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

Axons and oligodendrocytes are vulnerable to cerebral ischemia. The absence of quantitative methods for assessment of white matter pathology in ischemia has precluded in vivo evaluation of therapeutic interventions directed at axons and oligodendrocytes. The authors demonstrate here that the quantitative extent of white matter pathology was reduced by restoration of cerebral blood flow after 2 hours of middle cerebral artery occlusion. Focal ischemia was induced in anesthetized rats by intraluminal thread placement, either transiently (for 2 hours) or permanently. At 24 hours after induction of ischemia, axonal damage was determined by amyloid precursor protein (APP) immunohistochemistry, and the ischemic insult to oligodendrocytes was assessed by Tau-1 immunostaining in the same sections. In adjacent sections, ischemic damage to neuronal perikarya was defined histologically. The hemispheric extent of axonal damage was reduced by 70% in the transiently occluded animals from that in permanently occluded animals. The volumes of oligodendrocyte pathology and of neuronal perikaryal damage were reduced by 62% and 58%, respectively, in the transiently occluded animals. These results demonstrate that this methodologic approach for assessing ischemic damage in axons and oligodendrocytes can detect relative alterations in gray and white matter pathology with intervention strategies.
 ...
PMID:Quantitative assessment of ischemic pathology in axons, oligodendrocytes, and neurons: attenuation of damage after transient ischemia. 1082 26

Gunshot wounds to the brain usually lead to acute respiratory arrest or death after a brief survival period, even in cases involving only slight direct tissue damage. It can be assumed therefore that the damage extends beyond the zone of recognizable destruction and hemorrhages. To determine the true extent of the tissue injury resulting from gunshot wounds to the brain, we carried out microscopic investigations for reactive changes (emigration of leukocytes and macrophages, axonal expression of beta-amyloid precursor protein (beta-APP) in 10 cases of gunshot wound to the narrow channel of the brain with survival times >2h. Demonstration of leukocytes expressing naphthol AS-D chloroacetate esterase activity in the brain tissue at the border of the missile track established the vitality of the gunshot effect. The presence of macrophages (CD68-epitope) allowed demarcation of a 1-2mm wide necrotic zone around the permanent cavity. Within this zone and beyond, beta-APP showed an initial increase followed by a decline in the number of injured axons. Three types of beta-APP positive staining could be differentiated. In the immediate vicinity of the missile track beta-APP positive neurons were present at a distance of 2-4mm from the margin of the permanent cavity (type 1) as a result of primary injured neuronal tissue by the gunshot itself. At longer distances from the narrow channel and the permanent cavity single beta-APP positive axons or axon fragments and two additional types were found; type 2 shows a parallel, wave-like arrangement of the damaged fibers, which suggests that the injury was produced by mechanical acceleration of the brain tissue created by the energy the projectile expended within the brain; irregular aggregation of beta-APP positive axons or axon fragments within a local edema represents type 3, which may be attributed to secondary ischemia or edema.
 ...
PMID:Brain injury after survived gunshot to the head: reactive alterations at sites remote from the missile track. 1107 74

Choroid plexus (CP) is an important target organ for polypeptides. The fenestrated phenotype of choroidal endothelium facilitates the penetration of blood-borne polypeptides across the capillary walls. Thus, both circulating and cerebrospinal fluid (CSF)-borne polypeptides can reach their receptors on choroidal epithelium. Several polypeptides have been demonstrated to regulate CSF formation by controlling blood flow to choroid plexus and/or the activity of ion transport in choroidal epithelium. However, many ligand-receptor interactions occurring in the CP are not involved in the regulation of fluid secretion. Increasing evidence suggests that the choroidal epithelium plays an important role in hormonal signaling via a receptor-mediated transport into the brain (e.g., leptin) and helps to clear certain CSF-borne polypeptides (e.g., soluble amyloid beta-protein). Thus, impaired choroidal transport or insufficient clearance of polypeptides may contribute to pathogenesis of systemic or central nervous system (CNS) disorders, such as obesity or Alzheimer's disease. CP epithelium is not only a target but is also a source of neuropeptides, growth factors, and cytokines in the CNS. These polypeptides following their release into the CSF may exert distal, endocrine-like effects on target cells in the brain due to bulk flow of this fluid. Distinct temporal patterns of choroidal expression of several polypeptides are observed during brain development and in various CNS disorders, including traumatic brain injury and ischemia. Therefore, it is proposed that the CP plays an integral role not only in normal brain functioning, but also in the recovery from the injury. This review attempts to critically analyze the available data to support the above hypothesis.
 ...
PMID:Choroid plexus: target for polypeptides and site of their synthesis. 1113 50

