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)

Topographic analysis was performed of the distribution of Alzheimer's neurofibrillary tangles and the granulovacuolar degeneration of Simchowicz in the hippocampal cortex of patients with Alzheimer's dementia and mentally normal aged controls. A semiautomated scanning stage microscope was linked potentiometrically to an XY pen recorder in order to plot cytoarchitectonic "scattergrams" from the sequentially screened hippocampal formations. The density of both lesions per cubic mm of pyramidal cortex was quantified by measuring the area of each of six "zones", using a digitizer and programmable calculator. In elderly normal brains as well as those of Alzheimer's disease, the statistically most representative ranking order of predilection for neurofibrillary tangles (in decreasing severity) was: entorhinal cortex greater than subiculum greater than H1 greater than end-plate greater than presubiculum greater than H2. For granulovacuolar degeneration the best rank order was: subiculum greater than H1 greater than H2 greater than end-plate greater than entorhinal cortex greater than presubiculum. The notable similarities of both such orders of predilection to the well-recognized "selective vulnerability" of certain hippocampal neurones in clinical conditions of hypoxia, ischemia and epilepsy suggest some common, focally accentuated cytotoxic mechanism may underlie all these regional predispositions.
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PMID:Topographic distribution of neurofibrillary tangles and granulovacuolar degeneration in hippocampal cortex of aging and demented patients. A quantitative study. 65 88

Ca2+/calmodulin-dependent protein kinase II (CaMKII) exhibits a broad substrate specificity and regulates diverse responses to physiological changes of intracellular Ca2+ concentrations. Five isozymic subunits of the highly abundant brain kinase are encoded by four distinct genes. Expression of each gene is tightly regulated in a cell-specific and developmental manner. CaMKII immunoreactivity is broadly distributed within neurons but is discretely associated with a number of subcellular structures. The unique regulatory properties of CaMKII have attracted a lot of attention. Ca2+/calmodulin-dependent autophosphorylation of a specific threonine residue (alpha-Thr286) within the autoinhibitory domain generates partially Ca(2+)-independent CaMKII activity. Phosphorylation of this threonine in CaMKII is modulated by changes in intracellular Ca2+ concentrations in a variety of cells, and may prolong physiological responses to transient increases in Ca2+. Additional residues within the calmodulin-binding domain are autophosphorylated in the presence of Ca2+ chelators and block activation by Ca2+/calmodulin. This Ca(2+)-independent autophosphorylation is very rapid following prior Ca2+/calmodulin-dependent autophosphorylation at alpha-Thr286 and generates constitutively active, Ca2+/calmodulin-insensitive CaMKII activity. Ca(2+)-independent autophosphorylation of CaMKII also occurs at a slower rate when alpha-Thr286 is not autophosphorylated and results in inactivation of CaMKII. Thus, Ca(2+)-independent autophosphorylation of CaMKII generates a form of the kinase that is refractory to activation by Ca2+/calmodulin. CaMKII phosphorylates a wide range of neuronal proteins in vitro, presumably reflecting its involvement in the regulation of diverse functions such as postsynaptic responses (e.g. long-term potentiation), neurotransmitter synthesis and exocytosis, cytoskeletal interactions and gene transcription. Recent evidence indicates that the levels of CaMKII are altered in pathological states such as Alzheimer's disease and also following ischemia.
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PMID:Regulation and role of brain calcium/calmodulin-dependent protein kinase II. 133 43

The etiology of nerve cell death in neuronal degenerative disease is unknown, but it has been hypothesized that excitotoxic mechanisms may play a role. Such mechanisms may play a role in diseases such as Huntington's disease, Parkinson's disease, amyotropic lateral sclerosis, and Alzheimer's disease. In these illnesses, the slowly evolving neuronal death is unlikely to be due to a sudden release of glutamate, such as occurs in ischemia. One possibility, however, is that a defect in mitochondrial energy metabolism could secondarily lead to slow excitotoxic neuronal death, by making neurons more vulnerable to endogenous glutamate. With reduced oxidative metabolism and partial cell membrane depolarization, voltage-dependent N-methyl-D-aspartate (NMDA) receptor ion channels would be more easily activated. In addition, several other processes involved in buffering intracellular calcium may be impaired. Recent studies in experimental animals showed that mitochondrial toxins can result in a pattern of neuronal degeneration closely resembling that seen in Huntington's disease, which can be blocked with NMDA antagonists. NMDA antagonists also block neuronal degeneration induced by 1-methyl-4-phenylpyridium, which has been implicated in experimental models of Parkinson's disease. The delayed onset of neurodegenerative illnesses could be related to the progressive impairment of mitochondrial oxidative phosphorylation, which accompanies normal aging. If defective mitochondrial energy metabolism plays a role in cell death in neurodegenerative disorders, potential therapeutic strategies would be to use excitatory amino acid antagonists or agents to bypass bioenergetic defects.
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PMID:Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses? 134 66

