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Results for “selective vulnerability”

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At least 595 records · Page 33Linked to original sources

PubMed1999

Progressive parenchymal deposition of beta-amyloid precursor protein in rat brain following global cerebral ischemia.

In addition to producing acute neuronal necrosis within selectively vulnerable brain regions, our recent studies have shown that global cerebral ischemia may also be followed by protracted degenerative changes occurring over the course of 10 weeks. Chronic brain pathology may be associated with the abnormal deposition of beta-amyloid precursor protein (betaAPP). In the present study, we used a monoclonal antibody to the N-terminal portion of betaAPP to characterize the brains of rats surviving 1-10 weeks following 10 min of global brain ischemia produced by bilateral carotid artery occlusions plus systemic hypotension. After ischemia, increased betaAPP immunolabeling emerged in several brain regions. In the hippocampus, granular deposits appeared in the damaged CA1 area by 2 weeks, and by 4-10 weeks the remnants of necrotic CA1 neurons were also immunolabeled. In striatum and thalamus, regions with necrotic cell death also revealed granular betaAPP deposits. The neocortex was devoid of overt ischemic neuronal damage but revealed prominent betaAPP immunoreactivity. Large ovoid deposits of low-density betaAPP immunostaining occurred in cortical neurons at 1-2 weeks. At 4-10 weeks, large round or oval deposits immunoreactive for betaAPP appeared in several cortical regions. The highest density of deposits was seen in the temporal and piriform cortices. Our results indicate that abnormal betaAPP deposition may result from ischemic as well as chronic neurodegenerative processes.

Amyloid beta-Protein Precursor↗

PubMed1999

Ultrastructural localization of phosphorylated eIF2alpha [eIF2alpha(P)] in rat dorsal hippocampus during reperfusion.

During post-ischemic brain reperfusion there is a substantial reduction of protein synthesis in selectively vulnerable neurons. Normal protein synthesis requires a functional translation initiation complex, a key element of which is eukaryotic initiation factor 2 (eIF2), which in a complex with GTP introduces the met-tRNA(i). Phosphorylation of Ser(51) on the alpha subunit of eIF2 [eIF2alpha(P)] generates a competitive inhibitor of eIF2B, thereby preventing the replenishment of GTP onto eIF2, thus blocking translation initiation. It has been shown that the conditional expression of an eIF2alpha mutant (Asp substituted for Ser(51)) imitating the negative charge of Ser(51) (P) induces apoptosis. During the first 10 min of post-ischemic reperfusion, there is an approximately 20-fold increase in eIF2alpha(P) seen in the cytoplasm of CA1 hippocampal neurons, and, by 1 h, there is also accumulation of eIF2alpha(P) in the nucleus. We utilized post-embedding electron microscopical immunogold methods to examine the localization of eIF2alpha(P) during reperfusion. Immunogold particles (10 nm) were concentrated chiefly along the rough endoplasmic reticulum and in association with the membranes of the nuclear envelope in CA1 neurons. Aggregations of gold particles in the nucleus were concentrated: (1) within and around the nucleolus, (2) associated to strands of heterochromatin, and (3) along putative nuclear filaments. The presence of eIF2alpha(P) in the nucleolus probably reflects its association with nascent ribosomal subunits. The beta-subunit of eIF2 has a zinc finger and polylysine blocks analogous to those on other proteins that affect transcription. The association of eIF2alpha(P) with chromatin may have important implications for transcription.

Animals↗

PubMed2004

Lesion evolution in cerebral ischemia.

There is sound evidence from histopathological and magnetic resonance imaging (MRI) studies that focal ischemic brain lesions tend to increase in size over time. Considerable lesion growth was observed in models of animal stroke as well as in patients presenting with hemispheric stroke. In focal cerebral ischemia, lesions predominantly enlarge early within 12 hours after onset. Ischemic injury is caused by complete necrosis in most of the affected tissue. By contrast, in global cerebral ischemia as seen after cardiac arrest, lesions appear late (>12 h) in selectively vulnerable brain regions such as the hippocampus, and neurons are damaged by apoptotic cell death. The high and regionally distinct vulnerability of the brain explains why prolonged periods of global ischemia result in widespread loss of energy metabolites combined with diffuse brain edema and global damage. Postulated mechanisms involved in lesion growth include among others excitotoxicity, periinfarct depolarizations, lactacidosis, microcirculatory disturbances, and flow-metabolism uncoupling. Research in the field faces two main challenges. First,maturation phenomena of injury may require special imaging techniques to detect early ischemic changes. Second, the dynamic nature of the changes underlines the need to conduct longitudinal studies with a variety of imaging techniques (e. g., metabolic imaging, diffusion/perfusion MRI, positron emission tomography) that require a differentiated interpretation of the alterations observed.

