CCP Ab. Two prominent features of staining were evident: immunolabeling of degenerating astrocytes in proximity to blood vessels and staining within plaque-rich regions of the AD brain. Furthermore, co-localization of the GFAP-CCP Ab and an antibody specific to active caspase-3 was demonstrated within damaged astrocytes of the AD brain. These data suggest that the activation of caspases and cleavage of cellular proteins such as GFAP may contribute to astrocyte injury and damage in the AD brain.
 ...
PMID:Caspase-mediated cleavage of glial fibrillary acidic protein within degenerating astrocytes of the Alzheimer's disease brain. 1650 9

One of the most common chemicals that behaves as an endocrine disruptor is the compound 4,4'-isopronylidenediphenol, called bisphenol-A (BPA). We previously reported that prenatal and postnatal exposure to BPA potentiated central dopaminergic neurotransmission, resulting in supersensitivity to psychostimulant-induced pharmacological actions. Many recent findings have supported the idea that astrocytes, which are a subpopulation of glial cells, play a critical role in neuronal transmission in the central nervous system. The present study aimed to investigate the role of neurone-astrocyte communication in the enhancement of dopaminergic neurotransmission induced by BPA. We found that treatment of mouse purified astrocytes and neurone/glia cocultures with BPA in vitro caused the activation of astrocytes, as detected by a stellate morphology and an increase in levels of glial fibrillary acidic protein. A low concentration of BPA significantly enhanced the Ca2+ responses to dopamine in both neurones and astrocytes. Furthermore, a high concentration of BPA markedly induced the activation of caspase-3, which is a marker of neuronal apoptotic cell death in mouse midbrain neurone/glia cocultures. By contrast, treatment with 17beta-oestradiol (E2) had no such effects. Prenatal and neonatal exposure to BPA led to an enhancement of the dopamine-dependent rewarding effect induced by morphine. These findings provide evidence that BPA alters dopamine responsiveness in neurones and astrocytes and that, at least in part, it may contribute to potentiate the development of psychological dependence on drugs of abuse.
 ...
PMID:Dynamic changes in dopaminergic neurotransmission induced by a low concentration of bisphenol-A in neurones and astrocytes. 1668 33

Excessive light exposure leads to retinal degeneration in albino animals and exacerbates the rate of photoreceptor apoptosis in several retinal diseases. In previous studies we have described the presence of endothelin-1 (ET-1) and its receptors (ET-A and ET-B) in different sites of the mouse retina, including the retinal pigment epithelium, the outer plexiform layer (OPL), astrocytes, the ganglion cell layer (GCL), and vascular endothelia. After light-induced degeneration of photoreceptors, endothelinergic structures disappear from the OPL, but ET-1 and ET-B immunoreactivities increase in astrocytes. Here, we present novel observations about the course of light-induced retinal degeneration in BALB-c mice exposed to 1500 lux during 4 days with or without treatment with tezosentan, a mixed endothelinergic antagonist. Retinal whole mounts were immunostained with anticleaved caspase-3 (CC-3) serum to identify apoptotic photoreceptor cells within the outer nuclear layer (ONL). Glial activation was measured as glial fibrillary acidic protein (GFAP) immunoreactivity in retinal whole mounts and in Western blots from retinal extracts. Tezosentan treatment significantly reduced both the number of CC3-immunoreactive cells and GFAP levels, suggesting that inhibition of endothelinergic receptors could play a role in photoreceptor survival. Using confocal double immunofluorescence, we have observed that ET-A seems to be localized in bipolar cell dendrites, whereas ET-B is localized in horizontal cells. Our observations suggest the existence of an endothelinergic mechanism modulating synaptic transmission in the OPL. This mechanism could perhaps explain the effects of tezosentan treatment on photoreceptor survival.
 ...
PMID:Endothelin receptors in light-induced retinal degeneration. 1674 Oct 56

Perinatal hypoxic-ischemic injury is a common cause of neurologic disability mediated in part by Bcl-2 family-regulated neuronal apoptosis. The Bcl-2 protein family consists of both pro- (e.g. Bax, Bad, Bid, Bim) and anti-apoptotic (e.g. Bcl-2, Bcl-X(L)) proteins that regulate mitochondrial outer membrane integrity, cytochrome c release and caspase activation. Previous studies have implicated Bax as an important mediator of neuronal death in several models of brain injury, including neonatal hypoxia-ischemia (HI). In this study, we assessed the roles of several members of the pro-apoptotic BH3 domain-only Bcl-2 sub-family in an in vivo mouse model of neonatal HI. Seven-day old control and gene-disrupted mice underwent unilateral left carotid ligation followed by 45 min exposure to 8% oxygen and the extent of brain injury was assessed 2 days later. Following HI, mice deficient in Bad or Bim exhibited reduced activated caspase-3 and glial fibrillary acidic protein immunostaining in their brains compared to similarly treated control animals. Measurement of hippocampal area showed decreased parenchymal loss in both Bad- and Bim-deficient mice versus control animals. In contrast, loss of Bid, another BH3-only protein, provided no protection from neonatal HI brain injury. These results indicate that Bad and Bim are selectively involved in neuron death following neonatal HI and may be targets for therapeutic intervention.
 ...
PMID:Selective involvement of BH3-only Bcl-2 family members Bim and Bad in neonatal hypoxia-ischemia. 1678 Aug 16

A prominent feature of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) is the accumulation of enlarged, multipolar glial fibrillary acidic protein (GFAP) and brain lipid binding protein (BLBP) immunoreactive astroglia within and at the margins of the inflammatory demyelinative lesions. Whether this astrogliosis is due to both astroglial hyperplasia and hypertrophy or solely to astroglial hypertrophy is controversial. We now report that coincident with the first appearance of inflammation and clinical deficits in mice with myelin oligodendrocyte glycoprotein peptide (MOG peptide)-induced EAE, the radially oriented, bipolar, GFAP, and BLBP positive cells (adult radial glia) present in normal spinal cord white matter undergo mitosis and phenotypic transformation to hypertrophic astroglia. To facilitate visualization of relationships between these hypertrophic astroglia and dying and regenerating oligodendroglia, we used mice that express enhanced green fluorescent protein (EGFP) in cells of the oligodendroglial lineage. During the first week after onset of illness, markedly swollen EGFP+ cells without processes were seen within lesions, whereas EGFP+ cells that expressed immunoreactive cleaved caspase-3 were uncommon. These observations support the hypothesis that necrosis contributes to oligodendroglial loss early in the course of EAE. Later in the illness, EGFP+ cells accumulated amongst hypertrophic astroglia at the margins of the lesions, while the lesions themselves remained depleted of oligodendroglia, suggesting that migration of oligodendroglial lineage cells into the lesions was retarded by the intense perilesional gliosis.
 ...
PMID:Astrogliosis in EAE spinal cord: derivation from radial glia, and relationships to oligodendroglia. 1700 37


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>