Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Delivery of diagnostic agents to the central nervous system (CNS) poses several challenges as a result of the special features of CNS blood vessels and tissue fluids. Diffusion barriers exist between blood and neural tissue, in the endothelium of parenchymal vessels (blood-brain barrier, BBB), and in the epithelia of the choroid plexuses and arachnoid membrane (blood-CSF barriers), which severely restrict penetration of several diagnostic imaging agents. The anatomy of large vessels can be imaged using bolus injection of X-ray contrast agents to identify sites of malformation or occlusion, and blood flow measured using MRI and CT, while new techniques permit analysis of capillary perfusion and blood volume. Absolute quantities can be derived, although relative measures in different CNS regions may be as useful in diagnosis. Local blood flow, blood volume, and their ratio (mean transit time) can be measured with high speed tomographic imaging using MRI and CT. Intravascular contrast agents for MRI are based on high magnetic susceptibility agents such as gadolinium, dysprosium and iron. Steady-state imaging using agents that cross the BBB including (123)I- and (99m)Tc-labelled lipophilic agents with SPECT, gives a 'snapshot' of perfusion at the time of injection. Cerebral perfusion can also be measured with PET, using H(2)(15)O, (11)C- or (15)O-butanol, and (18)F-fluoromethane, and cerebral blood volume measured with C(15)O. Recent advances in MRI permit the non-invasive 'labelling' of endogenous water protons in flowing blood, with subsequent detection as a measure of blood flow. Imaging the BBB most commonly involves detecting disruptions of the barrier, allowing contrast agents to leak out of the vascular system. Gd-DTPA is useful in imaging leaky vessels as in some cerebral tumors, while the shortening of T(1) by MR contrast agents can be used to detect more subtle changes in BBB permeability to water as in cerebral ischemia. Techniques for imaging the dynamic activity of the brain parenchyma mainly involve PET, using a variety of radiopharmaceuticals to image glucose transport and metabolism, neurotransmitter binding and uptake, protein synthesis and DNA dynamics. PET methods permit detailed analysis of regional function by comparing resting and task-related images, important in improving understanding of both normal and pathological brain function.
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PMID:Delivery of imaging agents into brain. 1083 39

Spontaneous intracerebral hemorrhage (ICH) is the stroke subtype with highest mortality and morbidity. ICH can also occur following traumatic brain injury and thrombolysis for ischemic stroke and myocardial infarction. Development of ICH-induced hemispheric edema can elevate intracranial pressure and cause death. In survivors, edema-related white matter injury can lead to life-long neurological deficits. At present, there are no scientifically proven treatments for ICH. Heme oxygenase products, particularly iron and bilirubin, can be toxic to cells. In cerebral ischemia models, metalloporphyrins that are potent heme oxygenase inhibitors, reduce edema and infarct size. Tin-mesoporphyrin (SnMP) is a neuroprotectant that has also been used clinically to treat hyperbilirubinemia. Presently, we tested the hypothesis that SnMP treatment would reduce edema development following experimental ICH. We produced hematomas in pentobarbital-anesthetized pigs (9-11 kg) by infusing autologous blood into the frontal white matter. To maximize tissue concentrations, SnMP (87.5 microM in DMSO) or DMSO (vehicle controls) was included in the infused blood. Pig brains were frozen in situ at 24 hrs. following ICH and hematoma and edema volumes were determined on coronal sections by computer-assisted image analysis. We also examined the effects of SnMP in vitro on ferritin iron release, the formation of iron-induced thiobarbituric acid reactive substances (TBARS) and initial clot formation and hemolysis. SnMP treatment significantly reduced intracerebral mass following ICH. This was due to significant decreases in hematoma (0.68+/-0.08 vs. 1.39+/-0.30 cc, vehicle controls p<0.025) and edema volumes (edema = 1. 16+/-0.33 vs. 1.77+/-0.31 cc, p<0.05). In vitro, SnMP did not stabilize ferritin iron against reductive release nor did it decrease iron-induced TBARS formation in brain homogenates. SnMP or DMSO added to pig blood did not alter clot weights. In conclusion, SnMP reduced intracerebral mass in an ICH model by decreasing both hematoma and edema volumes SnMP's mechanism of action is presently unknown but may involve its potent inhibition of heme oxygenase activity. SnMP's effect appears unrelated to ferritin iron release, antioxidant activity or initial clot formation. Since SnMP treatment could be brain protective following ICH, further investigations into neurological and neuropathological outcomes and as well as into its mechanism of action are warranted.
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PMID:Tin-mesoporphyrin, a potent heme oxygenase inhibitor, for treatment of intracerebral hemorrhage: in vivo and in vitro studies. 1087 46

