SEARCH · PubMed Health

Results for “selective vulnerability”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 973 records · Page 54Linked to original sources

PubMed1992

Hypoxia-induced functional alterations in adult rat neocortex.

1. Brief periods of hypoxia (2-7 min) were induced in rat neocortical slices maintained in an interface-type recording chamber at 34-35 degrees C by changing the aerating gas from 95% O2-5% CO2 to 95% N2-5% CO2. Field potential (FP) and intracellular recordings were obtained in layers II/III of primary somatosensory cortex. Intracellular injection of biocytin revealed the characteristic morphology of supragranular spiny pyramidal neurons. 2. Excitatory synaptic transmission reversibly decreased by 45% as estimated from FP responses to orthodromic stimulation of the underlying white matter/layer VI. Excitatory postsynaptic potentials (EPSPs) were suppressed by 36% in amplitude and recovered within 2-3 min after reoxygenation. During the recovery period, EPSPs showed a reversible increase in duration by 72%. 3. Inhibitory synaptic transmission was completely blocked as determined in FP responses with a paired-pulse inhibition protocol. The fast inhibitory postsynaptic potential (IPSP) declined by 58% during hypoxia. The long-lasting IPSP was suppressed by 75% and showed incomplete recovery. During hypoxia, the amplitude of both IPSPs was significantly more strongly suppressed than the EPSP. 4. In 40% of the cells, hypoxia induced an early anoxic hyperpolarization with a reversal potential of E = -80.8 mV, followed by a postanoxic hyperpolarization (E = -89.4 mV). In a second group of cells (37%), a gradual anoxic depolarization with E = -57.5 mV was observed instead of an early hyperpolarization. In both groups of cells, the anoxic response was associated with a marked decrease in input resistance, by 42 and 31%, respectively. 5. The spike discharge frequency was reversibly suppressed by 71% during hypoxia. A transient hyperexcitability accompanied with a rise in input resistance and discharge rate was observed in 38% of the cells on reoxygenation. 6. The reversal potential of the anoxic hyperpolarization was unaffected by tetrodotoxin (TTX) but was significantly altered by application of the ATP-sensitive K+ channel (KATP) blocker gliquidone. Application of gliquidone additionally resulted in a significantly smaller hypoxia-induced decline in paired-pulse inhibition. 7. Increases in tissue high-energy phosphates induced by preincubating the slices in 25 mM creatine for greater than 2 h had a pronounced protective effect on excitatory and inhibitory synaptic transmission. 8. These data suggest a selective vulnerability of the neocortical inhibitory system during hypoxia. Our results further indicate that hypoxia activates a pre- and postsynaptic KATP conductance because of the decline in intracellular ATP.

Adenosine Triphosphate↗

PubMed1999

Membrane potential and intracellular Ca2+ oscillations activated by mGluRs in hippocampal stratum oriens/alveus interneurons.

Metabotropic glutamate receptors (mGluRs) are expressed heterogeneously in hippocampal interneurons, and their signal transduction cascades remain largely unclear. We characterized an oscillatory response activated by the mGluR agonist 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) in hippocampal interneurons of stratum oriens-alveus (OA) with simultaneous whole cell current-clamp recordings and intracellular Ca2+ imaging with confocal microscopy. 1S,3R-ACPD induced oscillatory membrane depolarizations and rises in intracellular Ca2+ that persisted in tetrodotoxin and were blocked by the antagonist of group I and II mGluRs (S)-alpha-methyl-4-carboxyphenylglycine. Membrane depolarizations and intracellular Ca2+ rises were blocked by extracellular Cd2+ and in Ca2+-free medium. mGluR responses therefore required Ca2+ influx via voltage-gated Ca2+ channels. 1S, 3R-ACPD responses were also antagonized by depleting intracellular stores with thapsigargin and ryanodine, indicating that Ca2+ release from intracellular stores was also necessary. These data suggest that oscillatory responses generated by group I/II mGluRs involve a coupling of Ca2+ entry through voltage-gated Ca2+ channels and Ca2+ release from internal stores. In contrast, 1S,3R-ACPD evoked only smaller depolarizations and intracellular Ca2+ rises, with no oscillations, in other hippocampal interneurons located in or near stratum lacunosum-moleculare. Thus mGluR-mediated oscillatory responses are specifically expressed in certain interneuron subtypes. This heterogeneous expression of glutamate and Ca2+ signaling pathways in specific interneurons may be relevant to their selective vulnerability to excitotoxicity.

