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 811 records · Page 45Linked to original sources

PubMed1993

Pathogenesis of mesial temporal sclerosis.

A relationship between epilepsy and damage to mesial temporal structures has long been recognized. Recent advances have clarified somewhat the issue of whether the pathological changes seen in mesial temporal sclerosis represent the cause or the effect of seizures. This paper reviews mesial temporal sclerosis from an historical perspective and summarizes recent developments in the fields of excitotoxicity, selective vulnerability, and synaptic reorganization as they pertain to the pathogenesis of mesial temporal sclerosis.

Animals↗

PubMed1998

Mutant CuZn superoxide dismutase in motor neuron disease.

CuZn superoxide dismutase (CuZn SOD) is one of several antioxidant enzymes that defend the cell against damage by oxygen free radicals. Mutations of the SOD1 gene encoding CuZn SOD are found in patients with familial amyotrophic lateral sclerosis (FALS), a progressive and fatal paralytic disease that is caused by the death of motor neurons in cortex, brainstem and spinal cord. The disease can be reproduced in transgenic mice by expression of mutant human CuZn SOD. Recent studies both in vitro and in vivo suggest that the effect of mutation is to enhance the generation of oxygen radicals by the mutant enzyme. Thus, mutation converts a protective, antioxidant enzyme into a destructive, prooxidant form that catalyses free radical damage to which motor neurons are selectively vulnerable. Recent studies of neuroprotective agents in the FALS model show that inhibition of oxidative mechanisms (copper chelation therapy, dietary antioxidants, and coexpression of bcl-2) delays disease onset but does not extend disease duration. In contrast, inhibition of glutamatergic or apoptotic mechanisms (riluzole, gabapentin, and coexpression of glutamatergic or apoptotic mechanisms (riluzole, gabapentin, and coexpression of an inhibitor of caspase-1) has no effect on disease onset but extends survival by increasing the duration of symptomatic disease. Thus, neuroprotective agents differentially target the processes underlying disease initiation and propagation.

Amyotrophic Lateral Sclerosis↗

PubMed1998

The role of the amyloid protein precursor (APP) in Alzheimer's disease: does the normal function of APP explain the topography of neurodegeneration?

Alzheimer's disease (AD) is the most common form of dementia in the aged population. Early-onset familial AD (FAD) involves mutations in a gene on chromosome 21 encoding the amyloid protein precursor or on chromosomes 14 or 1 encoding genes known as presenilins. All mutations examined have been found to increase the production of amyloidogenic forms of the amyloid protein (A beta), a 4 kDa peptide derived from APP. Despite the remarkable progress in elucidating the biochemical mechanisms responsible for AD, little is known about the normal function of APP. A model of how APP and A beta are involved in pathogenesis is presented. This model may explain why certain neuronal populations are selectively vulnerable in AD. It is suggested that those neurons which more readily undergo neuritic sprouting and synaptic remodelling are more vulnerable to A beta neurotoxicity.

Alzheimer Disease↗

PubMed2003

Cycles of aberrant synaptic sprouting and neurodegeneration in Alzheimer's and dementia with Lewy bodies.

Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) are the most common neurodegenerative disorders affecting the elderly. The cognitive and motor deficits in these diseases are associated with the disruption of neuritic substructure, loss of synaptic contacts in selectively vulnerable circuitries, and aberrant sprouting. Where as in AD, accumulation of misfolded forms of Abeta triggers neurodegeneration, in DLB accumulation of alpha-synuclein might play a central role. The mechanisms by which oligomeric forms of these proteins might lead to cycles of synapse loss and aberrant sprouting are currently under investigation. Several possibilities are being considered, including mitochondrial damage, caspase activation, lysosomal leakage, fragmentation of the Golgi apparatus, interference with synaptic vesicle transport and function, and interference with gene transcription and signaling. Among them, recent lines of research support the possibility that alterations in signaling pathways such extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 relevant to synaptic plasticity and cell survival might play a pivotal role. A wide range of cellular functions are affected by the accumulation of misfolded Abeta and alpha-synuclein; thus it is possible that a more fundamental cellular alteration may underlie the mechanisms of synaptic pathology in these disorders. Among them, one possibility is that scaffold proteins, such as caveolin and JNK-interacting protein (JIP), which are necessary to integrate signaling pathways, are affected, leading to cycles of synapse loss and aberrant sprouting. This is significant because both caveolar dysfunction and altered axonal plasticity might be universally important in the pathogenesis of various neurodegenerative disorders, and therefore these signaling pathways might be common therapeutic targets for these devastating diseases.