Heme oxygenase (HO) cleaves the heme ring to form biliverdin, which is rapidly reduced to bilirubin, carbon monoxide, and iron. HO1, the first form of the enzyme discovered, is an inducible protein, concentrated in tissues that are exposed to degrading red blood cells and stimulated by hemolysis and numerous other toxic perturbations to eliminate potentially toxic heme. By contrast, HO2 is constitutive and most highly concentrated in neural tissues. Carbon monoxide, formed from HO2, is a putative neurotransmitter in the brain and peripheral autonomic nervous system. HO1 regulates the efflux of potentially toxic iron from cells, as iron efflux is deficient in mice with targeted deletion of HO1 (HO1(-/-)), and transfection of HO1 facilitates iron efflux. Bilirubin appears to be a physiologic neuroprotectant. Activation of HO2 by phorbol esters, that stimulate protein kinase C to phosphorylate HO2, augments production of bilirubin which protects brain cultures from oxidative stress. Bilirubin itself in nanomolar concentrations is neuroprotective, while HO2 deletion (HO2(-/-)) leads to increased neurotoxicity in brain cultures and increased neural damage following transient cerebral ischemia in intact mice. Mechanisms whereby HO2 provides neuroprotection have not been clarified including whether protection is primarily associated with apoptotic or necrotic cell death. Moreover, the generality of neurotoxic stimuli influenced by HO2 has been unclear. We now demonstrate increased neuronal death in cerebellar granule cultures of HO2(-/-) mice with a selective augmentation of apoptotic death. We also demonstrate that HO2 transfection rescues apoptotic death. In intact mice, we show an increased incidence of apoptotic morphology in the penumbra area surrounding the infarct core in HO2(-/-) mice undergoing transient focal ischemia.
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PMID:Heme oxygenase-2 acts to prevent neuronal death in brain cultures and following transient cerebral ischemia. 1097 22

The possible persistence of a microvascular deficit at long time intervals after cerebral ischemia induction is not well established. In rats, we have generated in vivo maps of the regional cerebral blood volume (rCBV) at different time intervals after middle cerebral artery occlusion (MCAo) with the aim to evaluate the persistence of a rCBV deficit in the damaged area or in the surrounding regions. The rats were examined by magnetic resonance imaging (MRI) at different time intervals, starting from the first day until three months after ischemia and postmortem histological and ultrastructural correlation was obtained. All MRI experiments were carried out using an imager-spectrometer equipped with a 4.7 Tesla magnet. To produce the susceptibility-weighted rCBV images, a suspension of superparamagnetic iron oxide nanoparticles (AMI-25) was injected to the rat. In a control group (nonoperated or sham-operated rats), a symmetrical distribution of rCBV values was found between the two hemispheres (differences between left and right cortex below 8%). In the rats with MCAo an evident vascular asymmetry was found 24 h after ischemia (differences between left and right ranging from 22 and 77%) and reduced rCBV values were evident in the ischemic areas. In a time range following the 15th day most of the rats showed a complete recovery of the lesion while only four animals still had a small residual lesion, as probed by T2-weighted (T2W) images. In three of these four cases, the reduction of rCBV in the ipsilateral cortex with respect to the contralateral was greater than 20%. Correlation was found (Y > 0.8) between late rCBV measurement and the initial volume of the lesion (hyperintense region in T2W images). The postmortem measurements correlate much better with the rCBV data than with the T2W ones. In conclusion, the present work demonstrates that cortical lesions may result in a deficit of rCBV for long periods and that a mismatch between T2w and rCBV data can be present during the repair process.
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PMID:Regional cerebral blood volume mapping after ischemic lesions. 1098 35

