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Results for “neuronal vulnerability”

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PubMed2001

Activation of metabotropic glutamate receptor subtype 1/protein kinase C/mitogen-activated protein kinase pathway is required for postischemic long-term potentiation in the striatum.

Excessive stimulation of glutamate receptors is believed to contribute substantially in determining neuronal vulnerability to ischemia. However, how this pathological event predisposes neurons to excitotoxic insults is still largely unknown. By using electrophysiological recordings from single striatal neurons, we demonstrate in a corticostriatal brain-slice preparation that in vitro ischemia (glucose and oxygen deprivation) activates a complex chain of intracellular events responsible for a dramatic and irreversible increase in the sensitivity of striatal neurons to synaptically released glutamate. This process follows the stimulation of both N-methyl-D-aspartate and metabotropic glutamate receptors and involves the activation of the mitogen-activated protein kinase ERK via protein kinase C. This pathological form of synaptic plasticity might play a role in the cell type-specific neuronal vulnerability in the striatum, because it is selectively expressed in neuronal subtypes that are highly sensitive to both acute and chronic disorders involving this brain area.

Animals↗

PubMed1998

Cortical distribution of neurofibrillary tangles in Alzheimer's disease matches the pattern of neurons that retain their capacity of plastic remodelling in the adult brain.

The formation of neurofibrillary tangles in Alzheimer's disease shows a preferential involvement of certain cytoarchitecturally defined cortical areas suggesting systematic differences in regional neuronal vulnerability. The cellular and molecular nature of this selective neuronal vulnerability that follows a certain hierarchy of structural brain organization is largely unknown. In the present study, we compared the regional pattern of tangle density in Alzheimer's disease with systematic regional differences in neuronal plasticity that can be observed both during ageing and in Alzheimer's disease. Changes in dendritic length and arborization of Golgi-impregnated pyramidal neurons were analysed after three-dimensional reconstruction in 12 cortical areas. The intensity of dendritic remodelling that was observed during ageing as well as in Alzheimer's disease was regionally different and decreased in the following order: transentorhinal region > limbic areas (entorhinal region, hippocampus) > non-primary association areas (37, 40, 46) > primary sensory association areas (7, 18, 22) > primary sensory and motor cortex (17, 41, 4). These regional differences of neuronal plasticity follow the same pattern as the regional vulnerability to tangle formation in Alzheimer's disease. The results of the present study provide evidence that a high degree of structural neuronal plasticity might predispose neurons to tangle formation.

Adult↗

PubMed1998

A short episode of seizure activity protects from status epilepticus-induced neuronal damage in rat brain.

Kainic acid (KA)-induced status epilepticus (SE) in adult rats results in extensive neuronal damage throughout the limbic system and the loss of selectively vulnerable neuronal populations, particularly CA3 neurons. We investigated the effects of a short episode of seizure activity on neuronal death elicited by a subsequent prolonged SE episode. A short episode of seizure activity was produced by sub-cutaneous (s.c.) injection of KA followed after 1 h by pentobarbital administration. Twenty-four hours later, KA was administered again, and animals were sacrificed 3 days later. Neuronal damage was estimated by visual analysis of neuronal density. Our results show that a short episode of seizure activity did not produce neuronal damage but almost completely protected vulnerable neurons from KA-induced neuronal damage. These results extend to epileptic tolerance the notion of tolerance previously described in the case of ischemia.

Animals↗

PubMed1995

Spinal cord neurons are vulnerable to rapidly triggered kainate neurotoxicity in vitro.

Initial studies found glutamate injury to murine spinal cultures (14-17 days in vitro) to reflect contributions of both NMDA and AMPA/kainate receptors. Subsequent experiments found the spinal cultures to be more sensitive than cortical cultures to injury from prolonged low level kainate exposures, and, unlike cortical cultures, to be significantly damaged by relatively brief (30-60 min) kainate exposures. This rapidly triggered kainate damage to spinal neurons is Ca(2+)-dependent. Also, more than 40% of spinal neurons (in comparison to about 15% of cortical neurons) are subject to kainate-activated Co2+ uptake (Co2+(+) neurons), a histochemical technique that labels neurons with Ca(2+)-permeable AMPA/kainate channels. These spinal Co2+(+) neurons are very sensitive to Ca(2+)-dependent kainate injury, and show greater kainate-induced elevations in intracellular Ca2+ concentrations ([Ca2+]i) than other spinal neurons during low level kainate exposures. Thus, the heightened vulnerability of spinal neurons to kainate toxicity may at least in part reflect the large proportion that possess Ca2+ permeable AMPA/kainate channels, permitting receptor activation to trigger rapid Ca2+ influx and overwhelm the cells Ca2+ homeostatic capabilities.

