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Results for “selective vulnerability”

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PubMed2000

Glucocorticoids exacerbate insult-induced declines in metabolism in selectively vulnerable hippocampal cell fields.

Glucocorticoids (GCs), the adrenal steroids released during stress, can compromise the ability of hippocampal neurons to survive necrotic neurological insults. This GC-induced endangerment has energetic facets, in that it can be attenuated with energy supplementation. In the present report, we studied the effects of GCs on the metabolic response of specific hippocampal cell fields to necrotic insults. We used silicon microphysiometry, which allows indirect measurement of metabolism in real time in tissue explants. Aglycemia caused a significant decline in metabolism in dentate gyrus explants, but not in CA1 or CA3 explants. When coupled with our prior report of cyanide disrupting metabolism only in CA1 explants, and the glutamatergic excitotoxin kainic acid disrupting metabolism only in CA3 explants, this demonstrates that microphysiometry can detect the selective regional vulnerability that characterizes the hippocampal response to these necrotic insults. We then examined the effects of GCs on the response to these insults, monitoring explants taken from rats that were adrenalectomized, intact, or treated with corticosterone (the GC of rats) that produced circulating levels equivalent to those of major stressors. Increased exposure to GCs worsened the decline in metabolism in dentate gyrus explants induced by hypoglycemia, and in CA1 explants induced by cyanide (after eliminating the effects of glial release of lactate for the support of neuronal metabolism). Thus, GCs worsen the metabolic consequences of necrotic insults in hippocampal explants.

Animals↗

PubMed1982

Selective vulnerability of neural cells to viral infections.

A number of viruses selectively infect neurons and, in some cases, specific populations of neurons. The susceptible neuron need not be permissively infected to cause acute or chronic disease; therefore, infectious virus may not be recoverable and morphologically identifiable viral structures may not be detectable by ultrastructural structures. Polioviruses and the neurotropic murine retrovirus both cause paralytic disease with major pathological changes in motor neurons of the spinal cord. Both produce disease more readily in later life; in poliovirus because the mature animals are more susceptible to acute infection, and in the neurotropic retrovirus infections because of the long incubation period of the natural infection. In the acute inflammatory poliovirus infections, the motor neurons appear to be selectively infected and lysed by the virus, whereas in the chronic noninflammatory retrovirus infection, the effect may be indirect or may result from nonpermissive infection.

Animals↗

PubMed1993

Selective vulnerability and early progression of hippocampal CA1 pyramidal cell degeneration and GFAP-positive astrocyte reactivity in the rat four-vessel occlusion model of transient global ischemia.

Selective, delayed-onset vulnerability of hippocampal CA1 pyramidal cells has been reported as a unique phenomenon in man and the rat four-vessel occlusion (4-VO) model of global ischemia. This has become of great interest for clarification of CA1 pathophysiology and pharmacological intervention after global ischemia. Studies of pathophysiology and pharmacotherapy appear to be impeded by variability in specific criteria and duration of 4-VO ischemia for producing selective CA1 and differential CA1-CA3 damage. The goals of this study were to: (1) develop specific criteria for 4-VO ischemia to ensure selective, bilaterally symmetrical CA1 pyramidal cell damage, (2) examine the effects of 15 min of ischemia on concomitant CA1 cell necrosis and presence of remaining and/or "viable" neurons postischemia, (3) compare 15 and 30 min of ischemia on differential vulnerability of CA1-CA3 subfields, and (4) evaluate the effects of 15 min of ischemia on CA1 pyramidal cell necrosis and glial fibrillary acidic protein (GFAP)-positive astrocyte reactivity in CA1. After 15 min of ischemia, hippocampal pyramidal cell damage was well delineated, with CA1 severely damaged, but leaving CA3 virtually intact. In contrast, 30 min of ischemia produced severe CA1 and less severe CA3 necrosis. Histological evaluations across Days 1, 3, 6, and 14 indicated a significant delayed onset of CA1-CA3 cell necrosis by Day 3. Counting of remaining cells indicated a detectable loss of some large pyramidal neurons even 1 day after ischemia. Compared to controls, there was a differential increase in GFAP-positive astrocytes in CA1-CA3 after ischemia. The results provided quantitative data on the effects of specific 4-VO criteria and durations on: (1) selective CA1 cell necrosis, (2) differential CA1-CA3 cell vulnerability, (3) presence of postischemic remaining and/or viable neurons, and (4) prospect of a "therapeutic window" for pharmacological treatment of CA1 neuronal injury.