Animals↗

PubMed2001

Synaptically activated calcium responses in dendrites of hippocampal oriens-alveus interneurons.

Activation of metabotropic glutamate receptors (mGluRs) by agonists increases intracellular calcium levels ([Ca(2+)](i)) in interneurons of stratum oriens/alveus (OA) of the hippocampus. We examined the mechanisms that contribute to dendritic Ca(2+) increases in these interneurons during agonist activation of mGluRs and during synaptically evoked burst discharges, using simultaneous whole cell recordings and confocal Ca(2+) imaging in rat hippocampal slices. First, we found that the group I/II mGluR agonist 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD; 100 microM) increased dendritic [Ca(2+)](i) and depolarized OA interneurons. Dendritic Ca(2+) responses were correlated with membrane depolarizations, but Ca(2+) responses induced by ACPD were larger in amplitude than those elicited by equivalent somatic depolarization. Next, we used linescans to measure changes in dendritic [Ca(2+)](i) during synaptically evoked burst discharges and somatically elicited repetitive firing in disinhibited slices. Dendritic Ca(2+) signals and electrophysiological responses were stable over repeated trials. Peak Ca(2+) responses were linearly related to number and frequency of action potentials in burst discharges for both synaptic and somatic stimulation, but the slope of the relationship was steeper for responses evoked somatically. Synaptically evoked [Ca(2+)](i) rises and excitatory postsynaptic potentials were abolished by antagonists of ionotropic glutamate receptors. The group I/II mGluR antagonist S-alpha-methyl-4-carboxyphenylglycine (500 microM) produced a significant partial reduction of synaptically evoked dendritic Ca(2+) responses. The mGluR antagonist did not affect synaptically evoked burst discharges and did not reduce either Ca(2+) responses or burst discharges evoked somatically. Therefore ionotropic glutamate receptors appear necessary for synaptically evoked dendritic Ca(2+) responses, and group I/II mGluRs may contribute partially to these responses. Dendritic [Ca(2+)](i) rises mediated by both ionotropic and metabotropic glutamate receptors may be important for synaptic plasticity and the selective vulnerability to excitotoxicity of OA interneurons.

Animals↗

PubMed2006

Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors.

The Notch signaling pathway is required in both nonneoplastic neural stem cells and embryonal brain tumors, such as medulloblastoma, which are derived from such cells. We investigated the effects of Notch pathway inhibition on medulloblastoma growth using pharmacologic inhibitors of gamma-secretase. Notch blockade suppressed expression of the pathway target Hes1 and caused cell cycle exit, apoptosis, and differentiation in medulloblastoma cell lines. Interestingly, viable populations of better-differentiated cells continued to grow when Notch activation was inhibited but were unable to efficiently form soft-agar colonies or tumor xenografts, suggesting that a cell fraction required for tumor propagation had been depleted. It has recently been hypothesized that a small population of stem-like cells within brain tumors is required for the long-term propagation of neoplastic growth and that CD133 expression and Hoechst dye exclusion (side population) can be used to prospectively identify such tumor-forming cells. We found that Notch blockade reduced the CD133-positive cell fraction almost 5-fold and totally abolished the side population, suggesting that the loss of tumor-forming capacity could be due to the depletion of stem-like cells. Notch signaling levels were higher in the stem-like cell fraction, providing a potential mechanism for their increased sensitivity to inhibition of this pathway. We also observed that apoptotic rates following Notch blockade were almost 10-fold higher in primitive nestin-positive cells as compared with nestin-negative ones. Stem-like cells in brain tumors thus seem to be selectively vulnerable to agents inhibiting the Notch pathway.

Amyloid Precursor Protein Secretases↗

PubMedDate not supplied

Hypoxia-ischemia-induced apoptotic cell death correlates with IGF-I mRNA decrease in neonatal rat brain.