Animals↗

PubMed2000

The role of excitotoxicity in ALS--what is the evidence?

It is well accepted that excitotoxic mechanisms contribute to the pathogenesis of acute neuronal death in stroke, epilepsy, or brain trauma. It is less widely acknowledged that excitotoxic mechanisms play a role in the pathogenesis of chronic neurological disorders, in particular neurodegenerative diseases. However, evidence is accumulating that this mechanism is indeed part of the pathogenesis of late-onset neurodegenerative diseases. One of the clinical examples may be amyotrophic lateral sclerosis, a disease in which antiexcitotoxic strategies have neuroprotective effects in both, an established animal model and in man. In addition, there is accumulating neuropathological, pathobiochemical and pathophysiological evidence which indicates that excitotoxic mechanisms are part of the pathogenesis of the human disease and consequently part of the mechanisms explaining selective vulnerability ("pathoclisis") in the human motor system.

Amyotrophic Lateral Sclerosis↗

PubMed2006

An ultrastructural analysis of cellular death in the CA1 field in the rat hippocampus after transient forebrain ischemia followed by 2, 4 and 10 days of reperfusion.

An ultrastructural study was performed to investigate the type of cellular death that occurs in hippocampal CA1 field pyramidal neurons after 10 and 20 min of transient cerebral ischemia in the male adult Wistar rats, followed by 2, 4 and 10 days of reperfusion. The four-vessel occlusion method was used to induce ischemic insult for either 10 or 20 min, following which the animals were submitted to either 2, 4 or 10 days of reperfusion. The animals were then anaesthetised, and their brains removed, dehydrated, embedded, sectioned and examined under a transmission electron microscope. After ischemic insult, neurons from the CA1 field presented alterations, corresponding to the initial, intermediate and final stages of the degenerative process. The only difference observed between the 10 and 20 min ischemic groups was the degree of damage; the reaction was stronger in 20 min groups than in the 10 min groups. While neurons were found in the different stages of oncotic necrosis in all groups, differences were found between the groups in relation to prevalent stages. In both ischemic groups, after 2 days of reperfusion, the initial stage of oncotic necrosis was prevalent and large numbers of neurons appeared normal. In both groups, after 4 days of reperfusion, most of the neurons showed more advanced alterations, typical of an intermediate stage. In both groups, after 10 days of reperfusion, alterations corresponding to the intermediate and final stages of oncotic necrosis were also predominant. However, few intact neurons were identified and the neuropile appeared more organised, with numerous glial cells. In summary, the pyramidal neurons of the CA1 field displayed selective vulnerability and exhibited a morphological death pattern corresponding exclusively to an oncotic necrotic pathway.

Animals↗

PubMed1997

Transient expression of GAP-43 within the hippocampus after global brain ischemia in rat.