Animals↗

PubMed2003

Selective vulnerability of subplate neurons after early neonatal hypoxia-ischemia.

Neonatal hypoxia-ischemia in the preterm human leads to selective injury to the subcortical developing white matter, which results in periventricular leukomalacia (PVL), a condition associated with abnormal neurodevelopment. Maturation-dependent vulnerability of late oligodendrocyte progenitors is thought to account for the cellular basis of this condition. A high frequency of cognitive and sensory deficits with decreasing gestational age suggests pervasive abnormalities of cortical development. In a neonatal rat model of hypoxic-ischemic injury that produces the characteristic pattern of subcortical injury associated with human PVL, selective subplate neuron death is seen. The premature subplate neuron death occurs after thalamic axons have reached their targets in cortex. Thus, as expected, thalamocortical connections form normally, including patterned connections to somatosensory cortex. However, deficits in motor function still occur, as in babies with PVL. Subplate neuron cell death in PVL provides another mechanism for abnormal neurodevelopment after neonatal hypoxia-ischemia.

Animals↗

PubMedDate not supplied

Selective vulnerability of hippocampus and disturbances of memory storage after mild unilateral ischemia of gerbil brain.

The effect of selective injury of hippocampal neurons on the consolidation of memory traces was studied in gerbils (meriones unguiculatus) after production of mild cerebral ischemia. The right carotid artery was permanently ligated, and animals without gross neurological deficits ("symptom-negative" gerbils) were selected. Eight days and eight weeks after vascular ligation, cell counts of hippocampal neurons were carried out and correlated with regional blood flow and the acquisition of operant behaviour. Eight days after carotid artery occlusion, learning behaviour was significantly impaired although the number of hippocampal neurons had not changed and blood flow had even increased above normal. After eight weeks, learning behaviour and blood flow were normal but now a significant loss of pyramidal neurons was present in the CA1 and CA2 sectors of the hippocampus. Our observations demonstrate that it is possible to detect subtle functional disturbances by appropriate behavioural investigation before manifestation of selective injury of the hippocampus. Recovery of integrative function, despite persistent cellular damage, provides further evidence for central nervous plasticity.

Animals↗

PubMed1997

Selective damage to the cerebellar vermis in chronic alcoholism: a contribution from neurotoxicology to an old problem of selective vulnerability.

The curiously consistent localization of cerebellar cortical damage in chronic alcoholism is re-evaluated in the light of selective damage, with a similar topography in the cerebellar vermal region, in superficial siderosis in man and in experimental animals exposed to certain toxic substances. Attention is drawn to the capacity for Purkinje cell dendrites and Bergmann glia to extract materials from the CSF, and to the close anatomical relationships of the susceptible lobules I-II, IX and X to the roof of the IVth ventricle and to the cistern of the great cerebral veins. This restriction of damage to vermis and paravermis may reflect some compartmentalization of CSF flow within leptomeninges, consistently increasing exposure of these cerebellar surfaces to materials circulating in the CSF. In other circumstances when this pattern of damage is encountered it raises the question as to whether other environmental agents, gaining access to the CSF, may be similarly distributed.

Alcoholism↗

PubMed1989

Role for gamma-aminobutyric acid in selective vulnerability in gerbils.

We tested the efficacy of various putative neuroprotective agents in the gerbil model of delayed neuronal death. The selective loss of anterior CA1 neurons of the hippocampus 4 days after 5 minutes of bilateral ischemia was complete in greater than 90% of the gerbils examined. We tested 11 agents for their ability to protect against neuronal loss. Only those agents that were associated with the GABAergic system exhibited protection and only when administered before the ischemic insult. The possibility that delayed neuronal death is the result of a primary defect in inhibitory neurotransmission is considered.

Animals↗

PubMed2002

Selective vulnerability of corticocortical and hippocampal circuits in aging and Alzheimer's disease.

Alzheimer's disease (AD), a classic neurodegenerative disorder, is characterized by extensive yet selective neuron death in the neocortex and hippocampus that leads to dramatic decline in cognitive abilities and memory. Crucial subsets of pyramidal cells and their projections are particularly vulnerable. A more modest disruption of memory occurs often in normal aging, yet such functional decline does not appear to be accompanied by significant neuron death. However, the same circuits that are devastated through degeneration in AD are vulnerable to sublethal age-related biochemical and morphologic shifts that alter synaptic transmission, and thereby impair function. For example, in the monkey neocortex, pyramidal cells that are homologous to those that degenerate in AD do not degenerate with aging, yet they lose spines, suggesting that an age-related synaptic disruption has occurred. Such age-related synaptic alterations have also been reported in hippocampus. For example, NMDA receptors are decreased in certain hippocampal circuits with aging. NMDA receptors are also responsive to circulating estrogen levels, thus interactions between reproductive senescence and brain aging may also affect excitatory synaptic transmission in the hippocampus. Thus, the aging synapse may be the key to age-related memory decline, whereas neuron death is the more prominent and problematic culprit in AD.