Animals↗

PubMed1997

Myoclonic epilepsy and ragged red fibers (MERRF) syndrome: selective vulnerability of CNS neurons does not correlate with the level of mitochondrial tRNAlys mutation in individual neuronal isolates.

Selective vulnerability of subpopulations of neurons is a striking feature of neurodegeneration. Mitochondrially transmitted diseases are no exception. In this study CNS tissues from a patient with myoclonus epilepsy and ragged red fibers (MERRF) syndrome, which results from an A to G transition of nucleotide (nt) 8344 in the mitochondrial tRNALys gene, were examined for the proportion of mutant mtDNA. Either individual neuronal somas or the adjacent neuropil and glia were microdissected from cryostat tissue sections of histologically severely affected brain regions, including dentate nuclei, Purkinje cells, and inferior olivary nuclei, and from a presumably less affected neuronal subpopulation, the anterior horn cells of the spinal cord. Mutant and normal mtDNA were quantified after PCR amplification with a mismatched primer and restriction enzyme digestion. Neurons and the surrounding neuropil and glia from all CNS regions that were analyzed exhibited high proportions of mutant mtDNA, ranging from 97.6 +/- 0.7% in Purkinje cells to 80.6 +/- 2.8% in the anterior horn cells. Within each neuronal group that was analyzed, neuronal soma values were similar to those in the surrounding neuropil and glia or in the regional tissue homogenate. Surprisingly, as compared with controls, neuronal loss ranged from 7% of the Purkinje cells to 46% of the neurons of the dentate nucleus in MERRF cerebellum. Thus, factors other than the high proportion of mutant mtDNA, in particular nuclear-controlled neuronal differences among various regions of the CNS, seem to contribute to the mitochondrial dysfunction and ultimate cell death.

Adolescent↗

PubMed1988

Mechanisms of ischemic brain damage.

This article provides a brief review of recent developments regarding the pathophysiology of ischemic brain damage, and offers hypotheses explaining the pathogenesis of selective neuronal vulnerability and of tissue infarction, respectively. It is suggested that selective neuronal vulnerability, observed after brief periods of ischemia and after hypoglycemic coma, qualifies as an excitotoxic lesion, which causes postsynaptic damage to neurons innervated by excitatory amino acids by enhancing calcium influx. However, ischemic damage often involves glial and vascular cells as well, and causes infarction. It is hypothesized that this type of brain damage is related to acidosis and that enhanced acidosis is detrimental because it accelerates delocalization of protein-bound iron, with an ensuing free-radical damage to membrane lipids and proteins.

Acid-Base Equilibrium↗

PubMed2006

Targeting the alpha 7 nicotinic acetylcholine receptor to reduce amyloid accumulation in Alzheimer's disease pyramidal neurons.

Although there is still no known effective preventative treatment or cure for Alzheimer's disease (AD), the development of new drugs that target pathological features that appear early in the course of this disease and alleviate some of the early cognitive and memory symptoms is a laudable goal that may be one step closer. To date, the acetylcholinesterase inhibitors have been the most widely used AD drugs and have been somewhat successful in slowing loss of cognition. In the last few years, a number of studies have demonstrated that amyloid beta (1-42) (Abeta42), the predominant Abeta peptide species in amyloid plaques, first accumulates in vulnerable neurons prior to plaque formation. Recently, we have shown that many (if not most) amyloid plaques in the entorhinal cortex of AD brains are actually the lysis remnants of degenerated, Abeta42-overburdened neurons. Furthermore, the most vulnerable neurons appear to be those that abundantly express the alpha7 nicotinic acetylcholine receptor (alpha7nAChR), and internalization of Abeta42 appears to be facilitated by the high-affinity binding of Abeta42 to the alpha7nAChR on neuronal cell surfaces, followed by endocytosis of the resulting complex and its accumulation within the lysosomal compartment. This mechanism provides a reasonable explanation for the selective vulnerability of cholinergic and cholinoceptive neurons in AD brains and for the fact that Abeta42 is the dominant Abeta peptide species in both intraneuronal accumulations and amyloid plaques. In view of the pathophysiological consequences of Abeta42 binding to alpha7nAChR on neuronal surfaces that stem from excessive intraneuronal Abeta42 accumulation, the alpha7nAChR could be an important therapeutic target for treatment of AD. In addition, it further emphasizes the potential merits of new and effective therapeutic strategies pointed towards the goal of lowering of Abeta42 levels in the blood and cerebrospinal fluid as well as blocking Abeta42 in the blood from penetrating the blood-brain barrier and entering into the brain parenchyma.

