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)

To investigate the possible involvement of beta-amyloid (A beta) in disrupting neuronal function during ischemia, we examined whether overexpression of C-terminal fragments of beta-amyloid precursor protein (beta-APP) in transgenic (Tg) mice is capable of altering the capacity of hippocampus slices to recover synaptic transmission after transient hypoxic episodes. Recovery of synaptic transmission was monitored in area CA1 of perfused hippocampal slices prepared from both control and Tg mice. The results obtained indicate that hippocampal slices prepared from Tg mice exhibited a much lower level of recovery in synaptic transmission following reoxygenation. This reduction in the capacity of Tg slices to recover from hypoxia-induced impairment of synaptic transmission in the hippocampus does not appear to be related to pre-existing alterations in either functional or biochemical properties of glutamate receptors in Tg mice. The present results provide the first experimental evidence that overexpression of the C-terminal fragment of APP exacerbates functional damage of hippocampal neurons after hypoxic episodes.
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PMID:Hypoxia-induced loss of synaptic transmission is exacerbated in hippocampal slices of transgenic mice expressing C-terminal fragments of Alzheimer amyloid precursor protein. 1040 36

Experimental studies have shown that diffuse axonal injury is usually induced by positive or negative acceleration mechanisms. In order to determine the reliability of axonal injury (AI) as a marker of this type of traumatic insult, we compared cases of trauma-induced focal cortical hemorrhage without dural involvement (n = 67) with cases of trauma-induced subdural bleeding without cortical hemorrhage (n = 26). Both groups exhibited a wide range of post-traumatic survival times. The injuries in the first group were caused mainly by direct impact to the head, those in the second by acceleration/deceleration mechanisms. The investigations were based primarily on immunohistochemical demonstration of antibodies targeted to beta-amyloid precursor protein (beta-APP) in the pons as a marker of AI and the results were assessed semiquantitatively. No significant differences were found between the two groups. In both groups AI was detected in 80-100% of cases with survival times of more than 3 h and two thirds of all positive cases showed pronounced positivity. Additional comparison of cases of brain death due to mechanical trauma (n = 14) with cases of brain death due to non-mechanical trauma (n = 18) also disclosed no significant intergroup differences. Finally, investigations of the pons in cases of non-traumatic death due to cerebral hypoxia/ischemia (n = 51) demonstrated AI with the same frequency as in the other groups, although the expression tended to be less pronounced. Our results confirm that beta-APP expression in the pons is a reliable indicator of AI but does not discriminate between injuries caused by traumatic strain or shearing mechanisms and secondary damage due to cerebral hypoxia/ischemia or edema. In the large majority of cases with prolonged post-traumatic survival, it can therefore be assumed that AI in the pons is the consequence of primary and/or secondary events or a combination of both, as is common in non-missile head injury survived for more than 90-120 min. Therefore, positive differentiation of the type of biomechanical event based on this criterion alone is not possible.
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PMID:Pontine axonal injury after brain trauma and nontraumatic hypoxic-ischemic brain damage. 1043 37

The reperfusion of previously ischemic brain is associated with exacerbation of cellular injury. Reperfusion occasionally potentates release of intracellular enzymes, influx of Ca2+, breakdown of membrane phospholipids, accumulation of amyloid precursor protein or amyloid beta-(like) proteins, and apolipoprotein E. In this study, the effect of reperfusion injury on the activity of cerebral cortex enzymes acting on phosphatidyl [3H] inositol (PI) and [14C-arachidonoyl] PI was investigated. Moreover the effect of amyloid beta25-35 on PI degradation by phospholipase(s) of normoxic brain and subjected to ischemia-reperfusion injury was determined. Brain ischemia in gerbils (Meriones unguiculatus) was induced by ligation of both common carotid arteries for 5 min and then brains were perfused for 15 min, 2 h and 7 days. Statistically significant activation of enzyme(s) involved in phosphatidylinositol degradation in gerbils subjected to ischemia-reperfusion injury was observed. Nearly all gerbils showed a higher activity of cytosolic PI phospholipase C (PLC) at 15 min after ischemia. Concomitantly, the significant enhancement of the level of DAG and AA radioactivity at this short reperfusion time confirmed the active PI degradation by phospholipase(s) in cerebral cortex and hippocampus. After a prolonged reperfusion time of 7 days after ischemia, both cytosolic and membrane-bound forms of PI-PLC were activated. The question arises if alteration of membranes by the degradation of phospholipids occurring after an ischemic episode potentiates the effect of Abeta on membrane-bound enzymes. A neurotoxic fragment of amyloid, Abeta 25-35, incubated in the presence of endogenous Ca2+, increased significantly the PI-PLC activity of normoxic brain. In its non-aggregated form, Abeta 25-35 activates PI-PLC but in the aggregated form the enzymatic activity decreased. Thus, Abeta 25-35 exerts a similar effect on the membrane-bound PI-PLC from normoxic brain or subjected to ischemia reperfusion injury. We conclude that the degradation of phosphatidylinositol by cytosolic phosphoinositide-phospholipase C may contribute to the pathophysiology of delayed neuronal death following cerebral ischemia. Thus, a specific inhibitor of this enzyme(s) may offer therapeutic strategies to protect the brain from damage triggered by ischemia. Ischemia-reperfusion injury had no effect on Abeta-evoked alterations of synaptic plasma membrane-bound PI-PLC.
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PMID:Alteration of phosphoinositide degradation by cytosolic and membrane-bound phospholipases after forebrain ischemia-reperfusion in gerbil: effects of amyloid beta peptide. 1049 23

