UMLS:C0022116 - FACTA Search

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Query: UMLS:C0022116 (ischemia)
91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rasagiline (N-propargyl-1-(R)-aminoindan) is a selective, irreversible monoamine oxidase B (MAO B) inhibitor which has been developed as an anti-Parkinson drug. In controlled monotherapy and as adjunct to L-dopa it has shown anti-Parkinson activity. In cell culture (PC-12 and neuroblastoma SH-SY5Y cells) it exhibits neuroprotective and anti-apoptotic activity against several neurotoxins (SIN-1, MPTP, 6-hydroxydopamine and N-methyl-(R)-salsolinol) and ischemia. In vivo, it reduces the sequelae of traumatic brain injury in mice and speeds their recovery. The neuroprotective activity of rasagaline does not result from MAO B inhibition, since its S-enantiomer, TVP1022, which has 1000-fold weaker MAO inhibitory activity, exhibits similar neuroprotective properties. Introduction of a carbamate moiety into the rasagiline molecule to confer cholinesterase inhibitory activity for the treatment of Alzheimer's disease, resulted in compounds TV3326 [(N-Propargyl-(3R)Aminoindan-5-YL)-Ethyl Methyl Carbamate] and its S-enantiomer TV3279 [(N-Propargyl-(3S)Aminoindan-5-YL)-Ethyl Methyl Carbamate], which retain the neuroprotective activities of rasagiline and TVP1022. They also antagonize scopolamine-induced impairments in spatial memory. In addition, TV3326 exhibits brain-selective MAO A and B inhibitory activity after chronic administration and has antidepressant-like activity in the forced swim test. This is associated with an increase in brain levels of serotonin. The anti-apoptotic activity of these propargylamine-containing derivatives may be related to their ability to delay the opening of voltage-dependent anion channels (VDAC), which are part of the mitochondrial permeability transition pore. The propargylamine moiety is responsible for the increase in the mitochondrial family of Bcl-2 proteins, prevention in the fall in mitochondrial membrane potential, prevention of the activation of caspase 3, and of translocation of glyceraldehyde-3-phosphate dehydrogenase from the cytoplasm to the nucleus. The latter processes are closely associated with neurotoxin-induced apoptosis. Rasagiline interacts with and prevents the binding of PKI 1195 to the pro-apoptotic peripheral benzodiazepine receptor, which together with Bcl-2, hexokinase, porin, and adenine nucleotide translocator constitutes part of the VDAC. Furthermore, rasagiline, TV3326 and TV3279 are able to influence the processing of amyloid precursor protein by activation of alpha-secretase and increasing the release of soluble alpha APP in rat PC-12 and human neuroblastoma SH-SY5Y cells and in rat and mice cortex and hippocampus. This process has been shown to involve the upregulation of PKC and MAP kinase. It is quite likely that the induction of Bcl-2 and activation of PKC by rasagiline and TV3326 is closely linked to the anti-apoptotic action of these drugs and their ability to process APP by activation of alpha-secretase.
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PMID:Molecular basis of neuroprotective activities of rasagiline and the anti-Alzheimer drug TV3326 [(N-propargyl-(3R)aminoindan-5-YL)-ethyl methyl carbamate]. 1204 33

Quantification of damage in both grey and white matter is required for comprehensive assessment of neuroprotective drug efficacy. Although methods for quantification of neuronal perikaryal damage after ischemia are well established, assessment of axonal damage has been limited. This article describes a new method for quantitation of axonal injury after middle cerebral artery (MCA) occlusion in rats and its application to the study of the antioxidant ebselen. The methodology is based on immunohistochemical detection of amyloid precursor protein (APP) accumulation in deformed, swollen axons in zones of ischemia. Sixty-five axon-rich sites throughout the MCA territory are assessed for the presence (scored 1) or absence (scored 0) of accumulated APP in axonal swellings. Scores for individual sites are summated in predefined neuroanatomic regions (e.g. corpus callosum), stereotaxic levels, or for a total hemisphere APP score. Both intra-rater and inter-rater reproducibility were high (r = 0.87 and 0.80, respectively). Ebselen (1 mg kg(-1) hr(-1), intravenously) significantly reduced the volume of neuronal perikaryal damage (24%, P < 0.01) and axonal damage (total APP score reduced from 27 [23.9 to 35.1, 95% CI] to 21.5 [18.2 to 23.3], P = 0.002 with ebselen treatment). In conclusion, a robust and generally applicable method is described for assessing pathologic features in myelinated fiber tracts that is sensitive for detection of drug effects on axonal damage.
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PMID:New method for the quantitative assessment of axonal damage in focal cerebral ischemia. 1221 13