Hypoxia-ischemia induces apoptotic and necrotic cell death, which results partially from persistent alterations in cellular energy homeostasis. Insulin-like growth factor I (IGF-I) is an anabolic pleiotrophic factor required by developing neurons for their optimal proliferation, differentiation, and survival. To determine how cell death and changes in IGF-I gene expression relate to the extent of hypoxia-ischemia, we evaluated the time course of apoptosis in a neonatal hypoxia-ischemia model in relation to the cellular distribution of IGF-I and IGFBP5 mRNA. Severe hypoxia-ischemia results in an immediate decrease in neuronal IGF-I and IGFBP5 mRNA. The decrease in neuronal IGF-I mRNA was concurrent with an increase in the number of apoptotic cells. It is conceivable that the immediate decrease in IGF-I gene expression may contribute to the impending neuronal death and selective vulnerability of myelinogenesis during the perinatal period.

Animals↗

PubMedDate not supplied

In vivo quantification of brain volumes in subcortical vascular dementia and Alzheimer's disease. An MRI-based study.

Quantitative magnetic resonance imaging (MRI) was used to assess global and regional cerebral volumes in patients with a clinical diagnosis of subcortical vascular dementia (VD) and Alzheimer's disease (AD). Whole brain volume, cerebrospinal fluid volume, volumes of the temporal, frontal and parietal lobes, the cerebellum and the amygdala-hippocampus complex were determined using a personal computer-based software. Seventeen patients with VD, 22 patients with AD and 13 healthy controls were included. Analysis of covariance using age as covariate demonstrated significant mean differences between controls and dementia groups with respect to all morphological parameters. However, apart from the volume of the cerebellum no significant volumetric differences were found between VD and AD. These results indicate that MRI-based volumetry allows differentiation between AD or VD from normal controls and that measurement of cerebellar volume may be of use to separate vascular and degenerative dementia. However, since the distribution of cerebral atrophy in both dementia groups is very similar, it is suggested that the atrophic changes are not specific to the underlying cause but rather reflect the selective vulnerability of neuronal structures.

Aged↗

PubMed2001

Oxidant mechanisms in neonatal hypoxia-ischemia.

The neonatal brain appears to be selectively vulnerable to oxidative stress. Several potential mechanisms associated with altered reactive oxygen species metabolism would explain the increased susceptibility. They include increased accumulation of hydrogen peroxide with subsequent neurotoxicity. This enhanced neurotoxicity from H2O2 accumulation may be related to inadequate scavenging abilities of the immature nervous system, such as lower glutathione peroxidase activity. Contributing to the immaturity of the scavenging enzymes is the inability of the developing nervous system to maintain glutathione stores. The immature nervous system is rich in iron, and has more free iron than the mature nervous system. As H2O2 accumulates because of these improper defense mechanisms, it is exposed to this free iron. This exposure results in the generation of OH radical (Fenton reaction), a more potent free radical that can cause severe damage. The rapid conversion of H2O2 to OH in the setting of free iron sets up the immature nervous system for increased cytotoxicity. Understanding the molecular mechanisms of oxidative stress will lead to better therapies for neonatal hypoxia-ischemia.

Brain↗

PubMed2006

Mitogen-activated protein kinase signaling, oxygen sensors and hypoxic induction of neurogenesis.

In the adult nervous system, neuronal subpopulations sustain a hierarchical pattern of selective vulnerability to hypoxia. Hypoxia also activates quiescent neural progenitor cells (NPCs) resulting in their amplification and subsequent differentiation into neurons and glia. Use of rat organotypic hippocampal cultures facilitates examination of early signaling events in response to hypoxia and reoxygenation that result in neurogenesis. Cultures were exposed to hypoxia for up to 6 h followed by reoxygenation. CA1 neurons showed focal nuclear condensation by 2 h of hypoxia, but CA2 and CA3 neurons were spared. JNKs and c-Jun reached peak activation by 4 h, returning to basal levels by 6 h. Expression of oxygen sensors, hemoxygenase 2 and HIF1, were elevated by 30 min and 2 h, respectively. By 24 h of reoxygenation, there was proliferation of nestin-positive NPCs. With U0126, an upstream inhibitor of ERK activation, BrdU labeling was markedly reduced immunohistochemically as well as PCNA protein expression, suggesting a role for ERKs in the proliferation response. Immunohistochemically, antinestin detected NPCs and on Western blots reached peak levels by 24-48 h of reoxygenation. Proliferation and differentiation of endogenous NPCs in the area of neuronal loss further suggests that mechanisms potentially exist in vitro for replacement with functional neurons.