Neuroanatomical methods have been used to study selective vulnerability after global brain ischemia. A consistent pattern of ischemic neuronal damage is found in the rodent hippocampus with loss of CA1 neurons and of some cells in the hilus of the dentate gyrus. Very little is known about plastic changes that would be expected in ischemia-resistant areas such as CA3 neurons and granule cells. Neuronal plasticity after lesions may be indicated by changes in labeling with antibodies to the growth-associated protein 43 (GAP-43). Expression of GAP-43 as a marker for neuronal plasticity was studied here in the hippocampus after global brain ischemia. Halothane-anesthetized rats were subjected to 20 min of transient forebrain ischemia using four-vessel occlusion. In situ hybridization was used to study GAP-43 mRNA at 1, 3, 6, and 12 h and at 1, 3, and 7 days after ischemia. Immunostaining was carried out with two different antibodies to GAP-43 in brains which were perfusion-fixed after 1, 2, 4, and 7/8 days. In the control hippocampus, GAP-43 mRNA was localized to CA1-CA3 and the hilus. Moderate increases in cellular signals were seen in hilar cells and granule cells early after ischemia, and some changes occurred in CA3 at late stages. Hybridization was lost in CA1 due to cell death. With immunostaining, GAP-43 was not seen in the cytoplasm of neurons, whereas dense labeling occurred in a differentiated pattern in the axonal and dendritic layers. At 1 day after ischemia, neurons in the hilus of the dentate gyrus and in the stratum pyramidale and lucidum of CA3 showed strong cytoplasmic labeling for GAP-43. Few cells were labeled in these regions at 2 days, and none at later stages. Pyramidal cells in CA1 and CA3 areas and granule cells were never labeled. These studies demonstrate a transient expression of GAP-43 mRNA and protein in a subset of vulnerable neurons after transient brain ischemia. The cytoplasmic localization in hilar neurons could be due to increased synthesis of GAP-43 or to changes in axoplasmic transport. It is suggested that axonal damage occurs in hilar cells which stimulates GAP-43 expression. The increased production of trophic factors after ischemia in granule cells could also cause plastic changes in hilar cells. Since hilar neurons are in a strategic position to control the excitability of the dentate area, increased expression of GAP-43 may indicate an important pathophysiological process. In seizure experiments, strong expression of GAP-43 mRNA in granule cells was associated with abnormal mossy fiber sprouting and development of chronic epilepsy. The relevance of the minor GAP-43 mRNA upregulation after ischemia must be considered. The changes in CA3 neurons at several days after ischemia might represent a plastic response to a loss of CA1 neurons.

Analysis of Variance↗

PubMed2003

(r)-, but not (s)-alpha lipoic acid stimulates deficient brain pyruvate dehydrogenase complex in vascular dementia, but not in Alzheimer dementia.

In dementia of Alzheimer type (DAT), cerebral glucose metabolism is reduced in vivo, and enzymes involved in glucose breakdown are impaired in post-mortem brain tissue. Pyruvate dehydrogenase complex activity (PDHc) is one of the enzymes known to be reduced, while succinate dehydrogenase activity (SDH), another enzyme of oxidative glucose metabolism is unchanged. In dementia of vascular type (DVT), variable changes in glucose metabolism have been demonstrated in vivo, while changes of enzyme activities in post-mortem brain tissue are unknown. Here, PDHc and SDH activity were stimulated with each of the two stereoisomers of alpha lipoic acid in post-mortem parietal brain cortex of patients with DAT, DVT, and one case of Pick's disease and compared to stimulation effects in a control group, matched for age, sex, post-mortem delay, and storage time of brain tissue. PDHc in DAT and DVT, but not in Pick's disease was reduced. PDHc activity could be slightly stimulated by 10 micro M of the physiological stereoisomer (r)-alpha-lipoic acid, in controls and DVT (possibly also in Pick's disease), but not in DAT. In all groups investigated SDH was activated by 100 micro M and 1 mM of both isomers of alpha-lipoic acid, whereas 10 mM of both stereoisomers of alpha-lipoic acid caused an inhibition of both, PDHc and SDH activity. The loss of basal and of (r)-alpha-lipoic acid stimulated PDHc activity indicate that a functional or structural impairment of PDHc may exist in DAT and DVT which is not merely attributable to loss of mitochondria since basal and stimulated SDH activities are similar in controls, DVT and DAT, thus indicating selective vulnerability of PDHc.

Aged↗

PubMed2004

Neuromelanin inhibits enzymatic activity of 26S proteasome in human dopaminergic SH-SY5Y cells.