We have investigated in the rat, immunocytochemically, the expression of beta-amyloid peptide in glial cells following ischemia-reperfusion brain injury. The postischemic brain injuries were studied at survival times from 2 days to 12 months. The reactive astrocytes with indirect staining for beta-amyloid peptide were observed in brain till 7 days postischemia. beta-Amyloid positive astrocytes disappeared transiently on the 14 days and then reappeared in the 6 months and again disappeared at 9 months after brain injury. Transient ischemia temporarily induced beta-amyloid peptide expression in reactive astrocytes, but this expression peaked at 7 days and 6 months. A glial appearance of beta-amyloid peptide direct staining occurred at a time when extensive neuronal loss was evident.
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PMID:Glial expression of the beta-amyloid peptide in cardiac arrest. 1241 98

Vascular damage and reactive gliosis are found colocalized with amyloid deposits in Alzheimer's disease brain, suggesting that the cerebrovasculature may be a clinically relevant site of Alzheimer's disease pathology and may contribute to the neurodegeneration process in Alzheimer's disease. In ischemic conditions, amyloid precursor protein and amyloid peptide are reported to be upregulated in neurons and in extracellular space. Expression and distribution of amyloid precursor protein and amyloid peptide in astroglial cells were examined immunohistochemically after 10-min cardiac arrest. After reperfusion for 2, 7, and 14 days and 1, 6, 9, and 12 months, brains were immunostained. The indirect reactive astrocytes with fragments of the full-length amyloid precursor protein were observed in brains until 7 days postischemia. Direct immunoreactivity only of amyloid peptide and the C-terminal of amyloid precursor protein was also localized in the reactive astrocytes in ischemic brains at 6 months after ischemia. Ischemia temporarily induced amyloid peptide overexpression in reactive astrocytes, but this expression peaked at 7 days and 6 months. A glial appearance of amyloid peptide and C-terminal of amyloid precursor protein staining occurred when extensive neuronal loss and the onset of brain atrophy were evident. The localization of the C-terminal of amyloid precursor protein within ischemic astroglial cells underscores the likely importance of the C-terminal of amyloid precursor protein in the pathogenesis of ischemia as in Alzheimer's disease.
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PMID:Astroglial expression of the beta-amyloid in ischemia-reperfusion brain injury. 1248 Jul 38

The effects of acute hyponatremia on severe traumatic brain injury (TBI) in 35 adult male Sprague-Dawley rats were studied in a replicated focal and diffuse injury rat model. Such effects were assessed by the cerebral contusion volume and axonal injury (AI) densities, determined by quantitative immunoreactivity of beta-amyloid precursor protein, by blood-brain barrier (BBB) permeability based on endogenous IgG immunostaining, and by ultrastructural features. Significant increase of contusion volume (P < 0.05) and of AI in the segment of corpus callosum beneath the contusion (P < 0.05) and ipsilateral thalamus (P < 0.05) were observed at 4 h postinjury during the hyponatremic phase. No change in BBB permeability was observed in the hyponatremia + TBI (HT) groups. Significant swelling of perivascular astrocytic foot processes in the HT groups was seen at 4 h (P < 0.01) and 1 day postinjury (P < 0.01) by quantitative image analysis of ultrastructures. However, attenuated swelling of perivascular astrocytic foot processes in severely edematous medulla oblongata with simultaneous swelling of perikaryal astrocytic processes was observed in the HT 1-day group. The ultrastructural features were also correlated with the down-regulation of aquaporin-4 (AQP4) mRNA expression (P < 0.05). Results suggest that acute hyponatremia acts as one of the secondary insults following severe TBI. Such exacerbation may not be attributable to further disruption of BBB permeability, but rather to the ischemia resulting from the swelling of perivascular astrocytic foot processes impeding microcirculation. Down-regulated AQP4 mRNA expression may be one of the molecular mechanisms maintaining water homeostasis in diffusely injured brain exposed to acute hyponatremia.
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PMID:Impact of experimental acute hyponatremia on severe traumatic brain injury in rats: influences on injuries, permeability of blood-brain barrier, ultrastructural features, and aquaporin-4 expression. 1250 79