Cell-cycle-related proteins, such as cyclins or cyclin-dependent kinases, are re-expressed in neurons committed to death in response to a variety of insults, including excitotoxins, hypoxia and ischemia, loss of trophic support, or beta-amyloid peptide. In some of these conditions events that are typical of the mid-G1 phase, such as cyclin-dependent kinase 4/6 activation, are required for the induction of neuronal death. In other cases, the cycle must proceed further and recruit steps that are typical of the G1/S transition for death to occur. Finally, there are conditions in which cell-cycle proteins might be re-expressed, but do not contribute to neuronal death. We hypothesize that cell-cycle signaling becomes a mandatory component of neuronal demise when other mechanisms are not enough for neurons to reach the threshold for death. Under this scheme, the death threshold is set by the extent of DNA damage. Whenever the extent of DNA damage is below this threshold, a cell-cycle signaling becomes crucial for the induction of neuronal death through p53-dependent or -independent pathways.
 ...
PMID:Activation of cell-cycle-associated proteins in neuronal death: a mandatory or dispensable path? 1116 84

Our experiments were performed to test the hypothesis that human beta-amyloid peptide 42 (beta A) is able to enter and exit the brain parenchyma through the blood-brain barrier. In an effort to determine the effect of beta A in an animal model, we have injected beta A i.v. into rats following single and repeated brain ischemia. Rats were sacrificed at 3 and 12 months after injection and beta A was localized by monoclonal antibody (mAb) 4G8. The present observations revealed an abundant presence of beta A in the extracellular space of the brain, which appeared to be dilated, and a vigorous uptake of beta A into the cytoplasm of endothelial and ependymal cells, pericytes, astrocytes and neurons. Some of the beta A deposits were associated and/or had migrated to the vessels and to the ventricles, and by 3 months a significant amount of beta A was directly associated with the vessels and was observed inside the ventricular space. Virtually no soluble and aggregating beta A was found in brain tissue 1 year later. This suggests that phagocytic pericytes and astrocytes take up exogenous beta A in an attempt to clear the peptide from the brain extracellular space and deliver it to the circulation. Further, direct removal of beta A from the ventricles by the bloodstream is also possible. These observations suggest that a reverse transport of beta A across endothelial cells of microvessels represents one of the possible mechanisms responsible for removal of extravasated beta A. The findings of the present study indicate that in normal conditions beta A is rapidly cleared from the cerebrospinal fluid and brain parenchyma, suggesting that irreversible changes in the physico-chemical properties of the cerebrovascular endothelial cell surface are involved in beta A deposition in the brain in Alzheimer's disease (AD).
 ...
PMID:Possible reverse transport of beta-amyloid peptide across the blood-brain barrier. 1145 95

Severe traumatic brain injury (TBI) often leads to a bad outcome with considerable neurological deficits. Secondary brain injuries due to a rise of intracranial pressure (ICP) and global hypoxia-ischemia are critical and may be reduced in extent by mild hypothermia. A porcine animal model was used to study the effect of severe TBI, induced by fluid percussion (FP; 3.5+/-0.3 atm) in combination with a secondary insult, i.e., temporary blood loss with hypovolemic hypotension. Six-week-old juvenile pigs were subjected to this kind of severe TBI; one group was then submitted to moderate hypothermia at 32 degrees C for 6 h, starting 1 h after brain injury. Animals were killed after 24 h. TBI and hypothermia-associated alterations in the brains were investigated by immunohistochemistry with antibodies against microtubule-associated protein 2 (MAP-2) and beta-amyloid precursor protein (betaAPP). In addition, DNA fragmentation was investigated by the terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) method. Seven of the 13 normothermic TBI animals developed a secondary increase in ICP (TBI-NT-ICP) after an interval of several hours. None of the animals in the hypothermic trauma (TBI-HT) group exhibited a secondary ICP increase, indicating a protective effect of the treatment. TBI-HT animals showed significantly higher levels of MAP-2 immunoreactivity, lower levels of betaAPP immunoreactivity and less DNA fragmentation than the TBI-NT-ICP animals. Differences between the TBI-HT group and normothermic animals without an ICP increase (TBI-NT) were less marked. A considerable decrease in MAP-2 outside the site of TBI-FP administration was seen only in the TBI-NT-ICP animals. MAP-2 immunohistochemistry was thus a reliable marker of diffuse brain damage. Axonal injury was present in all TBI groups, indicating its special significance in neurotrauma. Thus, severe TBI caused by FP, combined with temporary blood loss, consistently produced traumatic axonal injury and focal brain damage. Mild hypothermia was able to prevent a secondary increase in ICP and its sequelae of diffuse hypoxic-ischemic brain injury. However, hypothermia did not afford protection from traumatic axonal injury.
 ...
PMID:Immunomorphological sequelae of severe brain injury induced by fluid-percussion in juvenile pigs--effects of mild hypothermia. 1148 13

