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 937 records · Page 52Linked to original sources

PubMed1986

Aminergic neurotransmitter and water content changes in rats after transient forebrain ischemia.

We have studied changes of cerebral monoamine metabolism and water content, during recirculation following global transient ischemia (20 min) using the four-vessel occlusion model in rats. Levels of monoamines and their metabolites were determined in cortex, striatum, hippocampus, and hypothalamus. Water content was evaluated by weight and by the analysis of T1 and T2 relaxation times in 1H-nuclear magnetic resonance. Norepinephine levels decreased; 3,4-dihydroxyphenylethylamine, 3,4-dihydroxyphenylacetic acid, and 5-hydroxytryptamine levels oscillated and levels of the end products homovanillic acid and 5-hydroxyindole-3-acetic acid increased. The regional changes were qualitatively similar but quantitatively different, and were greatest in the hippocampus, illustrating the concept of neuronal selective vulnerability. The changes suggest an initial monoamine depletion and catabolism due to massive release from stores followed by autoregulatory processes. The water content increased moderately, with a maximum at 1 h. The variations of T1 were similar, positively correlated with water content and more pronounced in the cortex than in the white matter. T2 was markedly altered over the entire 24-h period. Those latter parameters are positively correlated with 5-hydroxytryptamine concentration in the hypothalamus consistent with a relationship between 5-hydroxytryptamine and cerebral edema.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1993

Pre- and postmortem influences on brain RNA.

Many potentially valuable techniques for the understanding of human neurobiological and neuropathological processes require the use of RNA obtained from postmortem tissue. As with earlier neurochemical studies, there are two particular problems posed by such tissue in comparison with tissue from experimental animals. These are the postmortem interval and the condition of the patient prior to death, referred to as the agonal state. We review the nature and extent of the effects of postmortem interval and agonal state on RNA in brain tissue, with particular reference to the study of neuropsychiatric disorders. Perhaps surprisingly, postmortem interval has at most a modest effect on RNA. Abundant intact and biologically active RNA is present in tissue frozen 36 h or more after death. Postmortem interval does not account for the marked variability observed among human brains in all RNA parameters. Despite the overall stability of RNA after death, some evidence suggests that individual RNAs may undergo postmortem decay. Less attention has been paid to the effects of agonal state. The existing data indicate that events in the premortem period such as hypoxia and coma can affect the amount of some messenger RNAs. The nature of agonal state influences depends on the messenger RNA in question, though the basis for this selective vulnerability is unknown. No agonal state effect on overall RNA level or activity has been found. The data show that postmortem brain tissue can be used for RNA research. However, considerable attention must be paid to controlling for the influences of pre- and postmortem factors, especially when quantitative analyses are performed.

Animals↗

PubMed2004

Selective loss of NMDA receptor NR1 subunit isoforms in Alzheimer's disease.

Previous work had shown that the ratio of NMDA receptor NR1 subunit mRNA transcripts containing an N-terminal splice cassette to those that do not is markedly lower in regions of the Alzheimer's disease (AD) brain that are susceptible to pathological damage, compared with spared regions in the same cases or homotropic regions in controls. To elucidate the origins of this difference in proportionate expression, we measured the absolute levels of each of the eight NR1 transcripts by quantitative internally standardized RT-PCR assay. Expression of transcripts with the cassette was strongly attenuated in susceptible regions of Alzheimer's brain, whereas expression of non-cassette transcripts differed little from that in controls. The expression of other NR1 splice variants was not associated with pathology relevant to disease status, although some combinations of splice cassettes were well maintained in AD cases. The population profile of NR1 transcripts in occipital cortex differed from the profiles in other brain regions studied. Western analysis confirmed that the expression of protein isoforms containing the N-terminal peptide was very low in susceptible areas of the Alzheimer's brain. Cells that express NR1 subunits with the N-terminal cassette may be selectively vulnerable to toxicity in AD.

Aged↗

PubMed2006

Minocycline attenuates microglial activation but fails to mitigate striatal dopaminergic neurotoxicity: role of tumor necrosis factor-alpha.