The neuroprotective glial cell modulator propentofylline has been used in clinical trials involving more than 800 patients with vascular dementia (VaD). These data derive from two sources: a pooled group of VaD patients from four early phase III European trials, and a multinational European/Canadian phase III study (MN 305) that features a combined randomized withdrawal/delayed onset of progression design to evaluate the effect of propentofylline on disease progression. In the pooled studies, DSM-III-R criteria, Hachinski Ischemia Scores, computed tomography (CT), and magnetic resonance imaging (MRI) were used to select subjects with mild-to-moderate disease; in MN 305, National Institute of Neurological Disorders and Stroke/Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN) criteria and neurologic examinations (including CT and MRI scans) were used to select patients with possible or probable VaD. The use of a central rater to assess cerebrovascular disease in neuroradiologic examinations for study MN 305 was considered to be a key feature for reducing the heterogeneity of the VaD patient population. In addition, the inclusion of patients with possible VaD in this trial greatly increased the number of eligible patients; subgroup analyses revealed no substantial differences between patients with probable versus possible VaD, justifying their inclusion in the study. VaD patients exhibited a more pronounced placebo response in global assessments compared with the Alzheimer disease population in a parallel study. In addition, they experienced less deterioration over time with respect to cognitive and global assessments. Beneficial effects of propentofylline were consistently demonstrated in the domains of cognitive and global function for both VaD populations; however, no treatment benefits could be demonstrated for activities of daily living, possibly due to factors relating to the study population/design, the lack of a validated test instrument for such patients, the caregiver-related phenomenon of "tutoring," or the nature of the disease itself.
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PMID:Clinical trials of propentofylline in vascular dementia. European/Canadian Propentofylline Study Group. 1060 97

Memantine is a moderate-affinity, voltage-dependent, uncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors. In contrast to competitive NMDA antagonists, Memantine is well tolerated in humans and is being developed for the treatment of dementia. The pathogenesis of vascular dementia (VaD) is largely unknown, and is likely multifactorial, but it involves the impairment of blood circulation as a common denominator. There is broad evidence for the efficacy of Memantine in several animal models of ischemia. Memantine also acts on several secondary, potentially contributing factors in VaD such as neuronal depolarization, removal of magnesium block of NMDA receptors, chronic overstimulation of these receptors, and, possibly, mitochondrial dysfunction. Among others, it also has additional positive effects on long-term potentiation and cognition in standard animal models of impaired synaptic plasticity. Recently, clinical efficacy of Memantine has been shown in an etiologically mixed population of severely demented patients, including those with VaD. Given the difficulties of diagnosing VaD in clinical practice, an optimal antidementive drug should be beneficial in both Alzheimer disease and VaD. Preclinical data presented in this paper indicate that such benefits can be achieved with Memantine. In addition, phase II clinical data in dementia are summarized, and two ongoing pivotal trials in VaD are described. Suggestions for VaD guideline development are made regarding clinical instruments, and etiologies and severity stages are considered.
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PMID:Pharmacologic rationale for memantine in chronic cerebral hypoperfusion, especially vascular dementia. 1060 98

Brains from patients with Alzheimer's disease contain diffuse and senile amyloid plaques. Using an experimental model, we have addressed the issue whether diffuse plaques of amyloid persist, develop with time, or both, in rats injected with human beta-amyloid-(1-42)-peptide for 3 and 12 mon after brain ischemia. Rats receiving beta-amyloid peptide for 3 months after brain ischemia demonstrated widespread diffuse amyloid plaques in hippocampus and cerebral cortex. Neuronal, glial, ependymal, endothelial and pericyte cell bodies were observed filled with beta-amyloid peptide. No staining was observed in control brains. In the group alive 1 year no deposition of human beta-amyloid peptide was observed, too. Direct evidence that diffuse amyloid plaques can disappear in the brain is thus provided for the first time.
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PMID:Ischemic rats as a model in the study of the neurobiological role of human beta-amyloid peptide. Time-dependent disappearing diffuse amyloid plaques in brain. 1061 54

