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)

The present study examined the immunoexpression of the neuronal cytoskeletal proteins, MAP-2 and beta-tubulin within a timed series of rat fetal neocortical transplants. beta-tubulin is a major component of microtubules and MAP-2 regulates the assembly and stability of neuronal microtubules and is a major site for the phosphorylation cAMP dependent protein kinase in neurons. Both proteins are strongly expressed in the soma and dendrites of normal neurons. MAP-2 has been shown to be a sensitive marker for ischemia in neurons and is downregulated in this form of injury. Immunoexpression of both MAP-2 and beta-tubulin in grafted cortical neurons was markedly reduced when compared to age-matched or even perinatal specimens at all post-operative times. Dendritic staining was confined to random, thin processes with no laminar patterns and staining within somata was very weak. In some specimens, somatic expression was increased and dendrites were more robustly stained when a portion of the graft was juxtaposed to a fiber tract even though in other regions of the same graft there was very weak immunostaining. The present results corroborate previous studies of cortical transplants indicating an immature structure and metabolism, and it is suggested here that the primary factor is a sublethal form of ischemic injury. Another possibility for the relative paucity of cytoskeletal protein expression could be that transplanted neurons undergo a new developmental scheme (neodevelopment) that is brought about by truncated migration patterns and abnormal synaptic connections.
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PMID:Diminished expression of microtubule-associated protein (MAP-2) and beta-tubulin as a putative marker for ischemic injury in neocortical transplants. 772 37

The present study examined the immunocytochemical expression of important cytoskeletal proteins within the neurons of an extended series of neocortical grafts and smaller group of ventral mesencephalic (nigral) grafts. Using antibodies that were directed at all three neurofilament (NF) epitopes, NF-L, NF-M, and NF-H, we attempted to determine whether these neurons would have an altered cytoskeletal profile following the stress of transplantation, because previous studies have shown such changes following ischemia or direct brain injury. We studied phosphorylated NF protein, which is found predominantly in axons, nonphosphorylated NF protein, which is found predominantly in the somata-dendritic compartment, and MAP-2, a specific microtubule marker that is localized exclusively in the somato-dendritic compartment. The results show that in all neocortical grafts examined, both phosphorylated and nonphosphorylated NF immunoexpression was significantly downregulated and appeared only in relatively few axons and somatic profiles, respectively, even though there were numerous Nissl-stained neuronal profiles in the grafts. There was no particular pattern to the immunopositive profiles. At later times occasional neuronal profiles were positive for phosphorylated NF protein, suggesting a reaction to cellular injury. In contrast to neocortical grafts, the cytoskeletal profiles of MAP-2 and phosphorylated NF protein in nigral grafts appeared very similar to age-matched control although the nonphosphorylated NF protein expression did appear somewhat lessened at 1-2 mo postoperative. Because cytoskeletal proteins play important roles in neuronal size, shape, and structural stability, they may subserve key cellular issues in neural grafting. These results show a significant loss of cytoskeletal protein expression in neocortical grafts that does not occur in nigral grafts. These results suggest that fetal neurons from different brain regions (i.e., graft source) may respond differently to the grafting procedure insofar as their cytoskeletal makeup is concerned. In addition, a potential lack of appropriate growth substrates or synaptic contacts may also produce cytoskeletal alterations. As such, the cytoskeletal protein profiles in central nervous system (CNS) grafts may be useful markers for functional performance, perhaps reflecting a degree of cellular injury.
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PMID:Cytoskeletal protein immunoexpression in fetal neural grafts: distribution of phosphorylated and nonphosphorylated neurofilament protein and microtubule-associated protein 2 (MAP-2). 868 34

Following 5 min in vitro ischemia, total protein synthesis is dramatically and persistently inhibited in neurons in the rat hippocampal slice. This model system was used to explore the responses of individual proteins to this irreversible insult. In vitro ischemia inhibited new protein synthesis of most proteins analyzed; however, the synthesis of a 68/70 kDa protein was substantially stimulated for the first hour after ischemia. By 3 hr postischemia, its synthesis rates were depressed to 60% of control rates. Although the total amounts of most proteins were not significantly depleted for the first few hours after ail ischemic episode, there were several notable exceptions. The levels of HSC73, a constitutively expressed member of the 70 kDa stress protein family, were reduced after in vitro ischemia. In addition, MAP-2 (microtubule-associated protein-2) and alpha-tubulin were depleted in the early hours after the insult, with MAP-2 exhibiting a detectable depletion earlier than tubulin. In contrast, the levels and distribution of a 68 kDa neurofilament protein localized to CA3 pyramidal neurons in the slice, apparently distinct from the band whose new synthesis was stimulated, were not affected by the 5 min in vitro ischemia insult. Thus, the responses of individual proteins to ischemia varied considerably, These individual responses could play an important role in the damage mechanism that is initiated in response to in vitro ischemia.
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PMID:Time course of protein changes following in vitro ischemia in the rat hippocampal slice. 897 69