Recently, impairment of the ubiquitin-proteasome system is suggested to be responsible for the neuronal death in ageing and Parkinson's disease. The specific degeneration of dopamine neurons containing neuromelanin (NM) suggests that NM itself may be involved in the cellular dysfunction and death, even though the direct link has never been reported. We examined the effects of NM isolated from the human substantia nigra on the proteasome activity in human dopaminergic SH-SY5Y cells. NM reduced the activities of 26S proteasome, as shown in situ using a green fluorescent protein homologue targeted to 26S proteasome and also in vitro using ubiquitinated lysozyme as a substrate. However, NM did not affect 20S proteasome activity in vitro. NM reduced the amount of PA700 regulatory subunit of 26S proteasome, but did not affect that of alpha- and beta-subunits of 20S proteasome. These results suggest that NM may inhibit the ubiquitin-26S proteasome system, and determine the selective vulnerability of dopamine neurons in ageing and related disorders.

Adult↗

PubMed2005

Neuromelanin induces oxidative stress in mitochondria through release of iron: mechanism behind the inhibition of 26S proteasome.

Parkinson's disease is characterized by the selective depletion of dopamine neurons in the substantia nigra, particular those containing neuromelanin. Involvement of neuromelanin in the pathogenesis may be either cytotoxic or protective. Recently we found that neuromelanin reduces the activity of 26S proteasome. In this paper, the detailed mechanisms behind the reduced activity were studied using neuromelanin isolated from the human brain. Neuromelanin increased the oxidative stress, but synthetic melanin did not. Superoxide dismutase and deferoxamine completely suppressed the increase, indicating that superoxide produced by an iron-mediated reaction plays a central role. Iron was shown to reduce in situ 26S proteasome activity in SH-SY5Y cells and the reduction was protected by antioxidants. These results suggest that iron released from neuromelanin increases oxidative stress in mitochondria, and then causes mitochondrial dysfunction and reduces proteasome function. The role of neuromelanin is discussed in relation to the selective vulnerability of dopamine neurons in Parkinson's disease.

Acrolein↗

PubMed1998

Evaluation of neuronal loss, astrocytosis and abnormalities of cytoskeletal components of large motor neurons in the human anterior horn in aging.

In order to identify possible morphological changes which occur in the anterior horn of normal individuals during aging, 40 controls with no neurological disease were studied. Brain and spinal cord tissue was processed according to a brain banking protocol. Controls were grouped according to age in 10 year intervals. Serial sections (20 microm) of formalin fixed, paraffin-embedded tissue were obtained, from each cervical, thoracic and lumbar spinal cord segment. Every 5th section (until 2 mm) was stained with haematoxylin and eosin and the numbers of motor neurons in the anterior horn counted at x400 magnification. Descriptive statistical analysis was performed using the SPSS program. Parallel sections (5 microm) of the same spinal segments were immunostained with a panel of antibodies including glial fibrillary acidic protein (GFAP), tau, ubiquitin and two phosphorylated neurofilaments subunits. Significant neuronal loss with aging was found by regression line analysis where three equations were used to calculate the number of motor neurons by age in each spinal segment. In 24/40 cases spheroids were observed and they were more numerous in the lumbar segment. GFAP staining revealed a distinctive cellular pattern in the anterior horn of oldest cases. Large and intensely stained astrocytes were seen in the anterior horn of cases aged over 75 years. The number of astrocytes increased progressively with age up to 70 years. Some of the changes observed in the present study may be the result of a selective vulnerability of large motor neurons to aging which could play an important role in the progression of MND. Most of these changes may also have similar pathophysiological mechanisms.

Adult↗

PubMed1998

Normal and pathological aging--findings of positron-emission-tomography.

Normal aging of the brain is predominantly characterized by metabolic changes in the prefrontal cortex. While in middle age there is a trend to hyperfrontality, PET demonstrates in old age a decline of regional cerebral glucose metabolism in frontal areas. In progeric diseases, clinically apparent as premature aging, the metabolic pattern is similar like in normal aging but qualitatively more severe. In patients with the diagnosis of probable Alzheimer's disease (AD) hypometabolism in early dementia is typically present in heteromodal association areas. Hypometabolism then spreads to other cortical and subcortical regions suggesting a characteristic pattern of degeneration that reflects selective vulnerability within limbic-cortical networks. Synaptic plasticity, clinically apparent as cognitive reserve capacity, can be assessed by PET under specific cognitive activation. In AD it is reduced in comparison to age-matched normals and may be influenced by drugs giving trophic support to neurochemical systems.