Activated microglia are implicated in the pathogenesis of disease-, trauma- and toxicant-induced damage to the CNS, and strategies to modulate microglial activation are gaining impetus. A novel action of the tetracycline derivative minocycline is the ability to inhibit inflammation and free radical formation, factors that influence microglial activation. Minocycline is therefore being tested as a neuroprotective agent to alleviate CNS damage, although findings so far have yielded mixed results. Here, we showed that administration of a single low dose of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or methamphetamine (METH), a paradigm that causes selective degeneration of striatal dopaminergic nerve terminals without affecting the cell body in substantia nigra, increased the expression of mRNAs encoding microglia-associated factors F4/80, interleukin (IL)-1alpha, IL-6, monocyte chemoattractant protein-1 (MCP-1, CCL2) and tumor necrosis factor (TNF)-alpha. Minocycline treatment attenuated MPTP- or METH-mediated microglial activation, but failed to afford neuroprotection. Lack of neuroprotection was shown to be due to the inability of minocycline to abolish the induction of TNF-alpha and its receptors, thereby failing to modulate TNF signaling. Thus, TNF-alpha appeared to be an obligatory component of dopaminergic neurotoxicity. To address this possibility, we examined the effects of MPTP or METH in mice lacking genes encoding IL-6, CCL2 or TNF receptor (TNFR)1/2. Deficiency of either IL-6 or CCL2 did not alter MPTP neurotoxicity. However, deficiency of both TNFRs protected against the dopaminergic neurotoxicity of MPTP. Taken together, our findings suggest that attenuation of microglial activation is insufficient to modulate neurotoxicity as transient activation of microglia may suffice to initiate neurodegeneration. These findings support the hypothesis that TNF-alpha may play a role in the selective vulnerability of the nigrostriatal pathway associated with dopaminergic neurotoxicity and perhaps Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2006

Wild-type huntingtin protects neurons from excitotoxicity.

Huntingtin is a caspase substrate, and loss of normal huntingtin function resulting from caspase-mediated proteolysis may play a role in the pathogenesis of Huntington disease. Here we tested the hypothesis that increasing huntingtin levels protect striatal neurons from NMDA receptor-mediated excitotoxicity. Cultured striatal neurons from yeast artificial chromosome (YAC)18 transgenic mice over-expressing full-length wild-type huntingtin were dramatically protected from apoptosis and caspase-3 activation compared with cultured striatal neurons from non-transgenic FVB/N littermates and YAC72 mice expressing mutant human huntingtin. NMDA receptor activation induced by intrastriatal injection of quinolinic acid initiated a form of apoptotic neurodegeneration within the striatum of mice that was associated with caspase-3 cleavage of huntingtin in neurons and astrocytes, decreased levels of full-length huntingtin, and the generation of a specific N-terminal caspase cleavage product of huntingtin. In vivo, over-expression of wild-type huntingtin in YAC18 transgenic mice conferred significant protection against NMDA receptor-mediated apoptotic neurodegeneration. These data provide in vitro and in vivo evidence that huntingtin may regulate the balance between neuronal survival and death following acute excitotoxic stress, and that the levels of huntingtin may modulate neuronal sensitivity to excitotoxic neurodegeneration. We suggest that further study of huntingtin's anti-apoptotic function will contribute to our understanding of the pathogenesis of Huntingdon's disease and provide insights into the selective vulnerability of striatal neurons to excitotoxic cell death.

Animals↗

PubMed2006

Shift in the ratio of three-repeat tau and four-repeat tau mRNAs in individual cholinergic basal forebrain neurons in mild cognitive impairment and Alzheimer's disease.