Alzheimer Disease↗

PubMed2004

Astrocyte mitochondria in in vitro models of ischemia.

There is growing evidence that preservation of mitochondrial respiratory function during cerebral ischemia-reperfusion predicts the ultimate extent of tissue injury. Because neurons are selectively vulnerable to ischemic injury, many studies have focused on neuronal mitochondrial dysfunction in ischemia. However, positron emission tomography (PET) studies in animals and humans suggest that non-neuronal cells such as astrocytes may also experience mitochondrial metabolic compromise that contributes to ischemic necrosis. Astrocytes carry out a number of functions that are critical to normal nervous system function, including uptake of neurotransmitters, regulation of pH and ion concentrations, and metabolic support of neurons. Mitochondria are important for many of these actions. We have used a cell culture model of stroke, oxygen-glucose deprivation (OGD), to study the response of astrocyte mitochondria to ischemia, and to evaluate how changes in astrocyte mitochondrial function might affect neuronal survival and recovery after ischemia.

Animals↗

PubMed2004

Experimental strategy to identify genes susceptible to oxidative stress in nigral dopaminergic neurons.

Neuropathological evidence from both human and experimental models of Parkinson's disease (PD) firmly supports a significant role for oxidative stress (OS) in the death of dopaminergic (DA) neurons in substantia nigra. Largely unknown are the genes underlying selective susceptibility of nigral DA neuron to OS and how they effect nigral DA cell death. The major barriers to high-throughput identification of candidate genes are the paucity of nigral DA neurons as well as the dilution effect of non-DA cells both in primary cultures and brain tissues. To overcome these barriers, we have developed a DA cell line model, SN4741, appropriate for cDNA microarray analysis. Candidate genes were selected from both the microarray analysis and the molecular implication of their pathological mechanisms (i.e., decreased mitochondrial complex I activity and proteasomal dysfunction) of PD. Subsequent secondary validation tests were devised to characterize genes including clone #45 that may underlie selective vulnerability of nigral DA neuron to OS.

Cell Line↗

PubMed1987

Regional differences in arachidonic acid release in rat hippocampal CA1 and CA3 regions during cerebral ischemia.

Changes in the levels of arachidonic acid during ischemia in selectively vulnerable areas of the hippocampus were studied in the rat brain. Since neurons in the CA1 region are more vulnerable to ischemia than neurons in the adjacent CA3 region, the release of arachidonic acid in these two regions was measured during decapitation ischemia of 4- to 12-min duration. The concentration of free arachidonic acid increased with the duration of ischemia in both regions. However, the level was significantly higher in CA1 than in CA3 after 8 and 12 min of ischemia. This difference in arachidonic acid accumulation may reflect differences between the regions in agonist-dependent phospholipid breakdown as well as calcium-dependent phospholipase activity. The importance for the development of neuronal necrosis is discussed.

Animals↗

PubMed1987

Histopathological and hemodynamic consequences of complete versus incomplete ischemia in the rat.

The primary objective of this study was to compare the histopathological consequences of complete versus incomplete ischemia under experimental conditions that limit lactate accumulation. Fasted rats underwent 1 h of either complete or incomplete ischemia by a procedure combining bilateral common carotid artery occlusion, halothane-induced systemic hypotension, and CSF pressure elevation. Histopathological outcome was evaluated 4 h later and was graded on a 4-point scale. Incomplete ischemia resulted in ischemic neuronal damage within selectively vulnerable brain regions. In contrast, complete ischemia, in addition to diffuse neuronal damage, resulted in focal sites of parenchymal necrosis with vascular stasis. Perfusion defects were detected by carbon black infusion within cortical and subcortical regions following only 25 min of complete, but not incomplete, ischemia. Ultrastructural abnormalities at the same duration of complete ischemia included a high frequency of endothelial microvilli and compressed lumina with severe perivascular astrocytic swelling. When recirculation was instituted for 1 h following 1 h of complete ischemia, regions of nonperfusion were detected autoradiographically. Thus, when the degree of lactic acidosis is controlled, prolonged periods of complete ischemia result in a more severe pathological outcome compared to incomplete ischemia. Focally impaired postischemic cerebral perfusion appears to be an important factor in infarct formation under the present experimental conditions.

