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)

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.
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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.
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PMID:Dynamic changes in dopaminergic neurotransmission induced by a low concentration of bisphenol-A in neurones and astrocytes. 1668 33

Perinatal hypoxic-ischemic brain damage is a major cause of neuronal and behavior deficits, in which the onset of injury can be before, at or after birth, and the effects may be delayed. Pontosubicular neuron necrosis (PSN) is one of perinatal hypoxic-ischemic brain injury and its pathological peculiarity is neuronal apoptosis. In this study, we investigated whether apoptotic cascade of PSN used a caspase-pathway or not, and whether hypoglycemia activated apoptosis or not. Sections of the pons of PSN with and without hypoglycemia were stained using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) and immunohistochemistry for glial fibrillary acidic protein (GFAP), Bcl-2, Bcl-x and activated caspase 3. Additionally, we performed immunoblot analysis of Bcl-2, Bcl-x and activated caspase 3. TUNEL-positive cell was closely associated with the presence of karyorrhexis. Under combination of karyorrhectic and TUNEL-positive cells, number of apoptotic cells in premature brains was significantly more than in mature brains. Hypoxic-ischemic brain injury was considered to easily lead to apoptosis in premature infants. Moreover, as this pathophysiology, caspase-pathway activation contributed to neuronal death from caspase-immunoexpression analyses. PSN with hypoglycemia showed large number of apoptotic cells and higher expression of activated caspase 3. The result may be more severe with the background of hypoglycemia and prematurity complicated by hypoxia and/or ischemia.
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PMID:A histopathological study of premature and mature infants with pontosubicular neuron necrosis: neuronal cell death in perinatal brain damage. 1671 12

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.
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PMID:Endothelin receptors in light-induced retinal degeneration. 1674 Oct 56

Poorly controlled diabetes mellitus results in structural and functional changes in many brain regions. We demonstrate that in streptozotocin-induced diabetic rats cell death is increased and proliferation decreased in the cerebellum, indicating overall cell loss. Levels of both the proform and cleaved forms of caspases 3, 6 and 9 are increased, with no change in caspases 7, 8 or 12. Colocalization of glial fibrillary acidic protein (GFAP) and cleaved caspase 3 and GFAP in TUNEL-positive cells increased in diabetic rats. Changes in GFAP levels paralleled modifications in proliferating cell nuclear antigen (PCNA), increasing at 1 week of diabetes and decreasing thereafter, and proliferating GFAP-positive cells were decreased in the cerebellum of diabetic rats. These results suggest that astrocytes are dramatically affected in the cerebellum, including an increase in cell death and a decrease in proliferation, and this could play a role in the structural and functional changes in this brain area in diabetes.
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PMID:Activation of the intrinsic cell death pathway, increased apoptosis and modulation of astrocytes in the cerebellum of diabetic rats. 1675 3

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.
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PMID:Selective involvement of BH3-only Bcl-2 family members Bim and Bad in neonatal hypoxia-ischemia. 1678 Aug 16

Clinical observations suggest that certain gut and dietary factors may transiently worsen symptoms in autism spectrum disorders (ASD), epilepsy and some inheritable metabolic disorders. Propionic acid (PPA) is a short chain fatty acid and an important intermediate of cellular metabolism. PPA is also a by-product of a subpopulation of human gut enterobacteria and is a common food preservative. We examined the behavioural, electrophysiological, neuropathological, and biochemical effects of treatment with PPA and related compounds in adult rats. Intraventricular infusions of PPA produced reversible repetitive dystonic behaviours, hyperactivity, turning behaviour, retropulsion, caudate spiking, and the progressive development of limbic kindled seizures, suggesting that this compound has central effects. Biochemical analyses of brain homogenates from PPA treated rats showed an increase in oxidative stress markers (e.g., lipid peroxidation and protein carbonylation) and glutathione S-transferase activity coupled with a decrease in glutathione and glutathione peroxidase activity. Neurohistological examinations of hippocampus and adjacent white matter (external capsule) of PPA treated rats revealed increased reactive astrogliosis (GFAP immunoreactivity) and activated microglia (CD68 immunoreactivity) suggestive of a neuroinflammatory process. This was coupled with a lack of cytotoxicity (cell counts, cleaved caspase 3' immunoreactivity), and an increase in phosphorylated CREB immunoreactivity. We propose that some types of autism may be partial forms of genetically inherited or acquired disorders involving altered PPA metabolism. Thus, intraventricular administration of PPA in rats may provide a means to model some aspects of human ASD in rats.
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PMID:Neurobiological effects of intraventricular propionic acid in rats: possible role of short chain fatty acids on the pathogenesis and characteristics of autism spectrum disorders. 1695 May 24