Silent stroke is one of the risk factors of dementia. In the present study, we used a novel focal ischemic animal model to investigate the effects of comparatively small changes of cerebral blood flow (CBF) on the expression of beta-amyloid precursor protein (APP) mRNA. Focal ischemia was achieved by introducing a 4-0 monofilament to the bifurcation of anterior and middle cerebral arteries. Brain samples were harvested from ischemic core and penumbra of cortices at 1, 4 and 7 days following ischemia. The expression of APP mRNA was assessed by RT-PCR. The CBF was decreased to 50% for 1 day after stroke and recovered to 90% at the fourth day after stroke. The changes of CBF were accompanied by an increase in the expression of APP mRNA. APP mRNA increased to 208% and 152% in the penumbra and core ischemic regions, respectively, on the fourth day after MCAO and remained high through the seventh day of ischemia. This study suggests brain hypoperfusion enhances APP mRNA expression and may contribute to the progression of cognitive impairment after silent stroke.
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PMID:Hypoperfusion induces overexpression of beta-amyloid precursor protein mRNA in a focal ischemic rodent model. 1062 1

Some of the neurological deficits that emerge after aneurysmal subarachnoid hemorrhage (SAH) in humans are presumably caused by ischemic brain damage consequential to SAH-induced delayed cerebral vasospasm. This vasospasm probably results from an imbalance among vasoactive factors released from both the clot formed by extravasated blood and adjacent tissues, and in particular from a decrease in the endothelium-derived relaxing factor nitric oxide (NO). Brain ischemia is also known to elevate brain production and deposition of beta-amyloid, and to induce a delayed increase in total NO synthase (NOS) activity due to induction of expression of so-called induced NOS isoform, phenomena that may secondarily contribute to SAH-related brain damage. The aim of this study was to investigate the effects of treatment with the intracellular NO donor hydroxylamine on: (i) basilar arterial wall that remained in a direct contact with the clot, (ii) formation of the beta-amyloid precursor protein (beta-APP), (iii) total brain NOS activity, and (iv) neurological outcome in a 'two-hemorrhage' rat SAH model. Intraperitoneal (i.p.) administration of 0.18 mmol/kg hydroxylamine hydrochloride (12.5 mg/kg) twice daily for 7 days beginning immediately after the first 'hemorrhage' (intracisternal blood injection) reduced basilar arterial wall damage and attenuated post-SAH neurological deficit. It also reduced the SAH-related increases in hippocampal and cortical beta-APP immunoreactivities and hippocampal NOS activity measured 24 h after commencement of the treatment. These results indicate that intracellular NO donors that yield NO through the action of widely distributed enzymes in brain cells (cytochromes, catalase) can attenuate detrimental effects of SAH.
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PMID:Hydroxylamine attenuates the effects of simulated subarachnoid hemorrhage in the rat brain and improves neurological outcome. 1062 68

Evidence of the importance of the B vitamins folic acid, vitamin B-12, and vitamin B-6 for the well-being and normal function of the brain derives from data showing neurologic and psychologic dysfunction in vitamin deficiency states and in cases of congenital defects of one-carbon metabolism. The status of these vitamins is frequently inadequate in the elderly and recent studies have shown associations between loss of cognitive function or Alzheimer disease and inadequate B vitamin status. The question that arises is whether these B vitamin inadequacies contribute to such brain malfunctions or result from aging and disease. From a theoretical standpoint, these inadequacies could give rise to impairment of methylation reactions that are crucial to the health of brain tissue. In addition or perhaps instead, these inadequacies could result in hyperhomocysteinemia, a recently identified risk factor for occlusive vascular disease, stroke, and thrombosis, any of which may result in brain ischemia. Advances in the understanding of this putative relation between inadequate vitamin status and loss of cognitive function in the elderly are likely to be slow and may depend on the outcomes of both prospective studies and longitudinal studies in which nutritional intervention is provided before cognitive decline occurs.
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PMID:B vitamins, homocysteine, and neurocognitive function in the elderly. 1112 62

Transient brain ischemia in the rat produces a stereotyped pattern of selective neuronal degeneration which simulates early Alzheimer's disease (AD) pathology. The aim of the present study was to determine if apolipoprotein E (ApoE) variables are related to alterations in other proteins which play a central role in the pathogenesis of AD; amyloid precursor protein (APP) and beta-amyloid peptide (A beta). The postischemic time course of ApoE and APP and A beta immunoreactivity in brain was examined at survival time from 2 days to 1 year in rats subjected to 10 min cardiac arrest. These data indicate that there are long lasting alterations of ApoE and A beta after brain ischemia. The most likely stimulus for promoting increase of both ApoE and A beta expression are ischemic-reperfusion processes. Our data suggest that ApoE modulates the outcome following cerebral ischemia via molecular events in common with AD pathogenesis. We propose that ischemic-reperfusion processes in brain are the fountain-head of a cycle of molecular and cellular events that have neurodegenerative consequences which finally lead to AD.
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PMID:The role of apolipoprotein E in the deposition of beta-amyloid peptide during ischemia-reperfusion brain injury. A model of early Alzheimer's disease. 1081 22


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