Animals↗

PubMed1988

Long-term development of selective neuronal loss and the mechanism of protection by 2-amino-7-phosphonoheptanoate in a rat model of incomplete forebrain ischaemia.

Excitatory neurotransmission at the N-methyl-D-aspartate (NMDA) receptor is selectively blocked by 2-amino-7-phosphonoheptanoate acid (2-APH). Acute focal microinjection of 2-APH into the rat hippocampus partially protects against cytopathology developing in selectively vulnerable neurons after 30 min of ischaemia and 2 h of reperfusion. We show that this protective action of 2-APH does not involve alterations in local cerebral blood flow (CBF). Intermediate cytopathology and long-term neuronal survival has been assessed in rats receiving focal injections of (+/-) 2-APH, 20 micrograms in 1 microliter, into one dorsal hippocampus prior to and 4 and 10 h after a 10-min period of forebrain ischaemia. Cytopathology assessed 4 or 24 h after ischaemia shows no difference between the buffer and 2-APH-injected hippocampi. Assessment after 7 days survival shows a significant protection against neuronal loss in the CA1 zone of the 2-APH-injected hippocampus compared with the contralateral, buffer-injected hippocampus. Systemic injection of D(-)2-APH (675 mg/kg i.v. at 0 h, 4 h, and 10 h) affords significant protection to CA1 hippocampal neurones (as assessed after 7 days). These results suggest that maintained blockade of neurotransmission at the NMDA receptor in the postischaemic period can protect against delayed cell loss. The mechanism may be through antagonism of the excitotoxic action of an endogenous neurotransmitter acting in the postischaemic period.

2-Amino-5-phosphonovalerate↗

PubMed1990

Cerebral blood flow, glucose utilization, regional glucose, and ATP content during the maturation period of delayed ischemic injury in gerbil brain.

Coupling between local perfusion and metabolism was examined in Mongolian gerbils during the development of delayed neuronal death using a combination of double-tracer autoradiography and imaging of local energy state. Animals were anesthetized with 1.5% halothane and forebrain ischemia was produced by occluding both common carotid arteries. After 5 min of ischemia, brains were recirculated for 6 h and 1, 2, or 4 days. At the end of the experiment, regional cerebral blood flow (CBF) and glucose utilization (CMRglc) were determined in identical brain section with [131I]iodoantipyrine and [14C]deoxyglucose, respectively. Adjacent sections were taken for imaging of ATP and glucose using substrate-specific bioluminescence reactions. In the CA1 subfield of control animals, CBF and CMRglc amounted to 81 +/- 8 ml 100 g-1min-1 and 69 +/- 2 mumol 100 g-1min-1, respectively, and the calculated CBF/CMRglc ratio was 1.18 +/- 0.12 ml/mumol (mean +/- SD). After ischemia, the CBF/CMRglc ratio increased to 1.31 +/- 0.14, 1.43 +/- 0.16, 1.45 +/- 0.16, and 1.56 +/- 0.18 ml/mumol following 6 h and 1, 2, or 4 days recirculation, respectively. Glucose levels did not change during the 6 h to 4 day recirculation period in the hippocampal CA1 subfield. In the same region, ATP levels were unchanged during 6 h to 2 day postischemic recovery but reduced to about 70% after 4 days of recirculation. The results indicate that a mismatch of the flow--metabolism couple following transient ischemia does not appear to contribute to the postischemic maturation of delayed neuronal death in selectively vulnerable brain regions.

Adenosine Triphosphate↗

PubMed1990

Astrocytic acidosis in hyperglycemic and complete ischemia.

