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PubMedDate not supplied

Comparison of the somatosensory evoked potential and the direct cortical response following severe incomplete global ischemia: selective vulnerability of the white matter conduction pathways.

Eight cats were subjected to graded hemorrhagic hypotension following bilateral carotid ligation to produce incomplete global cerebral ischemia. Three additional cats served as controls. The somatosensory evoked potential (SEP) and direct cortical response (DCR) were monitored in all animals and in each case, the cortical component of the SEP was abolished during progressive ischemia while the morphology of the DCR was well-preserved but with reduced amplitude. Determinations of adenosine triphosphate (ATP), phosphocreatine (PCr), and lactate levels in cerebral cortex and white matter were made in five experimental cats and the three controls. At the time of failure of the cortical SEP, PCr was dramatically reduced and lactate moderately elevated in the white matter while ATP remained unchanged. Cortical lactate was only mildly elevated and PCr and ATP were unchanged accounting for preservation of the DCR. In this model of global ischemia, abolition of the cortical SEP is due to a block of stimulus conduction in white matter projection pathways. A hypothesis to explain the observed metabolic changes is presented and correlation is made to clinical situations.

Adenosine Triphosphate↗
PubMedDate not supplied

Effect of 5-minute ischemia on regional pH and energy state of the gerbil brain: relation to selective vulnerability of the hippocampus.

Adult male gerbils were submitted to 5-minute cerebral ischemia by bilateral carotid artery occlusion. At the end of ischemia and at various recirculation times ranging from 15 to 120 minutes, brains were frozen in situ and the regional distribution of ATP, glucose, and tissue pH was studied on coronal cryostat sections by bioluminescent and fluoroscopic techniques. During ischemia ATP was completely depleted, glucose decreased to less than 10% of control, and regional tissue pH decreased from 7.04-7.09 to about 6.0. After the beginning of recirculation tissue pH and the regional content of metabolites exhibited a triphasic course. After 15 minutes pH returned to or even above normal, and ATP- and glucose-induced bioluminescence normalized. However, there was a secondary deterioration of both tissue acidosis and the metabolic state after 30 minutes. After longer recirculation times changes again improved and returned to normal within 2 hours. These changes were similar in all brain regions with the exception of the CA1 sector of the hippocampus, where the transient normalization of tissue pH was absent after 15 minutes of recirculation. This finding is in line with the previously observed microcirculatory insufficiency of this area and demonstrates that the CA1 sector of the hippocampus suffers more pronounced postischemic acidosis than other less vulnerable regions of the brain.

Animals↗
PubMed1984

Selective vulnerability of the medullary thick ascending limb to anoxia in the isolated perfused rat kidney.

A specific anatomical lesion sharply localized to the cells of the medullary thick ascending limbs (mTAL) and characterized by mitochondrial swelling progressing to nuclear pyknosis and cell death is elicited reproducibly in isolated rat kidneys perfused for 15 or 90 min with cell-free albumin-Ringer's medium gassed with 5% CO2, 95% O2 (O2 content, 1.5 vol/100 ml). The lesion, involving about half of mTALs, appears first in mTALs removed from vascular bundles and near the inner medulla, areas most likely to be anoxic. Hypoxic perfusion (O2 content 0.12 vol/100 ml) exaggerates the lesion, wiping out gradations of damage and extending it to all mTALs. O2-enriched perfusions using rat erythrocytes (O2 content 7.1 vol/100 ml) completely eliminates the lesion (unless gassed with carbon monoxide). Similarly, supplementation of the perfusion medium with a purified hemoglobin (O2 content 5.8 vol/100 ml) prevents mTAL injury. Perfusion with a fluorinated hydrocarbon blood substitute, Oxypherol (O2 content 4.3 vol/100 ml) also attenuates the lesion. These findings suggest that the mTAL is exquisitely susceptible to anoxic damage because of low O2 supply imposed by the medullary vascular system and the high rate of metabolism mandated by active reabsorption of sodium chloride. The vulnerability of the mTAL to anoxic injury could play a key role in the pathogenesis of ischemic renal injury.

Animals↗
PubMedDate not supplied

Selective vulnerability of dopaminergic systems to industrial chemicals: risk assessment of related neuroendocrine changes.