Iron may catalyse the production of reactive oxygen species during post-ischemic reoxygenation and subsequently lead to brain damage. Ferritin, an iron sequestering and storage protein, can also be a source of iron after ischemic insult. However, its role in ischemia-reperfusion has not been carefully investigated. In the present study, we examined the temporal and spatial induction profiles of both H- and L-ferritin messenger RNA and protein in a well-defined focal cerebral ischemia model. Results of northern blot analysis showed a delayed and prolonged induction of both H- and L-ferritin messenger RNA in the ischemic cortex of rats subjected to 60min ischemic insult. A significant induction of both H- and L-ferritin messenger RNA was observed at 12h and remained elevated for up to 336h after the onset of reperfusion. At the peak level, quantitative analysis of the blot indicated a 2.5-fold and a six-fold increase in H- and L-ferritin messenger RNA, respectively, compared with the sham-operated controls. No apparent change in the levels of either messenger RNA was observed in the contralateral side. Results of in situ hybridization studies revealed constitutive expression of both H- and L-ferritin messenger RNA throughout the brain in sham-operated animals, in particular the hippocampus and the piriform cortex. Nevertheless, the signal intensity of H-ferritin messenger RNA was much higher than that of L-ferritin messenger RNA. Seventy-two hours after 60min ischemia, marked expression of H-ferritin messenger RNA was observed in the area surrounding the middle cerebral artery irrigated cortex, the medial part of the caudoputamen and in the subfield of the CA1 hippocampal region of the ipsilateral hemisphere. Similarly, a large induction of L-ferritin messenger RNA was also noted in several areas, including the middle cerebral artery irrigated cortex, the lateral part of the caudoputamen and the stratum pyramidale of the CA1 hippocampal region, which were totally different from areas where H-ferritin messenger RNA was found. At 336h after ischemia, increased expression of H-ferritin messenger RNA was observed in the peri-necrosis and ipsilateral thalamus regions, while L-ferritin messenger RNA was noted exclusively at the edge within the necrosis. Results of immunohistochemical study further revealed that ferritin immunoreactivity was present in the same areas where increased ferritin messenger RNA was found. Sixty-minute ischemia also led to iron deposition in discrete areas. Iron deposition was highly associated with the induction of ferritin, particularly in the macrophage- and microglia-positive areas where cell death or tissue necrosis was noted.In summary, our initial findings indicate that ischemic insult leads to induction of both H- and L-ferritin messenger RNA. In the present study, although the temporal induction profiles were similar, the major expression areas for these two genes were totally different. Ferritin immunoreactivity was observed in the same areas where increased ferritin messenger RNA was found. Ischemia also resulted in iron deposition, which highly associated with the ferritin immunoreactivity. The exact regulatory mechanism and pathological significance for the differential expression of H- and L-ferritin genes following ischemia/reperfusion remain to be clarified.
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PMID:Differential regulation of H- and L-ferritin messenger RNA subunits, ferritin protein and iron following focal cerebral ischemia-reperfusion. 1109 10

Rapid diffusion, blood oxygenation, and blood volume weighted echo planar imaging was used to monitor global cerebral ischemia by cardiac arrest in rats. Serial CBV measurements used intravascular iron oxide contrast media (iron dextran). ADC dropped by 5% within 20 sec of cardiac arrest, then continued to decay slowly until a larger rapid drop after 2 min. After iron oxide injection, the initial 5% drop was not observed. The transverse relaxation rate (R(2), R(*)(2) no iron injection) increased rapidly after cardiac arrest, peaking at about 30 sec, then declining towards baseline. The CBV dropped by about 50% within 20 sec. The initial 5% ADC drop may be a vascular artifact. The rapidity of the CBV-weighted signal drop suggests a flow-mediated contribution to the iron oxide contrast mechanism. Magn Reson Med 45:10-16, 2001.
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PMID:Comparison of diffusion, blood oxygenation, and blood volume changes during global ischemia in rats. 1114 79

Nitric oxide (NO) mediates a series of physiological processes, including regulation of vascular tone, macrofage-mediated neurotoxicity, platelet aggregation, learning and long-term potentiation, and neuronal transmission. Although NO mediates several physiological functions, overproduction of NO can be detrimental and play multiple roles in several pathological diseases. Accordingly, more potent inhibitors, more selective for neuronal nitric oxide synthase (nNOS) than endothelial NOS (eNOS) or inducible NOS (iNOS), could be useful in the treatment of cerebral ischemia and other neurodegenerative diseases. We recently described the synthesis of a series of imidazole derivatives. Among them N-(4-nitrophenacyl) imidazole (A) and N-(4-nitrophenacyl)-2-methyl-imidazole (B) were considered selective nNOS inhibitors. In the present study the action mechanism of compounds A and B was analyzed. Spectral changes observed in the presence of compound A indicate that this inhibitor exerts its effect without interaction with heme iron. Moreover compounds A and B, inhibit nNOS "noncompetitively" versus arginine, but "competitively" versus BH(4).
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PMID:Inhibition of neuronal nitric oxide synthase by N-phenacyl imidazoles. 1117 34