Nearly complete brain ischemia under normoglycemic conditions results in death of only selectively vulnerable neurons. With prior elevation of brain glucose, such injury is enhanced to include pancellular necrosis (i.e., infarction), perhaps because an associated, severe lactic acidosis preferentially injures astrocytes. However, no direct physiologic measurements exist to support this hypothesis. Therefore, we used microelectrodes to measure intracellular pH and passive electrical properties of cortical astrocytes as a first approach to characterizing the physiologic behavior of these cells during hyperglycemic and complete ischemia, conditions that produce infarction in reperfused brain. Anesthesized rats (n = 26) were made extremely hyperglycemic (blood glucose, 51.4 +/- 2.8 mM) so as to create potentially the most extreme acidic conditions possible; then ischemia was induced by cardiac arrest. Two loci more acidic than the interstitial space (6.17-6.20 pH) were found. The more acidic locus [4.30 +/- 0.19 (n = 5); range: 3.82-4.89] was occasionally seen at the onset of anoxic depolarization, 3-7 min after cardiac arrest. The less acidic locus [5.30 +/- 0.07 (n = 53); range 4.46-5.93)] was seen 5-46 min after cardiac arrest. A small negative change in DC potential [8 +/- 1 mV (n = 5); range -3 to -12 mV and 7 +/- 2 mV (n = 53); range +3 to -31 mV, respectively] was always seen upon impalement of acidic loci, suggesting cellular penetration. In a separate group of five animals, electrical characteristics of these cells were specifically measured (n = 17): membrane potential was -12 +/- 0.2 mV (range -3 to -24 mV), input resistance was 114 +/- 16 M omega (range 25-250 M omega), and time constant was 4.4 +/- 0.4 ms (range 3.0-7.9 ms). Injection of horseradish peroxidase into cells from either animal group uniformly stained degenerating astrocytes. These findings establish previously unrecognized properties of ischemic astrocytes that may be prerequisites for infarction from nearly complete ischemia: the capacity to develop profound cellular acidosis and a concomitant reduction in cell membrane ion permeability.

Acid-Base Equilibrium↗

PubMed1992

Influence of ischemia on blood-brain and blood-CSF calcium transport.

The objective was to explore whether the increased incorporation of 45Ca into selectively vulnerable neurons, observed after transient ischemia, can be explained by enhanced blood-tissue and/or enhanced blood-CSF transfer. Anesthetized rats were subjected to 15 min of forebrain ischemia, with recirculation for 20 or 60 min, or 24 h. The transfer constants (Kin) and unidirectional fluxes (Jin) for calcium in tissue and CSF were determined following i.v. injection of 45Ca, integration of the curve for plasma-specific activity over 10 min, and sampling of cisternal CSF, and tissue (cortex, caudoputamen, hippocampus, and cerebellum). Predictably, values for Kin and Jin in control animals were much larger in CSF than in tissues, and hippocampus had higher values than the other areas, probably because of its closeness to the lateral ventricle. Ischemia failed to alter the Kin and Jin values, demonstrating that the low permeability of blood-brain and blood-CSF barriers to calcium is upheld both in the immediate recirculation period, and after 24 h of recirculation. The results support the contention that the increased 45Ca incorporation during recovery is due to increased calcium cycling across functionally altered cell membranes.

Animals↗

PubMed2004

Gene regulation and DNA damage in the ageing human brain.

The ageing of the human brain is a cause of cognitive decline in the elderly and the major risk factor for Alzheimer's disease. The time in life when brain ageing begins is undefined. Here we show that transcriptional profiling of the human frontal cortex from individuals ranging from 26 to 106 years of age defines a set of genes with reduced expression after age 40. These genes play central roles in synaptic plasticity, vesicular transport and mitochondrial function. This is followed by induction of stress response, antioxidant and DNA repair genes. DNA damage is markedly increased in the promoters of genes with reduced expression in the aged cortex. Moreover, these gene promoters are selectively damaged by oxidative stress in cultured human neurons, and show reduced base-excision DNA repair. Thus, DNA damage may reduce the expression of selectively vulnerable genes involved in learning, memory and neuronal survival, initiating a programme of brain ageing that starts early in adult life.