Alzheimer Disease↗

PubMed1998

Protein nitration in Parkinson's disease.

Oxidative stress has been proposed as a pathogenetic mechanism in Parkinson's disease (PD). One mechanism of oxidative cellular injury is the nitration of protein tyrosine residues, mediated by peroxynitrite, a reaction product of nitric oxide and superoxide radicals. We demonstrate here the presence of nitrotyrosine immunoreactivity in Lewy bodies within melanized neurons and in amorphous deposits associated with intact and degenerating neurons. The core of the Lewy body was frequently intensely immunolabeled, while the rim was lightly labeled or unlabeled. This likely reflects the fact that tyrosine residues of neurofilament proteins are primarily localized to Lewy body cores, and suggests that nitrotyrosine is present in neurofilament protein itself. Although these observations are as yet unable to provide a definitive link between oxidative stress and neuronal dysfunction, they demonstrate that oxidative stress has occurred within the vulnerable neurons of PD, leaving a permanent marker of oxidative modification of neuronal proteins within the target cells of neurodegeneration. In addition, these observations provide a potential link between excitotoxicity and oxidative stress within the vulnerable neurons of PD and represent a pathogenetic mechanism in common with the 2 other major age-related neurodegenerative diseases, Alzheimer disease and amyotrophic lateral sclerosis.

Adult↗

PubMed1991

Neonatal striatal NADPH-diaphorase neurons are vulnerable to quisqualate and its analogue alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionate (AMPA).

A small population of neurons in the mammalian striatum and cerebral cortex contain NADPH-diaphorase. Recently, this class of neurons has been found in vitro to be selectively vulnerable to low concentrations of non-N-methyl-D-aspartate (NMDA) glutamate agonists. To determine if this pattern exists in vivo, we injected either quisqualate (QA) or its inotropic site analogue alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionate (AMPA) into the striatum of neonatal rat pups and found a dose-dependent loss of NADPH-diaphorase reactive neurons. These data suggest that the QA receptor may be present and functional at postnatal day 7 when other glutamate receptor subtypes have not yet fully developed and that QA is working through its inotropic site since AMPA causes the same dose-dependent cell death.

Animals↗

PubMed2006

Activation of the Akt/GSK3beta signaling pathway mediates survival of vulnerable hippocampal neurons after transient global cerebral ischemia in rats.

Recent studies have revealed that the phosphatidylinositol 3-kinase (PI3-K) pathway is involved in apoptotic cell death after experimental cerebral ischemia. The serine-threonine kinase, Akt, functions in the PI3-K pathway and prevents apoptosis by phosphorylation at Ser473 after a variety of cell death stimuli. After phosphorylation, activated Akt inactivates other apoptogenic factors, including glycogen synthase kinase-3beta (GSK3beta), thereby inhibiting cell death. However, the role of Akt/GSK3beta signaling in the delayed death of hippocampal neurons in the CA1 subregion after transient global cerebral ischemia (tGCI) has not been clarified. Transient global cerebral ischemia for 5 mins was induced by bilateral common carotid artery occlusion combined with hypotension. Western blot analysis showed a significant increase in phospho-Akt (Ser473) and phospho-GSK3beta (Ser9) in the hippocampal CA1 subregion after tGCI. Immunohistochemistry showed that expression of phospho-Akt (Ser473) and phospho-GSK3beta (Ser9) was markedly increased in the vulnerable CA1 subregion, but not in the ischemic-tolerant CA3 subregion. Double staining with phospho-GSK3beta (Ser9) and terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end labeling showed different cellular distributions in the CA1 subregion 3 days after tGCI. Phosphorylation of Akt and GSK3beta was prevented by LY294002, a PI3-K inhibitor, which facilitated subsequent DNA fragmentation 3 days after tGCI. Moreover, transgenic rats that overexpress copper/zinc-superoxide dismutase, which is known to be neuroprotective against delayed hippocampal CA1 injury after tGCI, had enhanced and persistent phosphorylation of both Akt and GSK3beta after tGCI. These findings suggest that activation of the Akt/GSK3beta signaling pathway may mediate survival of vulnerable hippocampal CA1 neurons after tGCI.

Animals↗

PubMed1998

A fluorescence confocal assay to assess neuronal viability in brain slices.