Glutamate is the major excitatory neurotransmitter in the mammalian brain, with receptors on every neuron in the central nervous system; it has major roles in fast synaptic transmission and in the establishment of certain forms of memory. More than 20 years ago Olney and his colleagues described the 'Excitotoxic Hypothesis' which postulates that, in addition to its normal function in the healthy brain, glutamate can kill neurons by prolonged, receptor-mediated depolarization resulting in irreversible disturbances in ion homeostasis. Therefore, glutamate is a two-edged sword; in certain undefined, adverse conditions it undergoes a transition from neurotransmitter to neurotoxin. Its toxicity has been implicated in the death of neurons in ischemia, epilepsy, and the neurodegenerative disorders such as Alzheimer's, Huntington's, and Parkinson's disease. Recent advances in the molecular cloning of the genes for the glutamate family of receptors has revealed a plethora of receptor subtypes and an unexpected level of complexity in the mechanisms of receptor expression and function.
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PMID:Cloning of the genes for excitatory amino acid receptors. 135 85

Recent studies have shown that the principal component of the senile plaque in Alzheimer's disease (AD), beta-amyloid protein (beta AP) can exert direct and indirect neurotoxicity in vitro. Because of the studies that demonstrated potentiation of excitatory amino acid toxicity by beta AP, we decided to test whether beta AP was able to potentiate damage in an in vivo model where excitotoxic damage is thought to be important. The present study evaluated the in vivo effects of beta AP implants in the brain of rats before and after being subjected to 10 min of transient global forebrain ischemia by 4-vessel occlusion (4-VO). Implants of either synthetic beta AP or prolactin (PRL), which was used as a control protein, were made into the striatum and the hippocampus of either the left (beta AP) or the right (PRL) cerebral hemisphere. The implants were made in a lipophilic, non-toxic vehicle so as to try and achieve sustained beta AP exposure. One group of animals was evaluated for direct in vivo effects within 1 week following implantation; the other group was subjected to 4-VO 3-4 days post-implantation for evaluation of potential indirect effects. This latter group was compared to the histopathology of animals subjected to 4-VO without prior implantation. In the group of animals evaluated for direct effects, no evidence of neurotoxicity was observed. Bielschowsky silver staining and immunostaining for ubiquitin were unremarkable in all lesions. beta AP was detected by immunocytochemistry in the parenchymal tissue that received beta AP implants. Marked glial activation was observed to be associated with experimental and control implants. Under the experimental conditions employed in this study, significant protection from ischemia rather than potentiation of damage was observed. These results suggest that beta AP may not be neurotoxic in rodents in vivo and that the lesions and/or trauma produced by the implantation procedure 3-4 days prior to 4-VO may have induced factors that were protective against ischemia-induced damage.
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PMID:In vivo effects of beta-amyloid implants in rodents: lack of potentiation of damage associated with transient global forebrain ischemia. 152 Nov 57

The differential diagnosis of vascular dementia (VD) and Alzheimer's disease (AD) based on clinical assessment and neuropsychologic testing is still associated with a relatively high degree of inaccuracy compared to neuropathology standards. This is especially true in the identification of mixed forms between AD and VD. The present study investigates the potential of neuroimaging methods in providing additional information in dealing with this problem. Magnetic resonance imaging (MRI) of the brain identified a relatively high percentage (39%) of patients with AD (with ischemia scores of 4 and less) with basal ganglia hyperintensities and also demonstrated basal ganglia lacunae and infarcts in some of these patients. These findings indicate that in these cases a vascular component, consistent with the mixed form of dementia, may contribute to the etiology of the disease. These findings also underscore the clinical usefulness of MRI in the further differentiation of the dementias.
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PMID:Does cerebrovascular insufficiency contribute to Alzheimer's disease? 177 62

Antagonists for the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor may have therapeutic potential as neuroprotectant agents in conditions of neuronal degeneration that include brain ischemia, Huntington's chorea, and Alzheimer's disease. Here we have investigated the pharmacological actions of LY274614, a structurally novel competitive NMDA receptor antagonist, for pharmacological selectivity and neuroprotectant effects following systemic administration. LY274614 potently displaced NMDA receptor ([3H]CGS19755) binding (IC50 = 58.8 +/- 10.3 nM), but had no appreciable affinity at [3H]AMPA or [3H]kainate receptor sites at up to 10,000 nM. NMDA-induced convulsions in neonatal rats or NMDA-induced lethality in mice are potently and selectively antagonized by i.p. or p.o. LY274614. Oral doses showed a delayed but prolonged duration of effect. In adult rats, the neurodegenerative effects (loss of choline acetyltransferase activity) following the intrastriatal infusions of NMDA or quinolinate, but not kainate, were prevented by LY274614 (2.5 to 20 mg/kg i.p.). LY274614 is an effective neuroprotectant agent against NMDA receptor-induced toxicity when administered systemically and is a promising therapeutic agent for conditions where glutamate plays a role in the pathology of neuronal degeneration.
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PMID:Neuroprotectant effects of LY274614, a structurally novel systemically active competitive NMDA receptor antagonist. 183 88

