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PubMed1994

Excitotoxicity and motor neurone disease: a review of the evidence.

Excitotoxic mechanisms have a well established role in the pathogenesis of neuronal injury following acute CNS insults such as ischaemia and trauma. Their role in the selective cell death which occurs in chronic neurodegenerative disorders such as motor neurone disease (MND) is more speculative. The traditional classification of glutamate receptor subtypes which mediate excitotoxicity requires modification in the light of new molecular data. There is much greater structural and functional diversity in this receptor family than previously envisaged and it is quite possible that specific populations of neurones will be characterised by a unique profile of glutamate receptor subtypes which may be a factor determining their selective vulnerability. The molecular mechanisms underlying excitotoxic neuronal injury are still being elucidated but it is clear that the cascade of events resulting from elevation of intracellular free calcium is likely to play a major role. As well as being a primary mechanism of neuronal injury, excitotoxicity can secondarily damage neurones whose energy metabolism is impaired from some primary pathological process. The 8 lines of evidence that primary or secondary excitotoxic mechanisms may be involved in the selective neuronal injury of MND are discussed. The evidence, while still circumstantial, is sufficient to warrant further research effort in this field, not least because the emergence of pharmacological agents which modify specific aspects of excitatory amino acid neurotransmission offer the possibility of therapeutic intervention in MND.

Animals↗

PubMed1993

Differential fatty acid release from CA1 and CA3 regions of rat hippocampal slices under hypoxia and hypoglycemia.

Rat hippocampal slices were subjected to hypoxia and/or hypoglycemia for 10 min, and free fatty acids released in CA1 and CA3 regions were separately analyzed. Fatty acid accumulation in CA1 was not so significant under hypoglycemia, but very prominent under hypoxia. Free fatty acid levels in CA3 were much less than those in CA1 even under hypoxia plus hypoglycemia. This observation seems to be consistent with the selective vulnerability of CA1 neurons seen in in vivo ischemia. The decreasing order of accumulation of free fatty acid species in CA1 was C16:0 > C18:0 > C18:1 > C20:4 > C22:6. The increment fold as compared to control level was decreasing as follows: C22:6, 28 times; C20:4, 13 times, C18:1, 10 times; C18:0 = C16:0, 3 times. The present experimental conditions using hippocampal slices provided a good in vitro model to prove the selective hypoxic damages of the CA1 subfield in terms of free fatty acid release in association with the membrane degradation.

Animals↗

PubMed2023

Single-cell transcriptomic atlas of Alzheimer's disease middle temporal gyrus reveals region, cell type and sex specificity of gene expression with novel genetic risk for MERTK in female.

Alzheimer's disease, the most common age-related neurodegenerative disease, is closely associated with both amyloid-ß plaque and neuroinflammation. Two thirds of Alzheimer's disease patients are females and they have a higher disease risk. Moreover, women with Alzheimer's disease have more extensive brain histological changes than men along with more severe cognitive symptoms and neurodegeneration. To identify how sex difference induces structural brain changes, we performed unbiased massively parallel single nucleus RNA sequencing on Alzheimer's disease and control brains focusing on the middle temporal gyrus, a brain region strongly affected by the disease but not previously studied with these methods. We identified a subpopulation of selectively vulnerable layer 2/3 excitatory neurons that that were RORB-negative and CDH9-expressing. This vulnerability differs from that reported for other brain regions, but there was no detectable difference between male and female patterns in middle temporal gyrus samples. Disease-associated, but sex-independent, reactive astrocyte signatures were also present. In clear contrast, the microglia signatures of diseased brains differed between males and females. Combining single cell transcriptomic data with results from genome-wide association studies (GWAS), we identified MERTK genetic variation as a risk factor for Alzheimer's disease selectively in females. Taken together, our single cell dataset revealed a unique cellular-level view of sex-specific transcriptional changes in Alzheimer's disease, illuminating GWAS identification of sex-specific Alzheimer's risk genes. These data serve as a rich resource for interrogation of the molecular and cellular basis of Alzheimer's disease.

Journal Article↗

PubMed1990

Ischemic damage in the striatum of adult gerbils: relative sparing of somatostatinergic and cholinergic interneurons contrasts with loss of efferent neurons.

The pattern of ischemia-induced cell death was examined with histochemical methods in the striatum of adult gerbils 4 and 7 days after transient forebrain ischemia. The results showed a massive loss of immunoreactivity to enkephalin and tachykinins, peptides present in striatal efferent neurons. In contrast, neurons expressing acetylcholinesterase activity, or choline acetyltransferase immunoreactivity, as well as neurons immunoreactive for somatostatin, were relatively preserved in areas of severe neuronal loss. The selective vulnerability of subpopulations of striatal neurons to transient ischemia in the adult is similar to that observed in the neonate and after local injections of agonists of N-methyl-D-aspartate receptors, but not of agonists of other glutamate receptor subtypes. It also presents striking similarities to the pattern of neuronal death observed in Huntington's disease. The results further support a role for overstimulation of a subtype of excitatory amino acid receptor in ischemia-induced cell death and show that the selective sparing of subpopulations of striatal interneurons after ischemic injury is not related to immaturity of these neurons but also occurs in the adult.