Hippocampal slice models are used to study the mechanisms of ischemia-induced neurotoxicity and to assess the neuroprotective potential of novel therapeutic agents. A number of morphological and functional endpoints are available to assess neuronal viability. The slice model also allows the study of selectively vulnerable neuronal populations within the same preparation. The fluorescence procedure described here provides a method of assessing the viability of neurons in rat hippocampal slices exposed to hypoxic-hypoglycemic conditions. Control and/or treated slices that had been subjected to a 10 min oxygen-glucose deprivation insult are double stained with calcein-AM (4 microM), which stains live cells green, and ethidium homodimer (6 microM), which stains the nucleus of dead cells red. The stained slices are then imaged using confocal microscopy. Vulnerable neurons in the CA1 region of slices deprived of oxygen and glucose became increasingly permeant to ethidium homodimer over the 4 h reperfusion period. Exposure to low Ca2+ concentration (0.3 mM) or the N-, P- and Q-type Ca2+ channel antagonist MVIIC (100 nM), which have been shown to be neuroprotective in this model of ischemia using field evoked post-synaptic potential (EPSP) measures as an endpoint, were also shown to be protective using the fluorescence assay.

Animals↗

PubMed2006

Prenatal glucocorticoid exposure affects learning and vulnerability of cholinergic neurons.

Prenatal treatment with synthetic glucocorticoids is commonly used as a treatment for women at risk of preterm delivery. However, little is known about the life-long consequences of these treatments on the fetus. In the present study, we evaluated cognitive function as well as susceptibility of cholinergic neurons to (192)IgG-saporin immunolesion in adult rats after prenatal glucocorticoid treatment. Morris water maze results revealed a significant difference in learning and memory function in adult rats that were prenatally exposed to dexamethasone, and further cognitive deficits after (192)IgG-saporin exposure. Choline acetyl transferase activity was decreased in the cortex of dexamethasone-treated rats compared with controls. In addition, rats prenatally exposed to either dexa, or betamethasone revealed a dramatic decrease in choline acetyl transferase activity compared to control rats after (192)IgG-saporin lesion. We report behavioral and biochemical evidence for altered cognitive function and increased susceptibility of cholinergic neurons to (192)IgG-saporin in adult rats after prenatal glucocorticoid treatment. Taken together, these results suggest that prenatal treatment with dexamethasone could affect cognitive functions and render cholinergic neurons more vulnerable to challenges later in life.

Animals↗

PubMed1998

Amelioration of hippocampal neuronal damage after global ischemia by neuronal overexpression of BCL-2 in transgenic mice.

BACKGROUND AND PURPOSE: Reports suggesting the involvement of apoptosis in ischemic neuronal damage have been accumulating, and protection against apoptotic death by BCL-2 has been shown in many types of cells. Overexpression of BCL-2 has been shown to reduce infarct size after focal ischemia. The purpose of the present study was to assess whether BCL-2 exerted its effect on selective neuronal vulnerability after transient global ischemia. METHODS: Transgenic mice overexpressing BCL-2 in neurons and their littermates were subjected to transient forebrain ischemia for 12 minutes, and the hippocampus was examined 7 days later with conventional histology, immunohistochemistry, and in situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling of fragmented DNA. RESULTS: Although both types of mice showed a similar degree of ischemic insult, transgenic mice showed a lesser degree of neuronal death together with DNA fragmentation in the hippocampus than their littermates. CONCLUSIONS: Overexpression of BCL-2 in neurons mitigates selective neuronal vulnerability in the hippocampus of transgenic mice after transient global ischemia.

Animals↗

PubMed1993

Hilar somatostatin neurons are more vulnerable to an ischemic insult than CA1 pyramidal neurons.

The effects of a very short ischemic insult on hilar somatostatin (SS) neurons were investigated in the gerbil hippocampus by means of immunocytochemistry and in situ hybridization histochemistry. A selective and significant loss of 40% of hilar SS neurons took place after 1 day, and a 60% loss after 7 days following 2 min of ischemia, while no SS neurons were lost during recirculation after 1 min of ischemia. Repeated 2-min periods of ischemia, which induced ischemic tolerance by vulnerable CA1 neurons, caused almost complete loss of hilar SS neurons. This study clearly demonstrates that hilar SS neurons are more vulnerable to ischemic insult than CA1 pyramidal neurons. Ischemic tolerance may be induced during the progressive loss of SS neurons in the hilus by changes in their synaptic connections to CA1 pyramidal neurons.

Animals↗

PubMed2002

Protective effect of apolipoprotein E against ischemic neuronal injury is mediated through antioxidant action.

