Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present study, we evaluated the time-course of caspase-3 activation, and the evolution of cell death following focal cerebral ischemia produced by transient middle cerebral artery occlusion in rats. Ischemia-induced active caspase-3 immunoreactivity in the striatum but not the cortex at 3 and 6 h time points post-reperfusion. Furthermore, using a novel approach to visualize enzymatic activity, deltaC-APP, a C-terminal cleavage product of APP generated by caspase-3, was found to immunolocalize to the same areas as active caspase-3. Double-labeling studies demonstrated co-localization of these two proteins at the cellular level. Further double-labeling experiments revealed that active caspase-3 was confined to neuronal cells which were still viable and thus immunoreactive for NeuN. DNA fragmentation, assessed histologically by terminal dUTP nick-end labeling (TUNEL), was observed in a small number of cells in the striatum as early as 3 h, but only began to appear in the cortex by 6 h. DNA fragmentation was progressive, and by 24 h post-reperfusion, large portions of both the striatum and cortex showed TUNEL positive cells. However, double-labeling of active caspase-3 with TUNEL showed only minimal co-localization at all time-points. Thus, caspase-3 activation is an event that appears to occur prior to DNA fragmentation. As a confirmation of the histological TUNEL data, 24 h ischemia also induced the generation of nucleosome fragments, evidenced by cell death enzyme-linked immunosorbent assay. Using a novel ischemia-induced substrate cleavage biochemical approach, spectrin P120 fragment, a caspase-specific cleavage product of alpha II spectrin, a cytoskeletal protein, was shown to be elevated by western blotting. Brain concentrations of both nucleosomes and spectrin P120 correlate with the degree of injury previously assessed by triphenyltetrazolium chloride staining and infarct volume calculation. Together, our findings suggest a possible association between caspase-3 activation and ischemic cell death following middle cerebral artery occlusion brain injury.
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PMID:Immunohistochemical and biochemical assessment of caspase-3 activation and DNA fragmentation following transient focal ischemia in the rat. 1240 27

A review is given summarizing different methods that have been applied to the specific forensic neuropathological question of brain hypoxia/ischemia. On the microscopic level the authors applied routine stains and immunohistochemistry (MAP2, ALZ 50, GFAP, CD68, beta-APP) for characterization of the functional activity of neurons as well as of different cell types in various brain areas. Moreover, using molecular techniques for evaluation of the mitochondrial 4977-bp deletion in correlation to hypoxia and to age brain tissue and single cell analyses are described. The demonstrated scope of methods and results give evidence of the wide spectrum of possibilities to visualize hypoxic brain injuries for determining the cause (and matter) of death and for reconstructing the time-dependent process.
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PMID:Methodical approach to brain hypoxia/ischemia as a fundamental problem in forensic neuropathology. 1460 62

Focal cerebral ischemia activates the nuclear protein poly(ADP-ribose) polymerase (PARP). Apoptosis-inducing factor (AIF) is a flavoprotein that is normally confined to the mitochondria, but translocates to the nucleus, as shown by in vitro models of neuronal injury. Using INO-1001, a novel potent inhibitor of PARP, we determined the role of PARP activation in the process of AIF translocation in a rat model of focal cerebral ischemia. The potency of INO-1001 as a PARP inhibitor and its cytoprotective potential in oxidant-challenged human neuronal SK-N-MC cells was first confirmed in vitro. PARP inhibition markedly reduced infarct size and improved neurological status in both transient and permanent models of MCA occlusion in Sprague-Dawley rats, with a therapeutic window of 6 h and 2 h in the transient and permanent ischemia models, respectively. The PARP inhibitor reduced the accumulation of poly(ADP-ribose) in the ischemic/reperfused hemisphere and reduced the accumulation of APP in the white matter of the affected hemisphere, consistently with protection against neuronal necrosis and axonal damage, respectively. Immunohistochemical analysis showed the appearance of AIF labeling in neuronal nuclei of the border zone ischemic area in the striatum after stroke. Cytoplasmatic (axonal) AIF staining was significantly diminished in the necrotic core of the striatum, while it was somewhat enhanced at the borderline ischemic territories of the white matter. Inhibition of PARP with INO-1001 reshifted the location of the apoptotic marker to the axons in the ipsilateral striatum. Thus, PARP inhibition is neuroprotective and regulates the ischemic nuclear translocation of AIF in stroke.
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PMID:Poly(ADP-ribose) polymerase inhibition protect neurons and the white matter and regulates the translocation of apoptosis-inducing factor in stroke. 1476 66