Animals↗

PubMedDate not supplied

Brain damage caused by ischemia: pathophysiological and pharmacological aspects.

The distribution of brain cell injury after ischemic challenge is remarkable because only discrete brain areas are damaged, whereas other structures exhibit a very high resistance (selective neuronal death). The calcium hypothesis, one of the hypotheses that has been formulated to explain this selective vulnerability, postulates that an increase in excitatory amino acid release and the large calcium influx during ischemia leads to insufficient energy production and to stimulation of lipases, proteases, and endonucleases. This paper reviews the experimental data concerning the relationship between cerebral blood flow, glucose consumption and hippocampal morphological damage. The neuroprotective effects of some drugs against ischemic damage have also been discussed.

Animals↗

PubMed1993

Transient hypodensity on CT scan during hypoglycemia.

A diabetic patient became hypoglycemic with right hemiparesis during a contrast-enhanced CT scan. The scan showed a nonenhancing hypodensity in the left internal capsule, that disappeared the following day after treatment with glucose. This is consistent with experimental models that show selective vulnerability of various brain regions to hypoglycemia.

Aphasia↗

PubMedDate not supplied

Effects of hemorrhagic hypotension on the cerebral circulation. III. Neuropathology.

A neuropathological examination was made of 15 cats anesthetized with alpha-chloralose, subjected to a stepwise reduction in mean arterial pressure by graded hemorrhagic hypotension. Five animals were sacrificed by perfusion-fixation at a mean arterial pressure of 75 mm Hg, 5 at a mean pressure of 35 mm Hg and 5 at 25 mm Hg. Ischemic brain damage was seen in only 5 animals, one sacrificed at a mean arterial pressure of 35 mm Hg and 4 at a pressure of 25 mm Hg. It was maximal in the selectively vulnerable areas and included the boundary zones between the major arteries of the cerebral hemispheres, the Ammon's horn and the thalamus.

Animals↗

PubMedDate not supplied

Opioid peptide levels in gerbil brain after transient ischemia: lasting depletion of hippocampal dynorphin.

Peptides derived from each of the 3 endogenous opioid precursors were measured in gerbil brain regions at various times after transient bilateral carotid artery occlusion using radioimmunoassays specific for beta-endorphin-, met-enkephalin-, and dynorphin A-related peptides. Lasting changes were observed only in the hippocampus. The most striking effect was on dynorphin A immunoreactivity, which was reduced by 30-40% as early as 1 hour after recirculation and remained at 50% of the control level for at least 1 week. In some experiments dynorphin levels showed a transient recovery at 24 hours. These results demonstrate a unique sensitivity of the dynorphin-containing dentate granule cell-mossy fiber pathway to transient ischemia. Although these cells remain histologically intact, the decrease in dynorphin level precedes and continues during the delayed loss of hippocampal CA1 neurons characteristic of this model and further defines the selective vulnerability of hippocampal circuitry following ischemia. These observations clearly identify the hippocampus as a well-defined brain region in which further studies of the postischemic pathophysiology of endogenous opioid peptides may provide a rational basis for evaluating the place of opiate pharmacology in stroke treatment.

Animals↗

PubMed1988

Immunohistochemical investigation of ischemic and postischemic damage after bilateral carotid occlusion in gerbils.