Molecular mechanisms underlying tauopathy remain undetermined. In the current study, single cell gene expression profiling was coupled with custom-designed cDNA array analysis to evaluate tau expression and other cytoskeletal elements within individual neuronal populations in patients with no cognitive impairment (NCI), mild cognitive impairment (MCI), and Alzheimer's disease (AD). Results revealed a shift in the ratio of three-repeat tau (3Rtau) to four-repeat tau (4Rtau) mRNAs within individual human cholinergic basal forebrain (CBF) neurons within nucleus basalis (NB) and CA1 hippocampal neurons during the progression of AD, but not during normal aging. A shift in 3Rtau to 4Rtau may precipitate a cascade of events in the selective vulnerability of neurons, ultimately leading to frank neurofibrillary tangle (NFT) formation in tauopathies including AD.

Acetylcholine↗

PubMed2006

Alpha-synuclein inhibits aromatic amino acid decarboxylase activity in dopaminergic cells.

Alpha-synuclein is a presynaptic protein strongly implicated in Parkinson's disease (PD). Because dopamine neurons are invariably compromised during pathogenesis in PD, we have been exploring the functions of alpha-synuclein with particular relevance to dopaminergic neuronal cells. We previously discovered reduced tyrosine hydroxylase (TH) activity and minimal dopamine synthesis in stably-transfected MN9D cells overexpressing either wild-type or A53T mutant (alanine to threonine at amino acid 53) alpha-synuclein. TH, the rate-limiting enzyme in dopamine synthesis, converts tyrosine to l-dihydroxyphenylalanine (L-DOPA), which is then converted to dopamine by the enzyme, aromatic amino acid decarboxylase (AADC). We confirmed an interaction between alpha-synuclein and AADC in striatum. We then sought to determine whether wild-type or A53T mutant alpha-synuclein might have affected AADC activity in dopaminergic cells. Using HPLC with electrochemical detection, we measured dopamine and related catechols after L-DOPA treatments to bypass the TH step. We discovered that while alpha-synuclein did not reduce AADC protein levels, it significantly reduced AADC activity and phosphorylation in our cells. These novel findings further support a role for alpha-synuclein in dopamine homeostasis and may explain, at least in part, the selective vulnerability of dopamine neurons that occurs in PD.

Animals↗

PubMed1988

Comparative protective effects of nicardipine, flunarizine, lidoflazine and nimodipine against ischaemic injury in the hippocampus of the Mongolian gerbil.

1. Morphological changes characterizing delayed neuronal death (DND) of selectively vulnerable CA1 pyramidal cells in the hippocampus of the Mongolian gerbil brain occurred 72 h after transient (5 min) bilateral occlusion of the common carotid arteries. 2. Different groups of animals were treated 15 min before carotid artery occlusion and twice daily during the 72 h post-ischaemia period with either saline alone, nicardipine, flunarizine, lidoflazine or nimodipine at doses of 500 micrograms kg-1 intraperitoneally. 3. At 72 h the animals were killed and their brains examined histologically. Absolute cell counts were made from 5 sites distributed linearly throughout the hippocampal CA1 subfield in each hemisphere to determine the percentage DND in each group. Normal brains and those of sham-operated animals were included in the study for comparison. 4. Features of DND were distributed evenly throughout the CA1 subfield in both hemispheres in all groups of gerbils. Nicardipine, lidoflazine and flunarizine, but not nimodipine, were protective. This protection extended linearly throughout the hippocampus without altering the pattern of neuronal damage. 5. Compared to saline-treated (78.3 +/- 2.9% DND) and nimodipine-treated (76.5 +/- 3.4% DND) gerbils, the overall protection afforded by nicardipine (41.8 +/- 3.8% DND) was statistically significant. The effects of lidoflazine (53.6 +/- 7.1%) and flunarizine (55.8 +/- 3.9% DND) were of borderline significance. 6. Abnormal neurones appeared in normal and sham-operated brains to the extent of 4.5 +/- 1.0% and 4.6 +/- 0.4%, respectively. Such changes can be attributed to fixation artefacts. 7. The results demonstrate that overall protection is conferred on ischaemic hippocampal CA1 neurones by nicardipine and to a lesser extent by flunarizine and lidoflazine, but not by nimodipine.