Huperzine A (HupA), isolated from Chinese herb Huperzia serrata, is a potent, highly specific and reversible inhibitor of acetylcholinesterase. It has been found to reverse or attenuate cognitive deficits in a broad range of animal models. Clinical trials in China have demonstrated that HupA significantly relieves memory deficits in aged subjects, patients with benign senescent forgetfulness, Alzheimer's disease (AD) and vascular dementia (VD), with minimal peripheral cholinergic side effects compared with other AChEIs in use. HupA possesses the ability to protect cells against hydrogen peroxide, beta-amyloid protein (or peptide), glutamate, ischemia and staurosporine-induced cytotoxicity and apoptosis. These protective effects are related to its ability to attenuate oxidative stress, regulate the expression of apoptotic proteins Bcl-2, Bax, P53 and caspase-3, protect mitochondria, and interfere with APP metabolism. Antagonizing effects on NMDA receptors and potassium currents may contribute to the neuroprotection as well. It is also possible that the non-catalytic function of AChE is involved in neuroprotective effects of HupA. The therapeutic effects of HupA on AD or VD are probably exerted via a multi-target mechanism.
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PMID:Neuroprotective effects of huperzine A. A natural cholinesterase inhibitor for the treatment of Alzheimer's disease. 1595 16

Proteolytic enzymes constitute around 2% of the human genome and are involved in many stages of cell development from fertilization to death (apoptosis). The identification of many novel proteases from genome-sequencing programs has suggested them as potential new therapeutic targets. In addition, several well-characterized metallopeptidases were recently shown to possess new biological roles in neuroinflammation and neurodegeneration. As a result of these studies, metabolism of the neurotoxic and inflammatory amyloid peptide (Abeta) is considered as a physiologically relevant process with several metallopeptidases being suggested for the role of amyloid-degrading enzymes. These include the neprilysin (NEP) family of metalloproteinases (including its homologue endothelin-converting enzyme), insulin-degrading enzyme, angiotensin-converting enzyme, plasmin, and, possibly, some other enzymes. NEP also has a role in metabolism of sensory and inflammatory neuropeptides such as tachykinins and neurokinins. The existence of natural enzymatic mechanisms for removal of amyloid peptides has extended the therapeutic avenues in Alzheimer's disease (AD) and neurodegeneration. The proteolytic events underlying AD are highly compartmentalized in the cell and formation of amyloid peptide from its precursor molecule APP (amyloid precursor protein) takes place both within intracellular compartments and in the plasma membrane, especially in lipid raft domains. Degradation of amyloid peptide by metallopeptidases can also be both intra- and extracellular depending on the activity of membrane-bound enzymes and their soluble partners. Soluble forms of proteases can be secreted or released from the cell surface through the activity of "sheddases"-another group of proteolytic enzymes involved in key cellular regulatory functions. The activity of proteases involved in amyloid metabolism depends on numerous factors (e.g., genetic, environmental, age), and some conditions (e.g., hypoxia and ischemia) shift the balance of amyloid metabolism toward accumulation of higher concentrations of Abeta. In this regard, regulation of the activity of amyloid-degrading enzymes should be considered as a viable strategy in neuroprotection.
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PMID:New insights into the roles of metalloproteinases in neurodegeneration and neuroprotection. 1767 58