Aging↗

PubMed2006

Cell culture models to investigate the selective vulnerability of motoneuronal mitochondria to familial ALS-linked G93ASOD1.

Mitochondrial damage induced by superoxide dismutase (SOD1) mutants has been proposed to have a causative role in the selective degeneration of motoneurons in amyotrophic lateral sclerosis (ALS). In order to investigate the basis of the tissue specificity of mutant SOD1 we compared the effect of the continuous expression of wild-type or mutant (G93A) human SOD1 on mitochondrial morphology in the NSC-34 motoneuronal-like, the N18TG2 neuroblastoma and the non-neuronal Madin-Darby Canine Kidney (MDCK) cell lines. Morphological alterations of mitochondria were observed in NSC-34 expressing the G93A mutant (NSC-G93A) but not the wild-type SOD1, whereas a ten-fold greater level of total expression of the mutant had no effect on mitochondria of non-motoneuronal cell lines. Fragmented network, swelling and cristae remodelling but not vacuolization of mitochondria or other intracellular organelles were observed only in NSC-G93A cells. The mitochondrial alterations were not explained by a preferential localization of the mutant within NSC-G93A mitochondria, as a higher amount of the mutant SOD1 was found in mitochondria of MDCK-G93A cells. Our results suggest that mitochondrial vulnerability of motoneurons to G93ASOD1 is recapitulated in NSC-34 cells, and that peculiar features in network dynamics may account for the selective alterations of motoneuronal mitochondria.

Amyotrophic Lateral Sclerosis↗

PubMed1986

Morphometric evaluation of post-ischemic capillary perfusion in selectively vulnerable areas of gerbil brain.

In gerbils the hemispheric blood flow was interrupted for 5 min by bilateral carotid artery occlusion to produce delayed selective destruction of the CA 1 sector of hippocampus. The influence of hemodynamic factors was studied by evaluating the microcirculation before and at two times after ischemia (3 min and 7 days), using Evans blue as an intravital vascular tracer. The density of perfused capillaries and the fractional volume of circulating blood were determined by quantitative morphometry and the values for the vulnerable CA 1 sector compared with those for the resistant CA 3 sector and cerebral cortex. In control animals the number of perfused capillaries in the CA 1 sector was about 20% lower, and the volume of circulating blood about 30% lower, than in the CA 3 sector or cerebral cortex. This difference was markedly enhanced after 5-min ischemia. During the early recirculation phase, capillary perfusion improved in the cortex, whereas in the CA 1 sector (and to a lesser degree also in the CA 3 sector) it declined. After 7 days, the density of perfused capillaries and the volume of circulating blood had returned to control levels in the cerebral cortex and CA 3 sector of hippocampus. In the CA 1 sector, in contrast, the microcirculation had further deteriorated. The density of perfused capillaries was less than 30%, and the circulating blood volume even less than 50%, of that in the cerebral cortex.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2006

Dopamine-induced stress signaling in COS-7 cells transfected with selectively vulnerable muscarinic receptor subtypes is partially mediated via the i3 loop and antagonized by blueberry extract.

Muscarinic receptors (MAChRs) are intimately involved in various aspects of both neuronal and vascular functioning, and there is selective oxidative stress sensitivity (OSS) among MAChR subtypes, with M1, M2, and M4 showing>OSS. OSS was assessed by determining the loss of ability of the cell to extrude or sequester Ca2+ following oxotremorine-induced depolarization following exposure to dopamine (DA) subtypes in transfected COS-7 cells. This OSS can be prevented by pretreatment with blueberry (BB) extract. Present studies were carried out to determine BB treatment of the cells transfected with wild type, truncated or chimeric [where the i3 loop of one receptor was switched with the i3 loop of the other; i.e., M1(M3i3) and M3(M1i3)] receptors would alter DA-induced changes in calcium buffering and would confer protection through alterations in pMAPK, pCREB or PKC signaling. These findings also suggest that BB may antagonize OS effects by lowering activation of pCREB and possibly PKCgamma induced by DA. In the truncated and chimeric receptors, results indicated that BB reduced OSS in response to DA in M1-transfected cells. However, BBs were also effective in preventing these Ca2+ buffering deficits in cells transfected with M1 receptors in which the i3 loop had been removed, but only partially enhanced the protective effects of the M3 i3 loop in the M1(M3i3) chimerics. A similar partial effect of BBs was seen in the M3(M1i3) chimerics which showed increased OSS in response to DA. It appears that antioxidants found in BBs might be targeting additional sites on these chimerics to decrease OSS.