Animals↗

PubMed1991

Blockade of intracellular actions of calcium may protect against ischaemic damage to the gerbil brain.

1. The brain cytoprotective effects of a putative calcium-associated protein kinase inhibitor, HA1077, as well as a calcium entry blocker nicardipine were evaluated in models of cerebral ischaemia in Mongolian gerbils. Morphological changes characterizing delayed neuronal death of selectively vulnerable CA1 pyramidal neurones in the hippocampus of the Mongolian gerbil brain occurred 7 days after transient bilateral occlusion of the common carotid arteries. 2. A single injection of HA1077 (1 and 3 mg kg-1, i.p.) 5 min after the occlusion led to a dose-dependent protection of the CA1 neurones. Repeated administrations of HA1077 (1 and 3 mg kg-1, i.p., twice daily for 7 days post-ischaemia) revealed an increase in the number of normal cells, compared to findings with a single administration. 3. In contrast to HA1077, nicardipine (0.3 and 1 mg kg-1, i.p.) did not reduce neuronal degeneration. 4. HA1077 did not interact with the ion channel within which MK-801 binds, as determined by receptor binding. 5. The calcium ionophore, A23187, caused a tonic contraction in canine cerebral arterial strips. HA1077, but not nicardipine, relaxed the A23187-induced contraction, concentration-dependently. 6. These results suggest that blockade of the intracellular actions of calcium may provide protection against ischaemic damage in the brain.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMedDate not supplied

Neonatal status convulsivus, spongiform encephalopathy, and low activity of Na+/K(+)-ATPase in the brain.

The first and second child of a family died from neonatal seizures with no detectable brain malformation, metabolic, infectious, or chromosomal etiology. Neuropathological examination of the brain of the second child who died at 11 days revealed a widespread spongy state and a selective vulnerability of the astrocytes characterized by numerous enlarged bare astrocytic nuclei and different forms of astrocyte degeneration. The glial cells were strongly positive for glial fibrillary acidic protein and vimentin immunocytochemical reaction. Cortical measurement of Na+/K(+)-ATPase revealed very low enzyme activity. We hypothesize that a defect of Na+/K(+)-ATPase of the astrocytes could be the common pathogenetic factor for the congenital status convulsivus and for the spongy state.

Astrocytes↗

PubMedDate not supplied

Occipital lobe epilepsy: a chronic condition related to transient occipital lobe involvement in eclampsia.

Eleven hours and 6 days, respectively, after childbirth 2 women exhibited hypertension and paroxysmal visual disturbances followed by tonic-clonic seizures and no other preeclamptic signs. Both developed partial epilepsy with occipital lobe seizures with no other neurologic defects. Neuroimaging showed no lesion during either the acute episode or 3-5 year follow-up. Selective vulnerability of the occipital lobes during eclamptic hypertensive encephalopathy was the probable pathophysiologic mechanism. Aggressive antihypertensive treatment during the acute phase may have exacerbated the risk of permanent cerebral damage.

Adult↗

PubMed1987

Chronic alcohol consumption reduces the cortical layer volumes and the number of neurons of the rat cerebellar cortex.

Past work showed that chronic alcohol consumption induces massive degeneration in the rat cerebellar cortex. In order to provide details of these effects, the cortical cell numbers and the cerebellar layer volumes were studied in adult rats fed alcohol for 1, 3, 6, 12, and 18 months and compared with respective age-matched controls. Significant decreases of granular and molecular layer volumes were found after 3 and 6 months of alcohol feeding, respectively. No significant differences were found in the Purkinje cell layer volume. Neuron countings showed that granule cells and molecular layer interneurons were the earliest and most severely affected populations. A decrease in the number of Purkinje cells was observed only after 18 months of alcohol consumption and Golgi cells were not significantly reduced. Thus, we concluded that cerebellar neurons have a selective vulnerability to alcohol which might alter the balance between excitatory and inhibitory limbs of the cerebellar circuitry.

Alcoholism↗

PubMed1991

Post-ischemic and kainic acid-induced c-fos protein expression in the rat hippocampus.