Increased serum prolactin (PRL) is a common finding among subjects exposed to styrene, perchloroethylene, lead (Pb), and manganese (Mn) at levels below the current threshold limit values. On a group basis, abnormally high basal PRL shows a dose-related distribution among workers exposed to styrene, Pb, and Mn. On the basis of dose-response relationships, the benchmark doses (BMD) for styrene metabolites in urine, lead in blood (Pb-B), and Mn in urine (Mn-U), are 4 mg/g creatinine, 112 micrograms/L, and 0.3 microgram/L, respectively. Noteworthy, the BMD for Mn-U and Pb-B is well below the upper reference limit. A shift in the distribution but not in the prevalence of abnormally high values of serum PRL was observed among perchloroethylene-exposed dry cleaners, which makes interpretation in terms of risk difficult. The measurement of PRL thus provides opportunities for early identification of excess exposure to neurotoxic chemicals affecting dopaminergic control of pituitary secretion. For styrene, Pb, and Mn the BMD provides an objective and statistically determined threshold, which seems to be in good agreement with the estimated no-observed-adverse-effect-level (NOAEL). The NOAEL, however, is based on traditional approaches that require the application of uncertainty factors, e.g., a default factor of 10 when extrapolating the NOAEL from the lowest-observed-adverse-effect-level (LOAEL). Due to its sensitivity to a number of potential confounders, caution must be exercised when using PRL as a screening test at the individual level. Also, age and sex dependent variations in susceptibility may hamper extrapolations from the occupational settings to the general population.

Biomarkers↗
PubMed2000

Use of evoked potentials to objectively differentiate between selective vulnerability of cochlear and vestibular end organ function.

Auditory nerve brainstem evoked responses (ABR) have been used for several decades to investigate cochlear function. Recently techniques have been developed to elicit similar recordings from the vestibular end organs - short latency vestibular evoked potentials (VsEPs). Both ABR and VsEP reflect appropriate end organ function and may therefore be used to investigate the vulnerability of these end organs to various experimental insults, such as noise exposure and ototoxic drugs.

Animals↗
PubMed2005

BACE1, a major determinant of selective vulnerability of the brain to amyloid-beta amyloidogenesis, is essential for cognitive, emotional, and synaptic functions.

A transmembrane aspartyl protease termed beta-site APP cleavage enzyme 1 (BACE1) that cleaves the amyloid-beta precursor protein (APP), which is abundant in neurons, is required for the generation of amyloid-beta (Abeta) peptides implicated in the pathogenesis of Alzheimer's disease (AD). We now demonstrate that BACE1, enriched in neurons of the CNS, is a major determinant that predisposes the brain to Abeta amyloidogenesis. The physiologically high levels of BACE1 activity coupled with low levels of BACE2 and alpha-secretase anti-amyloidogenic activities in neurons is a major contributor to the accumulation of Abeta in the CNS, whereas other organs are spared. Significantly, deletion of BACE1 in APPswe;PS1DeltaE9 mice prevents both Abeta deposition and age-associated cognitive abnormalities that occur in this model of Abeta amyloidosis. Moreover, Abeta deposits are sensitive to BACE1 dosage and can be efficiently cleared from the CNS when BACE1 is silenced. However, BACE1 null mice manifest alterations in hippocampal synaptic plasticity as well as in performance on tests of cognition and emotion. Importantly, memory deficits but not emotional alterations in BACE1(-/-) mice are prevented by coexpressing APPswe;PS1DeltaE9 transgenes, indicating that other potential substrates of BACE1 may affect neural circuits related to emotion. Our results establish BACE1 and APP processing pathways as critical for cognitive, emotional, and synaptic functions, and future studies should be alert to potential mechanism-based side effects that may occur with BACE1 inhibitors designed to ameliorate Abeta amyloidosis in AD.

Amyloid Precursor Protein Secretases↗
PubMed1989

Selective vulnerability of the brain: new insights into the pathophysiology of stroke.