Adult↗

PubMed2026

Functional genomic screens uncover FERMT2 as a critical regulator of YAP/TAZ-driven tumorigenicity.

YAP and TAZ are transcriptional regulators essential for mechanotransduction, development, and tissue homeostasis, whose dysregulation is implicated in multiple diseases, including cancer. To identify key regulators of YAP/TAZ signaling required for breast cancer cell fitness, we performed CRISPR/Cas9-based loss-of-function genetic screens both in vitro and in vivo. A custom sgRNA library targeting 216 candidate YAP/TAZ modulators was screened across three breast cancer cell lines. Among these, FERMT2, a component of the integrin signaling pathway, consistently emerged as a strong drop-out hit, highlighting its essential role in sustaining YAP/TAZ-dependent fitness. Bioinformatic analysis of large-scale cancer datasets further revealed genetic co-dependency between FERMT2, YAP, and TAZ, particularly in tumors with high YAP/TAZ expression. Functional validation through FERMT2 knockout and silencing demonstrated its requirement for proliferation, anchorage-independent growth, and tumorigenicity in triple-negative breast cancer cells. FERMT2 loss impaired YAP/TAZ nuclear accumulation, reduced the expression of YAP/TAZ target genes, and decreased phosphorylation at key tyrosine residues. Mechanistically, FERMT2 regulates YAP/TAZ independently of the canonical Hippo pathway through integrin-mediated activation of FAK. Consistent with this, glucocorticoid-driven FAK activation restored YAP/TAZ signaling in FERMT2-depleted cells. Partial epistasis analyses also indicate that FERMT2 modulates actin-dependent regulation of YAP/TAZ. Together, these findings identify FERMT2 as a pivotal upstream regulator of YAP/TAZ via FAK signaling, demonstrate that YAP/TAZ are principal effectors of integrin activity, and suggest that FERMT2 may represent a selective vulnerability in cancers with elevated YAP/TAZ signaling.

Humans↗

PubMed2026

A single-nucleus transcriptomic atlas of human inner ear development.

Hearing and balance rely on coordinated activity of multiple inner ear cell types, yet the mechanisms governing their development and specification in humans remain unclear. Consequently, this limits our understanding of how disease genes affect cell type formation and function, limiting the development of targeted treatments, including gene therapies. Here we present the Human Inner Ear Development snRNA-seq Atlas (HIEDRA), a single-nucleus transcriptomic atlas of the human inner ear spanning the first and second trimesters. HIEDRA maps sensory and nonsensory epithelia, neurons and mesenchyme-associated populations, including undercharacterized secretory cells required for ion homeostasis. We identify selective vulnerability in sensory and secretory lineages to disease-associated genes, infer regulatory networks and show that Hedgehog signaling suppression is required for secretory cell specification. We validate this mechanism in human inner ear organoids, expanding the model to include all major cell types. Altogether, these findings provide insights into human inner ear cell type specification, improve in vitro models and establish HIEDRA as a resource for investigating human inner ear development.

Journal Article↗

PubMed1998

Effects of depolarizing stimuli on calcium homeostasis in cultured rat motoneurones.

Intracellular calcium concentrations in individual rat motoneurones in enriched primary cultures were measured by Indo-1 fluorimetry. Motoneurones in the cultures were characterized morphometrically and by cholineacetyltransferase immunocytochemistry. Depolarization of the cells with glutamic acid or veratridine increased intracellular calcium levels, which returned to baseline only slowly after removal of the depolarizing agent. The use of selective agonists (N-methyl-D-aspartic acid, AMPA, kainic acid, quisqualic acid and 1R-3S-ACPD) and antagonists (MK 801 and CNQX) showed that the excitatory amino acid-evoked responses were mediated by AMPA/kainate receptors rather than by NMDA receptors. Depolarization-evoked calcium transients in motoneurones are blocked by the neuroprotective drug riluzole Calcium transients reflected entry of calcium from without the cell, and their blockade by nitrendipine and lanthanum chloride suggested that this entry took place primarily through voltage-dependent calcium channels. These findings may be relevant for understanding the selective vulnerability of motoneurones to excitotoxicity in amyotrophic lateral sclerosis, and the therapeutic activity of riluzole in the treatment of this disease.