We investigated progression and recovery of neuronal damage during and after global cerebral ischemia in gerbils after bilateral occlusion of the common carotid arteries, using the immunohistochemical method (reaction for tubulin and creatine kinase BB-isoenzyme). The earliest, but reversible, ischemic lesions occurred after 3 minutes' ischemia in the subiculum-CA1 and CA2 regions of the hippocampus. The lesions became irreversible after 4 minutes' ischemia. The ischemic and postischemic lesions in the cerebral cortex, thalamus, and caudoputamen were partially or completely reversible if the ischemic period was 5 minutes, whereas delayed degeneration occurred in the pyramidal cells of the medial CA1 region after reperfusion for 48 hours (delayed neuronal death). After 10 minutes' ischemia and subsequent reperfusion, delayed neuronal death extended from the medial to the lateral CA1 region; the ischemic and postischemic lesions in the cerebral cortex, thalamus, and caudoputamen also expanded during reperfusion. Our investigation demonstrates that selective vulnerability existed in global cerebral ischemia as in incomplete or regional ischemia and suggests that neurons in many areas of the brain possessed the potential for recovery, progressive deterioration, and even delayed neuronal death depending on the severity and duration of cerebral ischemia.

Animals↗

PubMed1988

Quantitative analysis of effects of kappa-opioid agonists on postischemic hippocampal CA1 neuronal necrosis in gerbils.

The ability of the kappa-opioid receptor agonists U50488H and U62066E (spiradoline mesylate) compared with the non-kappa close structural analogue U54494A to affect postischemic necrosis of the selectively vulnerable hippocampal CA1 neurons was examined in male Mongolian gerbils. The gerbils were treated with either saline vehicle or 10 mg/kg i.p. of one of the test drugs 30 minutes before and again 2 hours after a 10-minute period of bilateral carotid artery occlusion or sham occlusion under light methoxyflurane anesthesia. Seven days after ischemia and reperfusion the brains were perfusion-fixed, and hippocampal CA1 cells were counted in a blind fashion. In ischemic gerbils that received only vehicle, there was a 78.9% loss of CA1 neurons compared with sham-occluded gerbils. In contrast, in U50488H-treated gerbils, mean cell loss was reduced to 33.9% (p less than 0.01 vs. vehicle-treated group). U62066E was even more effective in reducing postischemic CA1 degeneration to only 20.7% (p less than 0.0001 vs. vehicle-treated group). However, treatment with the non-kappa analogue U54494A did not cause any apparent protection; the gerbils in this group showed an 80.7% loss of CA1 neurons. Our results are consistent with the hypothesis that kappa-receptor stimulation is associated with improved postischemic neuronal preservation.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1989

Effect of lidocaine on forebrain ischemia in rats.

We examined the effect of lidocaine on ischemic neuronal injury in the rat forebrain ischemia model. Cerebral ischemia was achieved with bilateral carotid artery occlusion and controlled hypotension to a mean of 50 torr for 10 minutes. Perfusion-fixation was performed 7 days after ischemia, subsequent to which the brains were sectioned coronally and stained with hematoxylin and eosin. Ischemic neuronal injury was quantitatively expressed (after direct counting) as a percentage of total neurons, that is, ischemic neurons divided by (ischemic neurons + normal neurons). Predictably, the selectively vulnerable hippocampal areas exhibited the most marked neuronal injury. In the CA1/CA2 sectors, lidocaine-treated rats demonstrated less injury (34 +/- 14%) than untreated (64 +/- 9%) or saline-treated (70 +/- 10%) rats. However, these superficially pronounced numerical differences were not of statistical significance (p greater than 0.05). In the CA3 sector, neuronal injury in lidocaine-treated rats (31 +/- 14%) was significantly different at p less than 0.05 from the untreated (80 +/- 5%) but not the saline-treated (59 +/- 13%) group. We conclude that lidocaine may have an only marginal beneficial effect on forebrain ischemia in rats.

Animals↗

PubMed1990

Therapeutic window of CA1 neuronal damage defined by an ultrashort-acting barbiturate after brain ischemia in gerbils.