The c-fos protein is a gene regulatory third messenger involved in long-term responses of cells to various stimuli. It can be used as a marker of neuronal activity. In the present immunohistochemical study the presence of c-fos protein (FP) in the rat brain from 1 h to 14 days after 10 min of cerebral ischemia was compared with that 3 h after an intraventricular injection of kainic acid. The kainic acid injection resulted in staining of dentate hilar cells, granule cells and hippocampal interneurones. The postischemic changes at Day 1 were sporadic CA1 pyramidal cells expressing the FP. At Day 2 FP was expressed with variable intensity in many pyramidal cells in the CA1. At Day 3 many necrotic CA1 pyramidal cells were seen. They did not express the FP, and the expression was less intense and found in fewer cells than at Day 2. At Days 3, 7 and 14 there was increasing gliosis without c-fos expression in the CA1. The study demonstrates a delayed postischemic synthesis of the gene regulatory protein c-fos preceding the necrosis in the selectively vulnerable CA1 region.

Animals↗

PubMed1987

Effects of subacute toluene exposure on protein phosphorylation levels in rat frontoparietal and striatal membranes.

Effects of subacute toluene exposure (80 p.p.m. toluene in air, 5 + 4 days, 6 h day-1) were analysed on calcium (Ca2+)- and cyclic adenosine monophosphate (cAMP)-induced protein phosphorylation levels in membrane preparations from the frontoparietal cortex and the striatum of the adult male rat. After protein separation by gel electrophoresis, the amount of radioactive phosphate incorporated from adenosine 5'-[gamma-32P] triphosphate, tetra-(ethylammonium) salt ([32P]ATP) was measured indirectly by autoradiography. The 21 most phosphorylated protein bands were then analysed by computerized image analysis. In the frontoparietal cortex no protein bands were significantly affected after cAMP-induced back phosphorylation, while after Ca2+ stimulation there was a decreased incorporation of [32P]ATP in a 22,000 protein band. In the striatum there was a reduced incorporation of [32P]ATP in a 26,000 protein band after cAMP-induced back phosphorylation, and in four bands of 20,000, 21,000, 52,000 and 134,000, respectively, after Ca2+ stimulation. The reduced incorporation of [32P]ATP in these proteins indicated increased original phosphorylation levels after toluene exposure. A comparison between the frontoparietal cortex and the striatum showed a selective vulnerability of phosphorylation processes in striatal membrane protein bands. In conclusion, toluene exposure at low doses augments membrane protein phosphorylation levels in the rat forebrain and especially in the striatum, probably leading to changes in information handling and/or metabolic changes.

Animals↗

PubMed1989

Influence of age and age-related diseases on olfactory function.

It is clear from this review that olfactory function is markedly altered in old age and in a number of age-related diseases. The deficits appear to be rather general and detectable by several types of olfactory tests. Considerable interindividual variability exists, however, and the physiologic bases of these changes are not clear. In many healthy elderly persons, smell loss appears to occur as a result of one or more causes, including viral insult, cumulated exposure to toxic fumes, head trauma, and calcification of the cribriform plate. Several reviews have appeared suggesting that the olfactory system may be a center of primary involvement in AD. Of particular interest is the hypothesis that environmental agents (related etiologically to the disease process) pass into the central nervous system via the highly active transport mechanisms of the olfactory receptors. This latter notion, although attractive, must be viewed conservatively, as it is possible that the olfactory pathways are simply selectively vulnerable to destruction by various disease processes. This may explain why Huntington's chorea and multiinfarct dementia, in addition to AD and PD, are associated with alterations in smell function. Although it is tempting to assume, as have authors such as Koss et al., that alterations in threshold function reflect peripheral olfactory dysfunction and that alterations in odor identification and other more demanding tasks reflect central olfactory dysfunction, there is little empirical support for such a simple dichotomy. Despite the fact that a peripheral/central distinction is useful in clinical audiology (where threshold loss is commonly associated with CN VIII pathology), an evaluation of the utility of this distinction in olfaction requires further research. The limited data suggest that both identification and detection deficits commonly arise from damage to the olfactory epithelium, even though identification deficits unassociated with detection deficits may occur in some central brain disorders. It is apparent from the studies reviewed in this chapter that considerable progress has been made during the last decade in elucidating the nature and prevalence of olfactory disturbances in elderly patients, as well as in patients with dementia-related diseases.(ABSTRACT TRUNCATED AT 400 WORDS)

Aged↗

PubMed1994

Short-term and long-term changes in the postischemic hippocampus.