Stroke is a major cause of morbidity and mortality in the United States with 250,000 cases per year. Cerebral ischemia is the largest category of stroke with cardiac arrest, profound hypotension, and vascular occlusion the principal causes. Traditional approaches to the treatment of ischemic stroke focus on maintaining cardiac output, blood pressure, cerebral blood flow, and on preventing thrombosis. Recently, attention has been focused on developing new therapies that are directed toward abnormal biochemical events at excitatory synapses. Ischemia causes impairment of brain energy metabolism and the release of excessive amounts of glutamate into the extracellular space. This process secondarily excites neurons and further depletes energy stores. The excitotoxic hypothesis of brain injury proposes that glutamate is a principal cause of damage in ischemia. Three components of this hypothesis have been tested and largely proved in experimental studies in tissue culture and in animal models of stroke. First, elevated concentrations of glutamate cause excessive excitation at a subset of glutamate receptors, the N-methyl-D-aspartate (NMDA) receptor. Second, excitation at this receptor leads to excessive influx of sodium chloride and water which causes acute neuronal damage, and calcium which causes delayed and more permanent damage. Third, pharmacologic blockade at the NMDA receptor-ion channel complex prevents ischemic neuronal damage. Studies using specific pharmacologic compounds that block glutamate's action hold particular promise for treating stroke in humans, including competitive antagonists at the NMDA glutamate binding site (for example, 2-amino-5-phosphonovalerate, AP5), noncompetitive antagonists at the calcium channel (for example, MK-801, dextromethorphan, ketamine), and agents that might be directed at the glycine, zinc, and magnesium sites.

Animals↗
PubMed1999

[Mechanisms of selective vulnerability of cholinergic neurons to neurotoxic stimuli].

Preferential loss of cholinergic neurons in course of several encephalopathies may result from the fact that they utilize acetyl-CoA not only for energy production, but also for acetylcholine synthesis. Changes in activities of acetyl-CoA metabolizing enzymes and shifts in acetyl-CoA compartmentalization, found in different animal models of brain pathologies and in human post mortem brain, are discussed in therms of their impact on cholinergic system integrity.

Acetyl Coenzyme A↗
PubMedDate not supplied

Oxidative damage and metabolic dysfunction in experimental Huntington's disease: selective vulnerability of the striatum and hippocampus.

The etiology of neuronal death in neurodegenerative diseases, including Huntington's disease (HD), is still unknown. There could be a complex interplay between altered energy metabolism, excitotoxicity and oxidative stress. Unilateral administration of quinilonic acid (QA), NMDA agonist, in rat striatum in a single dose of 150 nM was used as a model of HD. The other two groups of animals were pretreated immediately before QA application with nerve growth factor (NGF) and fibroblast growth factor (FGF), respectively. Control group was treated with 0.9% NaCl in the same manner. Content of total glutathione was not altered in the striatum and hippocampus of QA-treated animals, as well as in the groups pretreated with neurotrophic factors (NF), compared to controls. Content of reduced glutathione, a key antioxidant, was mutually depleted in the striatum and hippocampus of each experimental group. The reduced/total glutathione ratio was decreased in the QA-treated animals, but nearby or over the controls in each structure of the NF-treated groups. These results support the hypothesis that oxygen-free radicals contribute to the excitotoxic neuronal injury, and also that NF could be the potential neuroprotective agents in HD. Moreover, activity of cytochrome c oxidase, the last component in the mitochondrial respiratory chain, was mutually increased in each structure of QA-treated animals. This increase was less pronounced in the NF-treated groups. Striatal lesions led to the loss of tonic inhibitory inputs to the globus pallidus with consequent increase in the activity of GABAergic efferent pallidal neurons, suggesting that NF could functionally repair the altered striopallidal pathway.

Animals↗
PubMed2001

Selective vulnerability of embryonic cell populations to ethanol-induced apoptosis: implications for alcohol-related birth defects and neurodevelopmental disorder.

BACKGROUND: Ethanol-induced cell death has been characterized in very few stages of embryogenesis. This investigation comprehensively maps patterns of both programmed and ethanol-induced cell death in the central nervous system and craniofacial region at 0.5-day intervals from gestational day (GD) 6.5 to 11 in mice. METHODS: A teratogenic dosage of ethanol (2.9 g/kg) or vehicle was administered via two intraperitoneal injections to pregnant C57BL/6J mice at various stages of gestation. Cell death patterns were characterized using Nile blue sulfate vital staining and histological analysis of plastic sections. Confocal laser scanning microscopy of LysoTracker Red-stained specimens allowed for three-dimensional visualization of areas of apoptosis and precise sectional imaging of mouse embryos. Apoptosis was also documented using a TUNEL technique on histological sections. RESULTS: Normal programmed cell death in control embryos was noted in the prechordal plate region at GD 8, the neuroepithelium of the fourth ventricle and anterior neuropore at GD 9, and within the ganglia of cranial nerves V, VII-VIII, IX, and X at GD 10. Acute maternal ethanol administration 12 hr before examination resulted in a dramatic increase in apoptosis within sites of programmed cell death in the embryo. Moreover, ethanol-exposed specimens exhibited stage-dependent excessive cell death in other distinct cell populations, particularly within the developing central nervous system. Ethanol-induced apoptosis was notable as follows: GD 7.5-neuroectoderm; GD 8-neural plate and primitive streak; GD 9-alar plate and presumptive neural crest of the rostral hindbrain, especially at the mesencephalon/rhombencephalon junction; GD 9.5-10-branchial arches and rhombomeres; and GD 11-diencephalon, basal ganglia, pons, and developing cerebellum. CONCLUSIONS: The results of this study revealed developmental stage-specific cell populations of the developing brain and craniofacial region that are vulnerable to ethanol-induced apoptosis and provide new insight relative to the genesis of alcohol-related birth defects.