Recently we showed that the combination between MEOS and EE applied to rats for 7-15 days after traumatic brain injury (TBI) was associated with reduced CNS lesion volume and enhanced reversal of neuromotor dysfunction. In a continuation of this work, we tested whether these effects persisted for longer post-operative periods, e.g. 30 days post-injury (dpi). Rats were subjected to lateral fluid percussion (LFP) or to sham injury. After LFP, one third of the animals (injured and sham) was placed under conditions of standard housing (SH), one third was kept in EE-only, and one third received EE+MEOS. Standardized composite neuroscore (NS) for neurological functions and computerized analysis of the vibrissal motor performance were used to assess post-traumatic neuromotor deficits. These were followed by evaluation of the cortical lesion volume (CLV) after immunostaining for neuron-specific enolase, caspase 3 active, and GFAP. Finally, the volume of cortical lesion containing regeneration-associated proteins (CLV-RAP) was determined in sections stained for GAP-43, MAP2, and neuronal class III beta-tubulin. We found (i) no differences in the vibrissal motor performance; (ii) EE+MEOS rats performed significantly better than SH rats in NS; (iii) EE-only and EE+MEOS animals, but not SH rats, showed better recovery at 30 dpi than at 15 dpi; (iv) no differences among all groups in CLV (larger than that at 15 dpi) and CLV-RAP, despite a clear tendency to reduction in the EE-only and EE+MEOS rats. We conclude that EE+MEOS retards, but cannot prevent the increase of lesion volume. This retardation is sufficient for a continuous restoration of neurological functions.
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PMID:Late effects of enriched environment (EE) plus multimodal early onset stimulation (MEOS) after traumatic brain injury in rats: Ongoing improvement of neuromotor function despite sustained volume of the CNS lesion. 1696 73

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.
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PMID:Astrogliosis in EAE spinal cord: derivation from radial glia, and relationships to oligodendroglia. 1700 37

Considering that several pathways leading to cell death are activated in cerebral ischemia, we tested in mouse models of transient and permanent ischemia a drug cocktail aiming at distinct pharmacological targets during the evolution of ischemic injury. It consists of minocycline--an antibiotic with anti-inflammatory properties, riluzole--a glutamate antagonist, and nimodipine--a blocker of voltage-gated calcium channels. Administered 2 h after transient or permanent MCAO, it significantly decreased the size of infarction, by approximately 65% after transient and approximately 35% after permanent ischemia and markedly improve clinical recovery of mice. In both experimental models a three-drug cocktail achieved significantly more efficient neuroprotection than any of the components tested alone. However, some interesting observation emerged from the single-drug studies. Treatment with minocycline alone was efficient in both experimental models while treatment with glutamate antagonist riluzole conferred neuroprotection only after transient MCAO. Immunohistochemical analysis following three-drug treatment revealed reduced microglia/macrophages and caspase-3 activation as well as preserved GFAP immunoreactivity following transient ischemia. No detectable differences in the levels of Mac-2, GFAP and caspase-3 immunoreactivities were observed 72 h after permanent MCAO. These marked differences in the brain tissue responses to ischemic injury and to treatments suggest that different pathological mechanisms may be operating in transient and permanent ischemia. However, the three-drug cocktail exerted significant neuroprotection in both experimental models thus demonstrating that simultaneous targeting of several pathophysiological pathways involved in the evolution of ischemic injury may represent a rational therapeutic strategy for stroke.
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PMID:Differential neuroprotective effects of a minocycline-based drug cocktail in transient and permanent focal cerebral ischemia. 1723 87


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