Aging↗

PubMed2002

The neuromelanin of human substantia nigra and its interaction with metals.

Neuromelanin (NM) is a peculiar biochemical component of several neurons in the Substantia Nigra (SN), the target area of the degenerative process in Parkinson Disease (PD). SN NM has peculiarities as to its composition and an impressive capacity of chelating metals, iron in particular, but not exclusively. Gaining insights into the structural and functional characteristics of NM should help understanding the reasons of selective vulnerability of nigral neurons in many parkinsonian conditions. From the present data a protective role of NM can be postulated until the buffering capability toward heavy metals are exhausted. The overloading of NM with iron and other metals in neurons may trigger inflammatory and degenerative processes aggravating the underlying pathological condition.

Drug Interactions↗

PubMed2005

Atrophy of large myelinated axons in metallothionein-I, II knockout mice.

1. Metallothioneins (MTs) are small metal-binding proteins. The genes that encode MT isoforms I and II are also induced by metal at transcription level. Commonly expressed in the central nervous system (CNS) their putative function is protection against reactive oxygen species (ROS), however their role may not be restricted to this sole purpose. The physiological function of MTs in the peripheral nervous system (PNS) requires further investigation. 2. Examination of phrenic nerve cross-sections from MT-I and MT-II double knockout mice (MT-I, II KO) showed a significant reduction (P=0.0032) in the mean myelinated axons calibre compared to 129/Sv wild type (Wt) counterparts. 3. Analysis of the Gaussian spectra specifically attributes this atrophy to the large myelinated class (>or=4 microm) of axon considered selectively vulnerable in motor neuron disease (MND). Supporting the results, these axons also showed increased irregularity in shape. 4. In conclusion, MTs directly or indirectly influence the radial equilibrium of large myelinated motor axons.

Animals↗

PubMed2002

DNA base-excision repair enzyme apurinic/apyrimidinic endonuclease/redox factor-1 is increased and competent in the brain and spinal cord of individuals with amyotrophic lateral sclerosis.

Motor neurons degenerate in amyotrophic lateral sclerosis (ALS). The mechanisms for this neuronal cell death are not known, although apoptosis has been implicated. Oxidative damage to DNA and activation of p53 has been identified directly in motor neurons in cases of ALS. We evaluated whether motor neuron degeneration in ALS is associated with changes in the levels and function of the multifunctional protein apurinic/apyrimidinic endonuclease (APE/Ref-1). APE/Ref-1 functions as an enzyme in the DNA base-excision repair pathway and as a redox-regulation protein for transcription factors. The protein level and localization of APE/Ref-1 are changed in ALS. Immunoblotting showed that APE/Ref-1 protein levels are increased in selectively vulnerable central nervous system (CNS) regions in individuals with ALS compared to age-matched controls. Plasmid DNA repair assay demonstrated that APE from individuals with ALS is competent in repairing apurinic (AP) sites. DNA repair function in nuclear fractions is increased significantly in ALS motor cortex and spinal cord. Immunocytochemistry and single-cell densitometry revealed that APE/Ref-1 is expressed at lower levels in control motor neurons than in ALS motor neurons, which are decreased in number by 42% in motor cortex. APE/Ref-1 is increased in the nucleus of remaining upper motor neurons in ALS, which show a 38% loss of nuclear area. APE-Ref-1 is also upregulated in astrocytes in spinal cord white matter pathways in familial ALS. We conclude that mechanisms for DNA repair are activated in ALS, supporting the possibility that DNA damage is an upstream mechanism for motor neuron degeneration in this disease.

Aged↗

PubMed1978

Experimental stroke in gerbils: effect on translation and transcription.