Periventricular leukomalacia (PVL), the major substrate of neurologic deficits in premature infants, is associated with reduced white matter volume. Using immunomarkers of axonal pathology [beta-amyloid precursor protein (beta-APP) and apoptotic marker fractin], we tested the hypothesis that widespread (diffuse) axonal injury occurs in the gliotic white matter beyond the foci of necrosis in PVL, thus contributing to the white matter volume reduction. In a cohort of 17 control cases and 13 PVL cases with lesions of different chronological ages, diffuse axonal damage in PVL was detected by fractin in white matter sites surrounding and distant from acute and organizing foci of necrosis. Using beta-APP, axonal spheroids were detected within necrotic foci in the acute and organizing (subacute) stages, a finding consistent with others. Interestingly, GAP-43 expression was also detected in spheroids in the necrotic foci, suggesting attempts at axonal regeneration. Thirty-one percent of the PVL cases had thalamic damage and 15% neuronal injury in the cerebral cortex overlying PVL. We conclude that diffuse axonal injury, as determined by apoptotic marker fractin, occurs in PVL and that its cause likely includes primary ischemia and trophic degeneration secondary to corticothalamic neuronal damage.
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PMID:Diffuse axonal injury in periventricular leukomalacia as determined by apoptotic marker fractin. 1852 Mar 30

Beta-site APP cleaving enzyme-1 (BACE-1), is a rate-limiting enzyme for beta amyloid production. Beta amyloid induces the production of radical oxygen species and neuronal injury. Oxidative stress plays a key role in various neurological diseases such as ischemia and Alzheimer's disease. Recent studies suggest that oxidative stress induces BACE-1 protein upregulation in neuronal cells. Here, we demonstrate that naturally occurring compounds (-)-epigallocatechin-3-gallate and curcumin suppress beta amyloid-induced BACE-1 upregulation. Exposure of beta amyloid 1-42 to neuronal culture increased BACE-1 protein levels. (-)-Epigallocatechin-3-gallate or curcumin significantly attenuated beta amyloid-induced radical oxygen species production and beta-sheet structure formation. These two compounds have novel pharmacological effects that may be beneficial for Alzheimer's disease treatment.
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PMID:Epigallocatechin-3-gallate and curcumin suppress amyloid beta-induced beta-site APP cleaving enzyme-1 upregulation. 1869 18

In this study, we tested if caspase-3 inhibition decreased ischemia-induced Abeta elevation by reducing beta-secretase (BACE1) activity. Changes in caspase-3, Abeta and BACE1 levels were detected in rat striatum on different days after middle cerebral artery occlusion using immunostaining. We found that the positive labeled cells of activated caspase-3, Abeta, and BACE1 were significantly and time-dependently increased in the ipsilateral striatum. The results of Western blotting and RT-PCR showed that caspase-3 inhibitor Z-DEVD-FMK reduced BACE1 mRNA and protein levels, and inhibited its protease activity, thereby decreasing the amount of APP C99 and Abeta in ischemic brains. Moreover, Z-DEVD-FMK reduced BACE1 and GFAP double-labeled cells, but not GFAP protein levels or GFAP-labeled cells, in the ipsilateral striatum. Thus, we demonstrated that caspase-3 inhibition attenuated ischemia-induced Abeta formation by reducing BACE1 production and activity. This finding provides a therapeutic strategy for preventing Abeta accumulation and reducing the risk of neurodegeneration after stroke.
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PMID:Caspase inhibition attenuates accumulation of beta-amyloid by reducing beta-secretase production and activity in rat brains after stroke. 1880 88