Animals↗

PubMed2006

The effects of cerebral ischemia on the rat choroid plexus.

Although the blood-brain barrier effects of cerebral ischemia have been extensively examined, less attention has focused on ischemia-induced damage to the choroid plexuses that form the blood-cerebrospinal fluid (CSF) barrier (BSCFB). This study examined the rat lateral ventricle choroid plexuses (LVCP) in three ischemic models, bilateral common carotid artery occlusion (2VO)+hypotension with or without reperfusion and permanent middle cerebral artery (MCA) occlusion with or without a tandem common carotid artery occlusion. Blood flow was assessed using [(14)C]-N-isopropyl-p-iodoamphetamine, and LVCP injury by tissue edema, alterations in [(14)C]glutamine transport and BSCFB disruption (measured with [(3)H]inulin). 2VO+hypotension caused an 87% reduction in LVCP blood flow (P<0.01) and a progressive reduction in LVCP glutamine transport. In contrast to cortex, there was no LVCP hyperemia or delayed hypoperfusion on reperfusion, but there was marked BSCFB disruption. After 30 mins of 2VO+hypotension with 6 h of reperfusion, the [(3)H]inulin entry into CSF was increased threefold (P<0.05). Blood-CSF barrier rather than blood-brain barrier disruption appeared to be the main cause of enhanced [(3)H]inulin entry into hippocampus. Middle cerebral artery occlusion with and without a tandem common carotid artery occlusion only caused 53% and 38% reductions in LVCP blood flow but induced LVCP edema. Results suggest that the LVCP is selectively vulnerable to ischemic injury in terms of the absolute blood flows or, for the MCA occlusion models, the % reductions in flows required to induce injury. BCSFB disruption early after ischemia may enhance the movement of compounds from blood to areas close to the ventricular system and participate in delayed neuronal death.

Animals↗

PubMed2007

Dopamine receptor modulation of hypoxic-ischemic neuronal injury in striatum of newborn piglets.

Dopamine receptors regulate glutamatergic neurotransmission and Na(+),K(+)-ATPase via protein kinase A (PKA) and dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32)-dependent signaling. Consequently, dopamine receptor activation may modulate neonatal hypoxic-ischemic (H-I) neuronal damage in the selectively vulnerable putamen enriched with dopaminergic receptors. Piglets subjected to two durations of hypoxia followed by asphyxic cardiac arrest were treated with a D1-like (SCH23390) or D2-like (sulpiride) receptor antagonist. At 4 days of recovery from less severe H-I, the remaining viable neurons in putamen were 60% of control, but nearly completely salvaged by pretreatment with SCH23390 or sulpiride. After more severe H-I in which only 18% of neurons were viable, partial neuroprotection was seen with SCH23390 pretreatment (50%) and posttreatment (39%) and with sulpiride pretreatment (35%), but not with sulpiride posttreatment (24%). Dopamine was significantly elevated in microdialysis samples from putamen during asphyxia and the first 15 mins of reoxygenation. Pretreatment with SCH23390 or sulpiride largely attenuated the increased nitrotyrosine and the decreased Na(+),K(+)-ATPase activity that occurred at 3 h after severe H-I. Pretreatment with SCH23390, but not sulpiride, also attenuated H-I-induced increases in PKA-dependent phosphorylation of Thr34 on DARPP-32, Ser943 on the alpha subunit of Na(+),K(+)-ATPase, and Ser897 of the N-methyl-D-aspartate (NMDA) receptor NR1 subunit. These findings indicate that D1 and D2 dopamine receptor activation contribute to neuronal death in newborn putamen after H-I in association with increased protein nitration and decreased Na(+),K(+)-ATPase activity. Furthermore, mechanisms of D1 receptor toxicity may involve DARPP-32-dependent phosphorylation of NMDA receptor NR1 and Na(+),K(+)-ATPase.

Adenosine Triphosphatases↗