The effect of cerebral ischemia on polypeptide synthesis with isolated microsomes and DNA-dependent RNA polymerase activity with isolated nuclei was investigated by occlusion of right common carotid artery of gerbils. There was a prompt decline of microsomal polypeptide synthesis already at 30 min after occlusion of the artery, and at 4--5 h the specific radioactivity (dpm per microgram protein) was 50% of the control value. At 24 h, when the animals were only slightly responsive to external stimuli, the specific radioactivity of ischemic brain was only 20% of the control value. DNA-dependent RNA polymerase activity was unaffected for 1 h, and clear suppression did not appear until 3 h after occlusion. However, the extent of suppression was similar between polypeptide synthesis and RNA polymerase activity beyond 3 h after occlusion. Although more selective vulnerability of polypeptide synthesis thus exists in cerebral ischemia, the difference between two biochemical processes was not as striking as seen in cerebral anoxia. Focal progression of cerebral ischemia to diffuse infarction in gerbils was suggested as a possible explanation for the disparity in comparison to the diffuse effect in cerebral anoxia along with the difference in the magnitude of acidosis and depletion of energy reserve.

Animals↗

PubMed1985

Regional comparisons of brain glucose influx.

The regional influx of glucose across the blood-brain barrier and regional blood flow were studied simultaneously in conscious and restrained rats using the single pass bolus injection of [14C]butanol and [3H]D-glucose method. Glucose extraction by the cerebellum was about twice that of other brain regions. Thus, despite the lower cerebellar blood flow, the influx of glucose into the cerebellum was equivalent to that of the cerebral cortex and higher than that of the hippocampus over a wide range of plasma glucose concentrations. Because the local metabolic rate for glucose is higher in the cerebral cortex than in the cerebellum, the equal influx of glucose in these two regions means a relative oversupply of glucose to the cerebellum. In vivo analysis of blood to brain glucose transport kinetics showed similar plasma glucose concentrations at half-maximal transport (Kt) in brain regions that were studied. The values for Kt ranged between 4.4 and 5.1 mM. Maximal transport capability (Tmax), on the other hand, was similar in the cerebral cortex and cerebellum but significantly lower in the hippocampus (P less than 0.05). The higher ratio of glucose influx to glucose utilization in the cerebellum may explain the clinical and experimental findings of relative resistance of the cerebellum to hypoglycemia while the lower Tmax in the hippocampus may be the mechanism underlying its selective vulnerability during pathophysiologic conditions associated with marked increments in brain oxidative metabolism, such as status epilepticus.

Animals↗

PubMed1985

Octanoic acid-induced coma and reticular formation energy metabolism.

The medium chain fatty acid octanoic acid was injected i.p. into 20-22 g Swiss-Albino mice at a dose of 15 mumol/g. This dose produced a reproducible response consisting of a 3-4 min period of drowsiness, followed by coma. These mice as well as suitable controls were sacrificed by rapid submersion in liquid N2, or by microwave irradiation in a 7.3 kW microwave oven. Tissue from the reticular formation and the inferior colliculus was prepared for microanalysis of the energy metabolites glucose, glycogen, ATP and phosphocreatine. Results from this study showed a selective effect on energy metabolism in cells of the reticular formation. Both glucose and glycogen were elevated in the coma and precoma state. In addition, ATP and phosphocreatine were decreased in the reticular formation during coma. These results show a selective effect of octanoic acid on energy metabolism in the reticular formation both in the precoma stage, and during overt coma. The selective vulnerability of the reticular formation to metabolic insult may act in a beneficial manner to the animal by inducing coma. This lowers the overall demand for energy, thereby placing the animal in a milieu in which there is an increased chance for correction of the perturbation.

Adenosine Triphosphate↗

PubMed1985

Neuron-specific mitochondrial degeneration induced by hyperammonemia and octanoic acidemia.

The neuropathological consequences of acute exposure to the neurotoxicants ammonia and octanoic acid were investigated with the isolated, perfused canine brain preparation. After 1 h of combined hyperammonemia and octanoic acidemia, ultrastructural changes were apparent in all brain regions examined. The cell bodies of neurons were the primary sites of these alterations. Neuronal mitochondria were distended, and the lamellae of the mitochondrial cristae were separated. In some cases the lamellae had completely dispersed, leaving only matrix remnants. Mitochondria of adjacent astrocytes appeared normal. Thus, a characteristic population of brain mitochondria is selectively vulnerable to a combination of hyperammonemia and octanoic acidemia and may be related to the biochemical mechanisms underlying encephalopathies of hepatic origin.

Ammonia↗