Transgenic technology provides a powerful means of studying gene regulation and specific gene function with complex mammalian systems. In this study, the authors exploited the specific and discrete neuronal expression pattern mediated by promoter 1 of the Lmo-1 gene to study the neuroprotective effects of the inducible form of heat shock protein 70kD (hsp70i) in primary hippocampal cultures in a mouse model of global cerebral ischemia. Targeting expression of hsp70i to hippocampal neurons protected these cells significantly from toxic levels of glutamate and oxidative stress (for example, exposure to 10 micromol/L free iron produced a 26% increase in lactate dehydrogenase release from neurons cultured from wild-type mice, but a 7% increase in neurons cultured from hsp70i transgenic mice). Bilateral carotid occlusion (25 minutes) produced significantly less neuronal damage in the caudate nucleus and posterior thalamus in hsp70i transgenic mice than in wild-type littermates (for example, 21% +/- 9.3% and 12.5% +/- 9.0% neuronal damage in lateral caudate nucleus of wild-type and hsp70i transgenic mice, respectively, P < 0.05). The current study highlights the utility of targeted expression of transgenes of interest in cerebral ischemia and demonstrates that expression of hsp70i alone is sufficient to mediate the protection of primary neurons from denaturing stress and that expression of human hsp70i in vivo plays crucial role in determining the fate of neurons after ischemic challenge.
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PMID:Targeting expression of hsp70i to discrete neuronal populations using the Lmo-1 promoter: assessment of the neuroprotective effects of hsp70i in vivo and in vitro. 1148 33

Brain injury in the premature infant is a problem of enormous importance. Periventricular leukomalacia (PVL) is the major neuropathologic form of this brain injury and underlies most of the neurologic morbidity encountered in survivors of premature birth. Prevention of PVL now seems ultimately achievable because of recent neurobiologic insights into pathogenesis. The pathogenesis of this lesion relates to three major interacting factors. The first two of these, an incomplete state of development of the vascular supply to the cerebral white matter, and a maturation-dependent impairment in regulation of cerebral blood flow underlie a propensity for ischemic injury to cerebral white matter. The third major pathogenetic factor is the maturation-dependent vulnerability of the oligodendroglial (OL) precursor cell that represents the major cellular target in PVL. Recent neurobiologic studies show that these cells are exquisitely vulnerable to attack by free radicals, known to be generated in abundance with ischemia-reperfusion. This vulnerability of OLs is maturation-dependent, with the OL precursor cell highly vulnerable and the mature OL resistant, and appears to relate to a developmental window characterized by a combination of deficient antioxidant defenses and active acquisition of iron during OL differentiation. The result is generation of deadly reactive oxygen species and apoptotic OL death. Important contributory factors in pathogenesis interact with this central theme of vulnerability to free radical attack. Thus, the increased likelihood of PVL in the presence of intraventricular hemorrhage could relate to increases in local iron concentrations derived from the hemorrhage. The important contributory role of maternal/fetal infection or inflammation and cytokines in the pathogenesis of PVL could be related to effects on the cerebral vasculature and cerebral hemodynamics, to generation of reactive oxygen species, or to direct toxic effects on vulnerable OL precursors. A key role for elevations in extracellular glutamate, caused by ischemia-reperfusion, is suggested by demonstrations that glutamate causes toxicity to OL precursors by both nonreceptor- and receptor-mediated mechanisms. The former involves an exacerbation of the impairment in antioxidant defenses, and the latter, an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptor-mediated cell death. Most importantly, these new insights into the pathogenesis of PVL suggest potential preventive interventions. These include avoidance of cerebral ischemia by detection of infants with impaired cerebrovascular autoregulation, e.g. through the use of in vivo near-infrared spectroscopy, the use of free radical scavengers to prevent toxicity by reactive oxygen species, the administration of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptor antagonists to prevent glutamate-mediated injury, or the use of maternal antibiotics or anticytokine agents to prevent toxicity from maternal/fetal infection or inflammation and cytokines.
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PMID:Neurobiology of periventricular leukomalacia in the premature infant. 1164 46

Cells of the mononuclear phagocytotic system (MPS) are often found near to or within ischemic tissue and can potentially aggravate cellular damage. Hence, visualization of those cells would allow demarcation of putatively affected from intact tissue. Experimental MRI studies have shown that ultrasmall particles of dextran-coated iron oxide (USPIO) are internalized into cells of the MPS. To test if this cell tagging method may be also applied to cerebral infarction, USPIOs were administered to Fisher rats 5.5 h after permanent occlusion of the middle cerebral artery (pMCAO). During the first 2 days USPIO were preferentially found in patches within the lesion and in surrounding areas. On day 4, USPIOs expanded within the core of the lesion. On day 7 they were found predominantly within the boundary area. Histological analysis showed large populations of macrophages containing iron particles in the infarcted tissue. We conclude, therefore, that it is possible to monitor MPS activity after focal cerebral ischemia using USPIOs.
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PMID:Dynamic patterns of USPIO enhancement can be observed in macrophages after ischemic brain damage. 1167 56


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