We have demonstrated a far more widespread and selective ischemic cell damage than previously thought. In area CA3, a distinct subpopulation of interneurons, characterized by their spiny dendrites and their calretinin content, was selectively vulnerable in the absence of any other CA3 involvement. In the dentate hilus, four different types of spiny cells were consistently damaged. The common denominator in these two cell groups is the presence of spines on their dendrites and hence the greater density of mossy fiber innervation they receive. A common mechanism of cell death may be the presence of non-NMDA receptor subtypes that are highly permeable to calcium. We speculate that they may constitute an important control mechanism in the CA3 region and the hilus, and impairment of this mechanism may be causal to delayed neuronal death in CA1. We have also shown that neuronal degeneration does not end after delayed cell death of CA1 pyramidal cells. Our results suggest that there is progressive degeneration throughout the life of the animal and degeneration of additional cell populations (e.g. CA1 interneurons and CA3 pyramidal cells) may also occur secondary to the insult.

Animals↗

PubMed1996

APP gene family. Alternative splicing generates functionally related isoforms.

The Alzheimer's beta A4-amyloid protein precursor (APP) and the APP-like proteins (APLPs) are transmembrane glycoproteins with a similar modular domain structure. APP exists in 8 isoforms generated by alternative splicing of exons 7, 8, and 15, of which the L-APP mRNAs lacking exon 15 are ubiquitously expressed in rat tissues but not in neurons. Rat APLP2, the nearest relative of APP, is similarly expressed in 4 different isoforms due to alternative splicing of inserts encoding a Kunitz protease inhibitor domain (KPI, homologous to exon 7 of APP) and a divergent region of 12 amino acids on the NH2-terminal side of the transmembrane domain (12 aa exon). KPI-APLP2 transcripts are highly expressed in neurons, in contrast to KPI-APPs, while L-APLP2 mRNA isoforms lacking the 12 aa exon are predominantly expressed in non-neuronal rat tissues, similar to L-APPs. Further examination of the divergent domains in APP and APLP2 harboring the similarly alternatively spliced APP exon 15 and the 12 aa exon of APLP2 revealed some structural similarities of the amino acid sequences and the predicted secondary structures. In both L-APLP2 and L-APP, a putative xylosyl-transferase recognition site for chondroitin sulfate glycosaminoglycan attachment is present that is interrupted in APP and APLP2 isoforms expressing APP exon 15 or the 12 aa exon of APLP2. Thus, a related function of the divergent domains and the corresponding alternatively spliced APP and APLP2 isoforms in regulation of the binding properties of the ectodomain is suggested. Additionally, beta-secretase cleavage of APP might be sterically hindered selectively in proteoglycan L-APP but not in APP lacking the proteoglycan attachment site. Neurons which have a uniquely low portion of L-APP and high content of APP might therefore be especially susceptible to beta A4-protein liberation. This could explain the selective vulnerability of neurons that is observed in Alzheimer's disease.

Alternative Splicing↗

PubMed1997

Importance of vascular changes in selective neurodegeneration with thiamine deficiency.

These results demonstrate that early alterations in the BBB may underlie selective vulnerability in this model of chronic reduced oxidative metabolism. Changes in the BBB (IgG extravasation) precede alterations in APP processing and cell death. Since thiamine-dependent enzymes are also reduced in the brain in Alzheimer's disease, similar processes may be important in the pathophysiology of the disease.

Amyloid beta-Protein Precursor↗