Metabotropic glutamate (mGlu) receptors have been considered as potential targets for neuroprotective drugs, but the lack of specific drugs has limited the development of neuroprotective strategies in experimental models of acute or chronic central nervous system (CNS) disorders. The advent of potent and centrally available subtype-selective ligands has overcome this limitation, leading to an extensive investigation of the role of mGlu receptor subtypes in neurodegeneration during the last 2 years. Examples of these drugs are the noncompetitive mGlu1 receptor antagonists, CPCCOEt and BAY-36-7620; the noncompetitive mGlu5 receptor antagonists, 2-methyl-6-(phenylethynyl)pyridine, SIB-1893, and SIB-1757; and the potent mGlu2/3 receptor agonists, LY354740 and LY379268. Pharmacologic blockade of mGlu1 or mGlu5 receptors or pharmacologic activation of mGlu2/3 or mGlu4/7/8 receptors produces neuroprotection in a variety of in vitro or in vivo models. MGlu1 receptor antagonists are promising drugs for the treatment of brain ischemia or for the prophylaxis of neuronal damage induced by synaptic hyperactivity. MGlu5 receptor antagonists may limit neuronal damage induced by a hyperactivity of N-methyl-d-aspartate (NMDA) receptors, because mGlu5 and NMDA receptors are physically and functionally connected in neuronal membranes. A series of observations suggest a potential application of mGlu5 receptor antagonists in chronic neurodegenerative disorders, such as amyotrophic lateral sclerosis and Alzheimer disease. MGlu2/3 receptor agonists inhibit glutamate release, but also promote the synthesis and release of neurotrophic factors in astrocytes. These drugs may therefore have a broad application as neuroprotective agents in a variety of CNS disorders. Finally, mGlu4/7/8 receptor agonists potently inhibit glutamate release and have a potential application in seizure disorders. The advantage of all these drugs with respect to NMDA or AMPA receptor agonists derives from the evidence that mGlu receptors do not "mediate," but rather "modulate" excitatory synaptic transmission. Therefore, it can be expected that mGlu receptor ligands are devoid of the undesirable effects resulting from the inhibition of excitatory synaptic transmission, such as sedation or an impairment of learning and memory.
 ...
PMID:Metabotropic glutamate receptor subtypes as targets for neuroprotective drugs. 1152 8

The distribution patterns of amyloid precursor protein (APP) fragments were studied immunocytochemically in the rat brain before, after 10 min ischemia and following treatment by idebenone. Six months after brain ischemia intense staining for APP appeared in extra- and intracellular space. These findings indicate that APP is involved in the degeneration process of brain neuronal and glial cells following ischemia-reperfusion injury and anti-oxidative therapy did not prevent and/or stop this phenomenon.
 ...
PMID:No effect of anti-oxidative therapy on cerebral amyloidosis following ischemia-reperfusion brain injury. 1169 24

beta-amyloid (A beta), derived form the beta-amyloid precursor protein (APP), is important for the pathogenesis of Alzheimer's disease (AD), which is characterized by progressive decline of cognitive functions, formation of A beta plaques and neurofibrillary tangles, and loss of neurons. However, introducing a human wild-type or mutant APP gene to rodent models of AD does not result in clear neurodegeneration, suggesting that contributory factors lowering the threshold of neuronal death may be present in AD. Because brain ischemia has recently been recognized to contribute to the pathogenesis of AD, we studied the effect of focal brain ischemia in 8- and 20-month-old mice overexpressing the 751-amino acid isoform of human APP. We found that APP751 mice have higher activity of p38 mitogen-activated protein kinase (p38 MAPK) in microglia, the main immune effector cells within the brain, and increased vulnerability to brain ischemia when compared with age-matched wild-type mice. These characteristics are associated with enhanced microglial activation and inflammation but not with altered regulation of cerebral blood flow, as assessed by MRI and laser Doppler flowmetry. Suppression of inflammation with aspirin or inhibition of p38 MAPK with a selective inhibitor, SD-282, abolishes the increased neuronal vulnerability in APP751 transgenic mice. SD-282 also suppresses the expression of inducible nitric-oxide synthase and the binding activity of activator protein 1. These findings elucidate molecular mechanisms of neuronal injury in AD and suggest that antiinflammatory compounds preventing activation of p38 MAPK in microglia may reduce neuronal vulnerability in AD.
 ...
PMID:Beta-amyloid precursor protein transgenic mice that harbor diffuse A beta deposits but do not form plaques show increased ischemic vulnerability: role of inflammation. 1181 64

Cerebral amyloid angiopathy (CAA), defined by deposition of the beta-amyloid peptide in medium and small cortical and meningeal vessels, is a well-recognized cause of hemorrhagic stroke. This paper reviews the accumulating evidence supporting an additional role for CAA in producing vessel dysfunction, reduced cerebral blood flow and ischemia. Ischemic lesions are characteristic of several hereditary CAA syndromes, including a recently described mutation of the amyloid precursor protein associated with dementia (but not hemorrhagic stroke) in an Iowa family. Ischemic lesions are seen in some sporadic CAA patients as well, and recent data from transgenic mice suggest potential mechanisms by which beta-amyloid may alter vessel physiology. Future studies will seek to define the clinical importance of vascular beta-amyloid as a potential target for drug therapy in dementia.
 ...
PMID:Cerebral amyloid angiopathy and vessel dysfunction. 1190 Dec 42


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>