Animals↗
PubMed1991

[Selective vulnerability of peptide-containing neurons in cerebral ischemia; immunohistochemical study].

Histochemical changes in peptidergic and catecholaminergic neurons during ischemia were investigated in the cerebral neocortex of the gerbil. Catecholaminergic fibers were observed by catecholamine histofluorescence with glyoxylic acid solution, and peptidergic neuron systems such as vasoactive intestinal polypeptide (VIP), somatostatin (SOM), and neuropeptide Y (NPY) were observed by immunohistochemistry. Two hours after unilateral occlusion of the internal carotid artery, catecholaminergic fibers disappeared in the neocortex on the occlusion side, while peptidergic nerve fibers except for NPY fibers were intact after 2 hours of ischemia. NPY fibers had decreased in number on the occlusion side 2 hours after ischemia. VIP-, SOM-, and NPY-immunoreactive neurons showed a decrease of 60% six hours after ischemia, and these neurons completely disappeared in the cerebral neocortex 24 hours after ischemia. These results suggest that catecholaminergic neuron system is more vulnerable than the peptidergic one in ischemic event.

Animals↗
PubMed1991

Selective vulnerability in brain hypoxia.

In the adult human brain, acute hypoxic episodes result in a certain pattern of nerve cell damage from which a hierarchy of neuronal vulnerability can be formed. Among the most sensitive regions are the "older" brain structures like hippocampus and cerebellum. In these structures, the typical picture is loss of pyramidal and Purkinje cells. Also, the neocortex is among the vulnerable structures, and often a characteristic laminar neuron loss is found. In the neonatal brain, the pattern of damage is somewhat different after hypoxia-ischemia, where damage to the periventricular white matter is frequent in addition to the above-mentioned cortical damage. This review deals with a number of pathogenetic factors, including excessive formation of lactate, arachidonic acid, and free radicals, as well as an increased release of excitatory neurotransmitters. Experimental studies on the effect of calcium and glutamate receptor blockers in hypoxia-ischemia and their possibilities for treatment of ischemic-hypoxic damage in humans are critically evaluated.

Animals↗
PubMed1988

Selective vulnerability of glutathione metabolism and cellular defense mechanisms in rat striatum to manganese.

The present findings provide experimental evidence for the hypothesis that compromised cellular defense mechanisms, i.e., glutathione (GSH), GSH-peroxidase and catalase in the brain may be involved in neuronal degeneration caused by manganese (Mn) neurotoxicity. Moreover, data are presented demonstrating that the striatum is particularly susceptible to the deleterious effects of Mn. Specifically, exposure to subchronic MnCl2 produced significant reductions in GSH-peroxidase activity in the cytosol and mitochondrial fractions of the whole brain and the striatum. The decrease in GSH-peroxidase was most pronounced in the mitochondrial fraction of the striatum where the activity was reduced to 35% of the control. Catalase activity was also decreased in the striatum of rats treated with Mn but not in the whole brain. GSH content was markedly depleted (20% of the control) in the striatum, although only modestly decreased in whole brain (80% of the control). The alterations in the above parameters were accompanied by depletion of dopamine and dopamine metabolites in the striatum. The treatment of rats with Mn also decreased the activity of oxidized glutathione-reductase; the same treatment increased the activity of gamma-glutamyltranspeptidase. The activity of gamma-glutamylcysteine synthetase was not altered by Mn. The possible relevancy of the findings of this study to understanding the mechanism of Mn neurotoxicity of dopamine systems is discussed.

Animals↗