L-Glutamate is the major excitatory neurotransmitter in mammalian central nervous system, and excitatory amino acid transporters (EAATs) are essential for terminating synaptic excitation and for maintaining extracellular glutamate concentration below toxic levels. Although the structure of these channel-like proteins has not been yet reported, their membrane topology has been hypothesised based on biochemical and protein sequence analyses. In the case of an inadequate clearance from synaptic cleft and from the extrasynaptic space, glutamate behaves as a potent neurotoxin, and it may be related to several neurodegenerative pathologies including epilepsy, ischemia, amyotrophic lateral sclerosis, and Alzheimer disease. The recent boom of glutamate is demonstrated by the enormous amount of publications dealing with the function of glutamate, with its role on modulation of synaptic transmission throughout the brain, mainly focusing: i). on the structure of its receptors, ii). on molecular biology and pharmacology of Glu transporters, and iii). on the role of glutamate uptake and reversal uptake in several neuropathologies. This review will deal with the recent and most interesting published results on Glu transporters membrane topology, Glu transporters physiopathological role and Glu transporters medicinal chemistry, highlighting the guidelines for the development of potential neuroprotective agents targeting neuronal high-affinity sodium-dependent glutamate transporters.
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PMID:Neuronal high-affinity sodium-dependent glutamate transporters (EAATs): targets for the development of novel therapeutics against neurodegenerative diseases. 1257 Jul 95

The original neuroprotective hypothesis of estrogen was based on the gender difference in brain response to the ischemia-reperfusion injury. Additional clinical reports also suggest that estrogen may improve cognition in patients with Alzheimer disease. 17beta-Estradiol is the most potent endogenous ligand of estrogen, which protects against neurodegeneration in both cell and animal models. Estrogen-mediated neuroprotection is probably mediated by both receptor-dependent and -independent mechanisms. Binding of estrogen such as 17beta-estradiol to estrogen receptors (ERs) activates the homodimers of ER-DNA and its binding to estrogen response elements in the promoter region of genes such as neuronal nitric oxide synthase (NOS1) for regulating gene expression in target brain cells. In addition to the induction of NOS1, estrogen increases the expression of antiapoptotic protein such as bcl-2. Furthermore, our recent observations provide new molecular biologic and pharmacologic evidence suggesting that physiologic concentrations of 17beta-estradiol (<10 nM) activate ERs (ERbeta > ERalpha) and upregulate a cyclic guanosine 5'- monophosphate (cGMP)-dependent thioredoxin (Trx) and MnSOD expression following the induction of NOS1 in human brain-derived SH-SY5Y cells. We thus proposed that the estrogen-mediated gene induction of Trx plays a pivotal role in the promotion of neuroprotection because Trx is a multifunctional antioxidative and antiapoptotic protein. For managing progressive neurodegeneration such as Alzheimer dementia, our estrogen proposal of the signaling pathway of cGMP-dependent protein kinase (PKG) in mediating estrogen-induced cytoprotective genes thus fosters research and development of the new estrogen ligands devoid of female hormonal side effects such as carcinogenesis.
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PMID:Induction of antioxidative and antiapoptotic thioredoxin supports neuroprotective hypothesis of estrogen. 1277