Animals↗

PubMed1990

Selective vulnerability of cultured cortical glia to injury by extracellular acidosis.

Reduction of extracellular pH from 7.4 to 6.5 attenuated glutamate neurotoxicity in murine cortical neuronal and glial cultures, but if maintained for 24 h, resulted in morphological evidence of selective glial injury. Acid-induced gliotoxicity was examined quantitatively in cortical astrocyte cultures, using lactate dehydrogenase efflux as an index of cell damage. An exposure time of 9 h to pH 6.4 was sufficient to destroy about one third of the glia, whether or not 25 mM lactate was present. Furthermore, such acidosis increased the vulnerability of glia to injury by combined oxygen and glucose deprivation. These observations support the suggestion that the acidosis which accompanies ischemia in vivo may contribute to glial injury.

Acidosis↗

PubMed2006

Cellular and molecular mechanisms involved in the selective vulnerability of striatal projection neurons in Huntington's disease.

Neurodegenerative disorders affecting the central nervous system, such as Alzheimer's disease, Parkinson's disease, Huntington's chorea (HD) and amyotrophic lateral sclerosis are characterized by the loss of selected neuronal populations. Another striking feature shared by these diseases is the deposition of proteinaceous inclusion bodies in the brain, which may be intracytoplasmatic or intranuclear, or even extracellular. However, the density and prevalence of aggregates are not always directly related to neurodegeneration. Although some of these diseases are the result of mutations in known proteins, with HD a clear example, the expression and location of the affected protein do not explain the selective neurodegeneration. Therefore, other intrinsic mechanisms, characteristic of each neuronal population, might be involved in the neurodegenerative process. In this review we focus on several proposed mechanisms such as excitotoxicity, mitochondrial dysfunction and altered expression of trophic factors, which could account for the pathogenesis of HD.

Animals↗

PubMed2004

Selective vulnerability of dentate granule cells prior to amyloid deposition in PDAPP mice: digital morphometric analyses.

Increasing evidence from mouse models of Alzheimer's disease shows that overexpression of a mutant form of the amyloid precursor protein (APP) and its product, beta-amyloid peptide, initiate pathological changes before amyloid deposition. To evaluate the cytological basis for one of these early changes, namely reduced volume of the dentate gyrus (DG), we have used high-throughput diOlistic cell loading and 3D neuronal reconstruction to investigate potential dendritic pathology of granule cells (GCs) in 90-day-old PDAPP mice. Labeled GCs from fixed hippocampal slices were selected randomly and imaged digitally by using confocal laser-scanning microscopy. The dendritic complexity of GCs was quantified according to subordinate morphological parameters, including soma position within the granule cell layer (superficial versus deep) and topographic location within the DG (dorsal versus ventral blade) along the anterior-posterior hippocampal axis. Initial analysis, which included all sampled GC types, revealed a 12% reduction of total dendritic length in PDAPP mice compared with littermate controls. Further analysis, performed with refined subgroups, found that superficially located GCs in the dorsal blade were profoundly altered, exhibiting a 23% loss in total dendritic length, whereas neurons in the ventral blade were unaffected. Superficial GCs were particularly vulnerable (a 32% reduction) in the posterior region of the DG. Furthermore, the dendritic reductions of this select group were uniformly localized within middle-to-outer portions of the dentate molecular layer. We conclude that substantial dendritic pathology is evident in 90-day-old PDAPP mice for a spatially defined subset of GCs well before amyloid accumulation occurs.

Amyloid beta-Protein Precursor↗

PubMed1993

Neurological cholinesterases in the normal brain and in Alzheimer's disease: relationship to plaques, tangles, and patterns of selective vulnerability.