Recent studies have demonstrated that apolipoprotein E (APOE) deficiency worsened neuronal injuries after transient focal and global cerebral ischemia. However, the molecular mechanism underlying the protective effect of APOE remains uncertain, even though several mechanisms, including excitotoxicty, free radicals, and apoptosis, have been cited as causes of selective neuronal vulnerability in cerebral ischemia. In the present study, we first compared the vulnerability of cultured neurons prepared from APOE-knockout mice upon exposure to glutamate, hydrogen peroxide, and staurosporine. No significant difference in cell viability was observed after exposure to glutamate or staurosporine between APOE-deficient and wild-type mice. However, exposure to hydrogen peroxide significantly increased the level of cell death in APOE-deficient mice compared with that in wild-type mice. After transient forebrain ischemia for 12 min, APOE-deficient mice showed more neuronal death than wild-type mice. Pretreatment of APOE-deficient mice with vitamin E for 2 months markedly reduced neuronal death caused by ischemia. The results suggest that APOE exerted its neuroprotective effect against ischemia through its antioxidant action but not through mitigation of glutamate toxicity or blocking of apoptosis.

Animals↗

PubMed1999

Dietary restriction protects hippocampal neurons against the death-promoting action of a presenilin-1 mutation.

Alzheimer's disease (AD) is an age-related disorder that involves degeneration of synapses and neurons in brain regions involved in learning and memory processes. Some cases of AD are caused by mutations in presenilin-1 (PS1), an integral membrane protein located in the endoplasmic reticulum. Previous studies have shown that PS1 mutations increase neuronal vulnerability to excitotoxicity and apoptosis. Although dietary restriction (DR) can increase lifespan and reduce the incidence of several age-related diseases in rodents, the possibility that DR can modify the pathogenic actions of mutations that cause AD has not been examined. The vulnerability of hippocampal neurons to excitotoxic injury was increased in PS1 mutant knockin mice. PS1 mutant knockin mice and wild-type mice maintained on a DR regimen for 3 months exhibited reduced excitotoxic damage to hippocampal CA1 and CA3 neurons compared to mice fed ad libitum; the DR regimen completely counteracted the endangering effect of the PS1 mutation. The magnitude of increase in levels of the lipid peroxidation product 4-hydroxynonenal following the excitotoxic insult was lower in DR mice compared to mice fed ad libitum, suggesting that suppression of oxidative stress may be one mechanism underlying the neuroprotective effect of DR. These findings indicate that the neurodegeneration-promoting effect of an AD-linked mutation is subject to modification by diet.

Alzheimer Disease↗

PubMed1996

Expression of the apoptosis-effector gene, Bax, is up-regulated in vulnerable hippocampal CA1 neurons following global ischemia.

The observation that delayed death of CA1 neurons after global ischemia is inhibited by protein synthesis inhibitors suggests that the delayed death of these neurons is an active process that requires new gene expression. Delayed death in CA1 has some of the characteristics of apoptotic death; however, candidate proapoptotic proteins have not been identified in the CA1 after ischemia. We studied the expression of Bax protein and mRNA, a member of the bcl-2 family that is an effector of apoptotic cell death, after global ischemia in the four-vessel global ischemia model in the rat and compared these results with the expression of the antiapoptotic gene bcl-2. Bax mRNA and protein are both expressed in CA1 before delayed death, whereas bcl-2 protein is not expressed. Bcl-2 protein expression, but not that of Bax, is increased in CA3, a region that is ischemic but less susceptible to ischemic injury. In the dentate gyrus, both Bax and bcl-2 proteins are expressed. The selective expression of Bax in Ca1 supports the hypothesis that Bax could contribute to delayed neuronal death in these vulnerable neurons by an independent mechanism or by forming heterodimers with gene family members other than bcl-2.

Animals↗

PubMed2002

Neuroprotective effect of apolipoprotein E against ischemia.

Apolipoprotein E (APOE) deficiency has been shown to worsen neuronal injuries after cerebral ischemia. However, the molecular mechanism underlying the protective effect of APOE remains uncertain, even though several mechanisms including excitotoxicity, free radicals, and apoptosis have been cited as causes of selective neuronal vulnerability in cerebral ischemia. In the present study, we compared the vulnerability of cultured neurons prepared from APOE-knockout mice upon exposure to glutamate, hydrogen peroxide, and staurosporine. No significant difference in cell viability was observed after exposure to glutamate or staurosporine between APOE-deficient and wild-type mice. However, exposure to hydrogen peroxide significantly increased the level of cell death in APOE-deficient mice compared with that in wild-type mice. In the adult mice, after transient forebrain ischemia for 12 min, APOE-deficient mice showed more neuronal death than wild-type mice. Pretreatment of APOE-deficient mice with vitamin E for 2 months markedly reduced neuronal death caused by ischemia. The results suggested that APOE exerted the neuroprotective effect against ischemia through its antioxidant action, but not through mitigation of glutamate toxicity or blocking of apoptosis.

Animals↗