Brief focal ischemia leading to temporary neurological deficits induces delayed hyperintensity on T1-weighted magnetic resonance imaging (MRI) in the striatum of humans and rats. The T1 hyperintensity may stem from biochemical alterations including manganese (Mn) accumulation after ischemia. To clarify the significance of this MRI modification, we investigated the changes in the dorsolateral striatum of rats from 4 hours through 16 weeks after a 15-minute period of middle cerebral artery occlusion (MCAO), for MRI changes, Mn concentration, neuronal number, reactivities of astrocytes and microglia/macrophages, mitochondrial Mn-superoxide dismutase (Mn-SOD), glutamine synthetase (GS), and amyloid precursor protein. The cognitive and behavioral studies were performed in patients and rats and compared with striatal T1 hyperintensity to show whether alteration in brain function correlated with MRI and histological changes. The T1-weighted MRI signal intensity of the dorsolateral striatum increased from 5 days to 4 weeks after 15-minute MCAO, and subsequently decreased until 16 weeks. The Mn concentration of the dorsolateral striatum increased after ischemia in concert with induction of Mn-SOD and GS in reactive astrocytes. The neuronal survival ratio in the dorsolateral striatum decreased significantly from 4 hours through 16 weeks, accompanied by extracellular amyloid precursor protein accumulation and chronic glial/inflammatory responses. The patients and rats with neuroradiological striatal degeneration had late-onset cognitive and/or behavioral declines after brief focal ischemia. This study suggests that (1) the hyperintensity on T1-weighted MRI after mild ischemia may involve tissue Mn accumulation accompanied by Mn-SOD and GS induction in reactive astrocytes, (2) the MRI changes correspond to striatal neurodegeneration with a chronic inflammatory response and signs of oxidative stress, and (3) the subjects with these MRI changes are at risk for showing a late impairment of brain function even though the transient ischemia is followed by total neurological recovery.
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PMID:Magnetic resonance imaging shows delayed ischemic striatal neurodegeneration. 1468 83

Axon injury following cerebral ischemia has received little scientific attention compared to the abundance of information dealing with the pathophysiology of grey matter ischemia. There are differences in the initial response of grey and white matter to ischemia in vitro. In this study we investigate whether the vasoactive peptide, endothelin-1, can generate a focal ischemic lesion in the white matter and compare the findings with endothelin-1-induced lesions in the grey matter. Using a minimally invasive technique to microinject endothelin-1 into selected brain regions, we observed an acute reduction in local MRI perfusion in the injected hemisphere after 1 hour. Twenty-four hours after microinjection of 10 pmoles of endothelin-1, we observed a loss of neurons in the grey matter. At 72 hours, neutrophils were absent and a macrophage/microglia response and astrocyte gliosis were detected. No breakdown in the blood-brain barrier was detected. After injection of 10 pmoles endothelin-1 into the cortical white matter, we observed prolific amyloid precursor protein-positive immunostaining (indicative of axonal disruption) and an increase in tau-1 immunostaining in oligodendrocytes at 6 hours. Similar to the grey matter lesions, no neutrophils were present, a macrophage/microglia response did not occur until 72 hours and there was no disruption in the blood-brain barrier. Focal injections of endothelin-1 into specific areas of the rat CNS represent a model to investigate therapeutic approaches to white matter ischemia.
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PMID:Focal lesions in the rat central nervous system induced by endothelin-1. 1469 3

This study examined the late microvascular consequences of brain ischemia due to cardiac arrest in rats. In reacted vibratome sections scattered foci of extravasated horseradish peroxidase were noted throughout the brain and did not appear to be restricted to any specific area of brain. Ultrastructural investigation of leaky sites frequently presented platelets adhering to the endothelium of venules and capillaries. Endothelial cells demonstrated pathological changes with evidence of perivascular astrocytic swelling. At the same time, we noted C-terminal of amyloid precursor protein/beta-amyloid peptide (CAPP/betaA) deposits in cerebral blood vessels, with a halo of CAPP/betaA immunoreactivity in the surrounding parenchyma suggested diffusion of CAPP/betaA out of the vascular compartment. Changes predominated in the hippocampus, cerebral and entorhinal cortex, corpus callosum, thalamus, basal ganglia and around the lateral ventricles. These data implicate delayed abnormal endothelial function of vessels following ischemia-reperfusion brain injury as a primary event in the pathogenesis of the recurrent cerebral infarction.
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PMID:Blood-brain barrier dysfunction and amyloid precursor protein accumulation in microvascular compartment following ischemia-reperfusion brain injury with 1-year survival. 1475 18

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