Granulocyte colony stimulating factor (G-CSF) is a multi-modal hematopoietic growth factor, which also has profound effects on the diseased CNS. G-CSF has been shown to enhance recovery from neurologic deficits in rodent models of ischemia. G-CSF appears to facilitate neuroplastic changes by both mobilization of bone marrow-derived cells and by its direct actions on CNS cells. The overall objective of the study was to determine if G-CSF administration in a mouse model of Alzheimer's disease (AD) (Tg APP/PS1) would impact hippocampal-dependent learning by modifying the underlying disease pathology. A course of s.c. administration of G-CSF for a period of less than three weeks significantly improved cognitive performance, decreased beta-amyloid deposition in hippocampus and entorhinal cortex and augmented total microglial activity. Additionally, G-CSF reduced systemic inflammation indicated by suppression of the production or activity of major pro-inflammatory cytokines in plasma. Improved cognition in AD mice was associated with increased synaptophysin immunostaining in hippocampal CA1 and CA3 regions and augmented neurogenesis, evidenced by increased numbers of calretinin-expressing cells in dentate gyrus. Given that G-CSF is already utilized clinically to safely stimulate hematopoietic stem cell production, these basic research findings will be readily translated into clinical trials to reverse or forestall the progression of dementia in AD. The primary objective of the present study was to determine whether a short course of G-CSF administration would have an impact on the pathological hallmark of AD, the age-dependent accumulation of A beta deposits, in a transgenic mouse model of AD (APP+ PS1; Tg). A second objective was to determine whether such treatment would impact cognitive performance in a hippocampal-dependent memory paradigm. To explain the G-CSF triggered amyloid reduction and associated reversal of cognitive impairment, several mechanisms of action were explored. (1) G-CSF was hypothesized to increase activation of resident microglia and to increase mobilization of marrow-derived microglia. The effect of G-CSF on microglial activation was examined by quantitative measurements of total microglial burden. To determine if G-CSF increased trafficking of marrow-derived microglia into brain, bone marrow-derived green fluorescent protein-expressing (GFP+) microglia were visualized in the brains of chimeric AD mice. (2) To assess the role of immune-modulation in mediating G-CSF effects, a panel of cytokines was measured in both plasma and brain. (3) To test the hypothesis that reduction of A beta deposits can affect synaptic area, quantitative measurement of synaptophysin immunoreactivity in hippocampal CA1 and CA3 sectors was undertaken. (4) To learn whether enhanced hippocampal neurogenesis was induced by G-CSF treatment, numbers of calretinin-expressing cells were determined in dentate gyrus.
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PMID:Granulocyte colony stimulating factor decreases brain amyloid burden and reverses cognitive impairment in Alzheimer's mice. 1950 Jun 57

Prenatal hypoxia ischemia is a major cause of neurodevelopmental impairment in the newborn, associated with risk for motor, behavioral and cognitive impaired outcomes. We used an established mouse model of maternal hypoxia to examine the immediate molecular responses of signaling pathways associated with both cell death and neurogenesis. We also characterized responses to maternal pre-treatment with MgSO(4). Maternal hypoxia at embryonic day 17 (E17) failed to trigger inflammation or cell death in fetal brain at 24 h after hypoxia. However, maternal hypoxia decreased levels of neuronal migration signaling: Reelin (53% of control), Disabled 1 (Dab1, 77% of control), and amyloid precursor protein (APP, 64% of control) 2 h after the insult. These changes persisted for 24 h. At later times, Reelin levels in hippocampi of newborns in the maternal hypoxia-treated group increased compared to controls. Full protection from maternal hypoxia effects on hippocampal Reelin levels resulted from maternal pre-treatment with MgSO(4). Hypoxia and MgSO(4) increased radial and lateral migration distance in the CA1 four days after the insult, while in the DG the hypoxia treatment alone increased migration. Maternal hypoxia and MgSO(4) pre-treatment also stimulated hippocampal expression of genes related to neurogenesis, such as BDNF and NeuroD4. Taken together, the long-term neurodevelopmental outcome of prenatal and perinatal hypoxia may depend on perturbation of developmental signals that affect neuronal migration.
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PMID:Impaired migration signaling in the hippocampus following prenatal hypoxia. 1963 90


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