There are two types of imaging instruments, single-photon emission computed tomography (SPECT) and positron emission tomography (PET) that use radiopharmaceuticals for the diagnosis of brain disorders. Brain perfusion imaging agents, labeled either with 123I or 99mTc, are useful in detecting various cerebral vascular abnormalities, such as stroke and transient ischemia with SPECT. The management of other neurological disorders (i.e., in Alzheimer's, epilepsy, schizophrenia, and head trauma patients) may also be benefitted by these agents. The exact trapping mechanisms and their relationships with potential clinical applications still remain to be elucidated. Imaging studies using 18F fluorodeoxyglucose with PET is currently the most promising diagnostic tool for the evaluation of local glucose metabolism related to various disease states, such as Alzheimer's disease, brain tumor, and epilepsy. In the past few years significant progress has been made in the design and characterization of new CNS neuronal and postsynaptic receptor imaging agents for PET and SPECT. The new diagnostic agents are aimed at measurements of localization and changes of neuronal function. It is likely that these types of agents have potential for clinical application, especially in the diagnosis of psychiatric disorders that do not involve morphological changes.
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PMID:Overview of radiopharmaceuticals for diagnosis of central nervous disorders. 193 Jun 79

A total of 87 patients with mild or moderate degree of dementia of the Alzheimer type (AD) or vascular dementia (VD) was identified (DSM-III criteria), and their cognitive capacity was evaluated by means of rating scales and psychometric tests. Three years later 30 patients (34%) were dead. Significantly more VD than AD patients died. Eight of the survivors declined to participate in a follow-up study, and 1 patient was excluded by mistake. Of the survivors, 17 had indisputably suffered cognitive decline during the follow-up period (4 VD and 13 AD, 35%). In the case of 11 patients (2 VD and 9 AD) cognitive decline remained doubtful, and 20 patients (9 VD and 11 AD, 42%) underwent no intellectual deterioration during the follow-up period. The results underline the problems of early diagnosis of dementia according to DSM-III criteria. For both sexes a high ischemia score and a low body mass index predicted death. A low score on a verbal fluency test predicted death for men but not for women, and a high difference between systolic and diastolic blood pressure increased the risk of death for men but not for women.
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PMID:The accuracy of early diagnosis and predictors of death in Alzheimer's disease and vascular dementia--a follow-up study. 195 Jun 29

Amino acids such as L-glutamate und L-aspartate are major excitatory neurotransmitters in the mammalian central nervous system (CNS) and potential neurotoxins (excitotoxins), which can destroy central neurons by excessive activation of respective receptors. In the last three decades evidence has accumulated that excitatory amino acids (EAA) are involved in many neurological diseases and that pharmacological intervention offers prospects of novel and more effective therapies. Three different receptor types for EAA have been identified, each being named by the selective agonist to which it is preferentially sensitive, i.e. N-methyl-D-aspartate- (NMDA), kainate- and quisqualate-receptors. In this review interest is focused primarily on the NMDA-receptor, whose structure has been subject of numerous electrophysiological and biochemical studies. Today, it is well established that the NMDA-receptor-ionophore complex has an agonist binding site for glutamate, NMDA and related EAAs which is coupled with an ion channel permeable to Na+, K+, Cl- and Ca2+. Four other binding sites for glycine, phencyclidine, Mg2+ and Zn2+ have been identified which can differentially modulate the function of the NMDA receptor. An additional polyamine binding site has recently been reported. Numerous studies on experimental animals demonstrate that modulators of NMDA-mediated neurotransmission may have antiepileptic, anxiolytic, muscle-relaxant and memory-enhancing effects. Particular interest has gained the possible neuroprotective efficacy of NMDA-receptor antagonists in neurological diseases such as hypoxia/ischemia, hypoglycemia, epilepsy and chronic neurodegenerative disorders (Huntington's, Alzheimer's and Parkinson's disease, amyotrophic lateral sclerosis, and AIDS encephalopathy).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[The N-methyl-D-aspartate receptor complex. Various sites of regulation and clinical consequences]. 197 26


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