Neonatal rats were subjected to transient cerebral hypoxic-ischemia (HI, unilateral occlusion of the common carotid artery +7.70% O2 for 100 min) and allowed to recover for up to 14 days. Calpain caseinolytic activity was found to increase in both hemispheres for at least 20 hr. Hypoxic exposure per se increased the activity of calpains, more pronounced in a membrane-associated fraction, probably through interaction with cellular components, whereas HI introduced a loss of activity, most likely through consumption and loss of proteases. Consecutive tissue sections were stained with antibodies against calpastatin, alpha-fodrin, the 150-kDa breakdown product of alpha-fodrin (FBDP, marker of calpain proteolysis) or microtubule-associated protein 2 (MAP-2, marker of dendrosomatic neuronal injury). Areas with brain injury displayed a distinct loss of MAP-2, which clearly delineated the infarct. FBDP accumulated in injured and borderline regions ipsilaterally, and a less conspicuous, transient increase in FBDP also occurred in the contralateral hemisphere, especially in the white matter. The cytosolic fraction (CF) and the membrane and microsomal fraction (MMF) of cortical tissue were subjected to Western blotting and stained with antibodies against calpain, calpastatin and the 150-kDa breakdown product of alpha-fodrin (FBDP). Calpain immunoreactivity decreased bilaterally in the CF during the insult (62-68% of controls) and remained significantly lower during early recovery, whereas the MMF showed no significant changes. This translocation of calpains coincided with the appearance of FBDP in the ipsilateral, HI hemisphere, displaying a significantly higher level of FBDP from immediately after the insult until at least 1 day of recovery (204-292% of controls). No significant changes in FBDP were found in the contralateral, undamaged hemisphere, despite translocation of calpains in both hemispheres, a prerequisite for calpain activation. This discrepancy may be related to changes in the endogenous inhibitor, calpastatin. Calpastatin protein was found to decrease during and shortly after HI in the ipsilateral, but not the contralateral, hemisphere. The inhibitory activity of calpastatin also tended to decrease after HI, indicating that a reduction of calpastatin may be necessary for extensive calpain activation to occur. The mRNA of m-calpain increased in the HI hemisphere 48 hr after the insult (167%, p < 0.001), a time point when the protein was also increased. In summary, our findings indicate that calpains are activated during HI and in the early phase of reperfusion after HI, preceding neuronal death.
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PMID:The calpain proteolytic system in neonatal hypoxic-ischemia. 936 79

The temporal pattern of protein synthesis inhibition was examined in grafted neocortical neurons using [(3)H]valine in vivo autoradiography. Neuronal uptake levels of systemically administered (3)H-labeled amino acids which cross the blood-brain barrier (BBB) via endothelial cell neutral carriers have long been a hallmark in studies of experimental ischemic pathology; there is likely a strong correlation between persistent protein synthesis inhibition and the progression of cell damage. Because the grafting procedure involves the loss of blood flow and the subsequent reperfusion of the donor tissue there are, mechanistically, important similarities to reversible ischemia models. The effects of ischemic injury on grafted CNS neurons are not fully understood. Quantitative analysis of grain distribution in individual graft or control (adjacent host cortex) neurons indicated an initial breakdown of the amino acid barrier system, subsequent recovery, and progressive reduction of amino acid uptake by 1 year. Up to 3 weeks after surgery grafts were flooded with the [(3)H]valine tracer but individual neurons contained relatively few silver grains. After this time, the tracer was normally distributed within graft neurons but at significantly lower levels than in controls. Grain density gradually decreased over time such that 12-month grafted neurons had approximately half that compared to control and only 58% of that in 2-month grafts; the 12-month levels were comparable to those observed at early (10 days) postoperative times. Autoradiography of immunostained sections for MAP-2, SMI 311 (neurofilament marker), and neuron-specific enolase showed reduced expression of these proteins in neurons coupled with weak amino acid tracer uptake. The results further suggest that grafted neurons bear intriguing similarities to neurons placed at ischemic risk, particularly "penumbral" neurons, which are affected by reduced blood flow and are metabolically weakened. The loss of BBB properties in early grafts may also extend to the endothelial cell amino acid carrier system, and the delayed revascularization process could affect neuronal uptake mechanisms.
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PMID:Protein synthesis inhibition in neocortical grafts evaluated by systemic amino acid uptake autoradiography. 1073 33

Previous studies have shown a reduction of dopaminergic D(2) receptors (D(2)R) in the striatum after hypoxia-ischemia in newborn rats. We show here an early and transient reduction of mRNA D(2)R in nonatrophic brains following hypoxia-ischemia. The left carotid artery of P7 rats was ligated followed by hypoxia for 2 h. The rats were sacrificed after 24 h, 48 h and 14 days. D(2)R mRNA was studied by in situ hybridization, the cell number by conventional histology, and neuronal and astrocyte differentiation by immunohistochemistry. A 20% reduction of striatal mRNA D(2)R occurred 24 h after hypoxia-ischemia, whereas no reduction was observed after 48 h and 14 days. There were no differences in total cell number and in the expression of neuronal (MAP-1, MAP-2) and astrocyte (GFAP) markers between both brain hemispheres nor between control and hypoxia-ischemia animals. The early decrease in mRNA D(2)R could explain the delayed reduced D(2)R after neonatal hypoxia-ischemia.
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PMID:mRNA D(2) dopaminergic receptor expression after hypoxia-ischemia in rat immature brain. 1147 53