Butyrylcholinesterase (BChE) and an altered form of acetylcholinesterase (AChE) accumulate in the plaques and tangles of Alzheimer's disease (AD). The sources for these plaque- and tangle-bound cholinesterases have not been identified. We now report that AChE and BChE activities with pH preferences and inhibitor selectivities identical to those of plaque- and tangle-bound cholinesterases are found in the astrocytes and oligodendrocytes of control and AD brains. These glial-type cholinesterases are selectively inhibited by indolamines and protease inhibitors. In control brains glial-type cholinesterases appear confined to the intracellular space, whereas in patients with AD they decorate plaques and tangles as well. In control and AD brains AChE-positive glia are distributed throughout the cortical layers and subcortical white matter, whereas BChE-positive glia reach high densities only in the deep cortical layers and white matter. In non-AD control brains, the ratio of BChE to AChE glia was higher in entorhinal and inferotemporal cortex, two regions with a high susceptibility to the pathology of AD, than in primary somatosensory and visual cortex, two areas with a relatively lower susceptibility to the disease process. There was no age-related differences in the density or distribution of cholinesterase-positive glia. In comparison with age-matched control specimens, AD brains had a significantly higher density of BChE glia and a lower density of AChE glia in entorhinal and inferotemporal regions but not in the primary somatosensory or visual areas. These results suggest that glia constitute a likely source for the cholinesterase activity of plaques and tangles and that a high ratio of BChE- to AChE-positive glia may play a permissive or causative role in the neuropathology of AD.

Acetylcholinesterase↗

PubMed1994

Cortical neurones exhibiting kainate-activated Co2+ uptake are selectively vulnerable to AMPA/kainate receptor-mediated toxicity.

Kainate-activated Co2+ uptake, a histochemical method that identifies cells bearing Ca2+-permeable AMPA/kainate receptors, labels approximately 15% of murine cortical neurones in cell culture. While exposure times exceeding several hours were needed for AMPA or kainate to destroy most cultured cortical neurones, the subpopulation exhibiting kainate-activated Co2+ uptake was selectively destroyed after AMPA or kainate exposures of only 10-60 min. No selective loss was seen after exposure to NMDA. Kainate toxicity on Co2+ uptake-positive neurones was dependent on extracellular Ca2+ concentration, and associated with an increase in intracellular free Ca2+ even in the absence of extracellular Na+. These results suggest that a distinct subpopulation of cortical neurones expresses AMPA/kainate receptors linked to Ca2+-permeable channels, and that this characteristic conveys enhanced vulnerability to kainate-induced, Ca2+-mediated, damage.

Animals↗

PubMed2000

Ca(2+)-permeable AMPA receptors and selective vulnerability of motor neurons.

To evaluate the role of excitotoxicity in the pathogenesis of amyotrophic lateral sclerosis (ALS), we compared the sensitivity of motor neurons and that of dorsal horn neurons to kainic acid (KA). Short exposure to KA resulted in the death of motor neurons, while dorsal horn neurons were unaffected. This selective motor neuron death was completely dependent on extracellular Ca(2+) and insensitive to inhibitors of voltage-operated Ca(2+) or Na(+) channels. It was also completely inhibited by the specific AMPA antagonist LY300164 and by Joro spider toxin (JSTx), a selective blocker of AMPA receptors that lack the edited GluR2 subunit. KA selectively killed those motor neurons that stained positive for the Co(2+) histochemical staining, a measure for the presence of Ca(2+)-permeable AMPA receptors. These results suggest that Ca(2+) entry via Ca(2+)-permeable AMPA receptors is responsible for the selective motor neuron death. As the Ca(2+) permeability of the AMPA receptor is regulated by its GluR2 subunit, we stained motor neurons for GluR2. Immunoreactivity was present in all motor neurons, albeit to a variable degree. However, double-staining experiments demonstrated that motor neurons clearly expressing GluR2, also expressed Ca(2+)-permeable AMPA receptors. This indicates that despite the abundant expression of GluR2, this subunit is excluded from a subset of AMPA receptors and that the activation of these receptors is responsible for the selective motor neuron death.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed2004

Extraocular muscles have fundamentally distinct properties that make them selectively vulnerable to certain disorders.

While skeletal muscles generally perform specific limited roles, extraocular muscles (EOMs) have to be responsive over a wider dynamic range. As a result, EOMs have fundamentally distinct structural, functional, biochemical and immunological properties compared to other skeletal muscles. While these properties enable high fatigue resistance and the rapid and precise control of extraocular motility, they might also explain why EOMs are selectively involved in certain disorders, such as chronic progressive external ophthalmoplegia (CPEO), myasthenia gravis and Graves' ophthalmopathy. This review first gives an overview of the novel myofibre classification in EOMs and then focuses on those properties that might explain why ophthalmoplegia should be so prominent in these disorders.

Adaptation, Physiological↗