Previous therapeutic studies on the prevention of selective vulnerability of neurons in the hippocampus have suggested that the critical period for induction of delayed neuronal injury occurs early during recirculation. To determine the onset and duration of this period, an ultrashort-acting barbiturate (methohexital) was infused into the left carotid artery of 47 gerbils after various times of recirculation following 10 minutes of bilateral forebrain ischemia. Neuronal density in the left CA1 sector was determined 7 days later by counting the number of surviving neurons per millimeter of pyramidal cell layer. In 16 saline-treated gerbils, less than 10% of the CA1 neurons survived the 10 minutes of ischemia. Postischemic carotid infusion of methohexital improved neuronal survival, the degree of improvement depending on the timing and duration of the methohexital infusion. When carried out during the initial 40 minutes of recirculation, methohexital infusion for 10 minutes increased the number of surviving neurons to approximately 60% of that in five sham-operated control gerbils. This increase was significant for infusions carried out between the 10th and 20th minutes (n = 6, p less than 0.05) and between the 30th and 40th minutes (n = 6, p less than 0.05) of recirculation. Methohexital infusion for 20 minutes increased neuronal survival to 95% and 73% of that in the controls when carried out between the 0th and 20th minutes (n = 5, p less than 0.005) and between the 20th and 40th minutes (n = 5, p less than 0.005) of recirculation, respectively. Protection was nonsignificant for 10- or 20-minute methohexital infusions carried out after the 40th minute of recirculation. Our results demonstrate that the pathologic processes leading to delayed neuronal injury in the CA1 sector are induced during the initial 40 minutes of recirculation and that barbiturates are able to reverse these processes only if given during this period.

Animals↗

PubMed1990

Calcium-calmodulin binding in ischemic rat neurons after calcium channel blocker therapy.

Calcium channel blockers such as nicardipine improve outcome after global cerebral ischemia and may attenuate ischemic neuronal injury by preventing calcium influx and binding to calmodulin. We followed the temporal and regional sequence of neuronal calcium-calmodulin binding in normal rats (n = 6), untreated ischemic rats (n = 15), and ischemic rats treated with 0.05 mg/kg/hr s.c. nicardipine (n = 13). After 30 minutes of four-vessel occlusion, 40-microns brain sections were incubated in an anti-calmodulin antibody specific for calmodulin not bound to calcium and brain protein. Light-microscopic sections were examined immediately after ischemia and after 2 and 24 hours of reperfusion. Extensive staining of unbound calmodulin was seen in all hippocampal regions and in the cortex in normal rats. In untreated ischemic control rats, staining was lost, indicating calcium-calmodulin binding immediately after ischemia in all regions. However, after 24 hours, staining returned to normal in the cortex and dentate, and minimal staining returned in CA1 and CA3. Nicardipine-treated animals had significantly less calcium-calmodulin binding in CA1 and in the dentate after 2 hours of reperfusion. This study demonstrates that in clinically relevant doses nicardipine has a limited effect on calcium-calmodulin binding in selectively vulnerable regions after severe ischemia.

Animals↗

PubMed1992

A rat model of severe neonatal hypoxic-ischemic brain injury.

BACKGROUND AND PURPOSE: Perinatal hypoxic-ischemic brain injury is a common problem with severe neurological sequelae. In this report we describe in detail a simple model of hypoxia-ischemia in the neonatal rat that gives rise to severe neocortical infarction and to selective hippocampal neuronal necrosis. METHODS: Seven-day-old Simonsen Wistar rat pups underwent bilateral carotid artery ligation under methoxyflurane anesthesia and, after a 4 to 6-hour recovery, were exposed to 60 minutes of hypoxia (6.5% O2); they were perfusion-fixed 3 days later for histological study. Brain temperature was monitored throughout this treatment. RESULTS: We found that 64 +/- 3% of neocortex above the rhinal sulcus was infarcted; this infarction was evenly distributed through the cerebral hemispheres. In the hippocampus, neuronal necrosis was selective for the internal (hilar) layers of granule cells of the dentate gyrus, with relative sparing of CA1 pyramidal cells. In addition, brain temperature was tightly controlled throughout the experimental manipulations. CONCLUSIONS: The present model is easy and sensitive and provides an infarct of sufficient severity and homogeneity to make it well suited for pharmacological and biochemical studies directed toward therapeutic amelioration and mechanisms of hypoxic-ischemic brain damage, respectively. In addition, the pattern of damage in the hippocampus is quite different from that seen in the adult brain, which should be helpful in studying the ontogeny of selective vulnerability.

Animals↗