Following 5 or 10 min of global ischemia in the adult gerbil there is a tenfold increase in the birth of new cells in the subgranular zone of dentate gyrus of the hippocampus as assessed using BrdU incorporation. This begins at 7 days, peaks at 11 days, and decreases thereafter. Over the next month approximately 25% of the newborn cells disappear. Of the remaining cells, 60% migrate into the granule cell layer where two-thirds become NeuN, calbindin and MAP-2 immunostained neurons. The remaining 40% of the cells migrate into the dentate hilus where 25% of these become GFAP labeled astrocytes. It is proposed that ischemia-induced neurogenesis contributes to the recovery of function, and specifically may serve to improve anterograde and retrograde recent memory function that is lost following global ischemia in animals and man.
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PMID:Neurogenesis following brain ischemia. 1194 34

Previous studies have demonstrated that sublethal ischemic insults protect from subsequent ischemia in the intact brain. There are two windows for the induction of tolerance by ischemic preconditioning (IPC). One occurs within 1 h following IPC, and the other one develops from 1 to 3 days after IPC. The goal of this study was to determine whether IPC neuroprotection may be mediated by expression of known neuroprotective genes and to characterize the temporal and spatial expression patterns of these genes. IPC was produced by bilateral carotid artery occlusions and hypotension (50 mmHg) for 2 min. After various survival times, the expression of MAP-2, brain-derived neurotrophic factor (BDNF), c-jun, c-fos, nerve growth factor (NGF) and HSP70 was assessed by in situ hybridization of coronal brain sections with 35S labeled probes. BDNF, NGF, and c-jun were significantly upregulated in the hippocampus. c-fos was detected in the hippocampus, cortex and striatum. HSP70 mRNA was induced in the cortex, hippocampus, striatum, and thalamus. MAP-2 showed no change in expression, confirming previous studies that no cell death occurs following IPC. The increase in expression of these stress-related, neurotrophic and immediate early genes in response to a mild preconditioning insult may help mediate the protection of vulnerable neurons to subsequent lethal ischemic insults.
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PMID:Effect of ischemic preconditioning on the expression of putative neuroprotective genes in the rat brain. 1210 96

Stroke is the third leading cause of death in the US, with a prevalence of 750,000 patients per year, and a social cost estimated at $50 billion. Current therapeutics are targeted at restoring blood flow rather than on preventing the actual mechanisms associated with neuronal cell death. Here, we show that, following transient (2 h) middle cerebral artery occlusion (tMCAO) in male, Wistar rats, neuronal damage determined using MAP-2 staining increased progressively after the tMCAO. Notably, such neuronal degeneration was first associated with a decrease in p-Akt in both the focus and penumbra of the infarct region and, later with an increase in cytosolic cytochrome C levels in cortical neurons in the infarct area. These findings implicate that Akt alterations and consequent release of cytochrome C are involved in neuronal death. To further address this issue, NXY-059 (disodium 4-[(tert.-butylimino)methyl]benzene-1,3-disulfonate N-oxide) administered i.v. (30 mg/kg bolus, followed by 30 mg/kg/h infusion for up to 24 h), commencing 1 h after reperfusion, not only prevented the increase in infarct area but also attenuated the postreperfusion increase in neuronal cytosolic cytochrome C and the postperfusion decrease in neuronal p-Akt. Thus, NXY-059, by preventing mitochondrial cytochrome C release by maintaining activation of the Akt pathway, appears to protect neurons from damage after ischemia.
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PMID:NXY-059 maintains Akt activation and inhibits release of cytochrome C after focal cerebral ischemia. 1217 60

Apoptosis-inducing factor (AIF) triggers apoptosis in a caspase-independent manner. Here we report for the first time involvement of AIF in neuronal death induced by cerebral ischemia. Unilateral cerebral hypoxia-ischemia (HI) was induced in 7-day-old rats by ligation of the left carotid artery and hypoxia (7.7% O2) for 55 min. AIF release from mitochondria and AIF translocation to nuclei was detected immediately after HI, and only in damaged areas, as judged by the concurrent loss of MAP-2. AIF release was detected earlier than that of cytochrome c. Cells with AIF-positive nuclei displayed nuclear condensation and signs of DNA damage. The number of AIF-positive nuclei showed a positive correlation with the infarct volume 72 h post-HI, and this was not changed by treating the animals with boc-Asp-fmk (BAF), a multicaspase inhibitor. BAF treatment reduced the activity of caspase-3, -2 and -9 (78, 73 and 33%, respectively), and prevented caspase-dependent fodrin cleavage in vivo, but did not affect AIF release from mitochondria or the frequency of positive nuclear AIF or DNA damage 72 h post-HI, indicating that these processes occurred in a caspase-independent fashion. In summary, AIF-mediated cell death may be an important mechanism of HI-induced neuronal loss in the immature brain.
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PMID:Involvement of apoptosis-inducing factor in neuronal death after hypoxia-ischemia in the neonatal rat brain. 1287 72


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