Acetylcholinesterase↗

PubMed1993

Early degeneration of calretinin-containing neurons in the rat hippocampus after ischemia.

The mechanism of delayed death of pyramidal cells in the hippocampal CA1 region and the acute death of various types of hilar neurons after ischemia is still unknown. Excitotoxicity may play a role in ischemic cell death, a prerequisite of which is the development of increased excitability or an enhanced excitatory transmission in the selectively vulnerable subfields of the hippocampus. Such changes may take place upon the loss or malfunction of local inhibitory neurons in the early postischemic period. In the present study we examined the vulnerability of non-pyramidal neurons containing a recently discovered calcium binding protein, calretinin, in the rat hippocampus following 15 min ischemia induced by four-vessel occlusion. Immunostaining for calretinin enabled us to visualize a new type of spiny non-pyramidal cell in the hippocampus specifically associated with the mossy fiber system. This cell type is present exclusively in regions where mossy fiber terminals occur, i.e. in the hilus of the dentate gyrus and in stratum lucidum of the CA3 subfield. A selective loss of immunoreactivity in these neurons was already observed at 12-24 h after ischemia, when the pyramidal cells in the CA1 region showed no signs of damage. At a survival time of two to three days, most if not all spiny calretinin-immunoreactive cells had disappeared from the hippocampus. Other types of calretinin-containing GABAergic neurons were also reduced in number, but only at a time when CA1 pyramidal cells also started to degenerate, i.e. two to three days after ischemia. We speculate that the early loss of spiny calretinin-containing cells, together with other non-pyramidal cells associated with the mossy fiber system (somatostatin-containing neurons and mossy cells of the hilus), may result in pathological network activity in the hippocampus, which may ultimately lead to an increased excitatory transmission and delayed pyramidal cell death in the CA1 region.

Animals↗

PubMed1994

Poor correlation between delayed neuronal death induced by transient forebrain ischemia, and immunoreactivity for parvalbumin and calbindin D-28k in developing gerbil hippocampus.

In the normal developing hippocampus of the gerbil, parvalbumin-immunoreactive neurons first appear in the stratum pyramidale of CA3 at postnatal day 15 (P15), and in CA2 and hilus of the dentate gyrus from P21 onwards. Immunoreactive terminals also follow the same sequence from CA3 to CA1 to reach adult patterns by the end of the 1st month. Calbindin D-28k immunoreactivity is seen in the external part of the upper blade of the dentate gyrus at P5, and progresses to the granule cell and molecular layers of the whole gyrus by P15, except for a thin band of immature cells located at the base of the granule cell layer which are calbindin negative. Calbindin immunoreactivity in mossy fibers progresses from the external to the hilar region of CA3 during the same period. A few immunoreactive cells are also found in the stratum radiatum/lacunare of the CA3, but no calbindin-immunoreactive cells are observed in the CA1 and CA2 subfields. The adult pattern of calbindin immunoreactivity is reached at P21. Vulnerability following transient forebrain ischemia for 20 min was examined in the hippocampal formation of gerbils during postnatal development. No cellular damage was seen in animals aged 7 days. Dying cells were observed at the base of the granule cell layer of the dentate gyrus in animals aged 15, 21 and 30 days. Pyramidal cells in the CA3 subfield were also sensitive to ischemia in gerbils aged 15 days, and less frequently in animals aged 21 days. The adult pattern of cellular damage, characterized by selective vulnerability of the CA1 subfield, was seen from day 30 onwards.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1996

Coordinate IGF-I and IGFBP5 gene expression in perinatal rat brain after hypoxia-ischemia.

Insulin-like growth factor I (IGF-I) is an anabolic pleiotrophic factor essential for postnatal rat brain development, especially during the first 21 days, the "critical growth period." Cerebral hypoxic-ischemic insults occurring during the perinatal period can result in neuronal necrosis and permanent brain damage. To understand the regulation of the action of IGF-I in response to such a metabolic insult, we investigated the gene expression of IGF-I, type I IGF receptor, IGF binding protein (IGFBP)2, and IGFBP5 during the first 72 h after hypoxia-ischemia in the immature rat. At 1 h of recovery, messenger RNA (mRNA) levels of all IGF system components were decreased throughout the hemisphere ipsilateral to the carotid artery ligation. This decrease is more pronounced at 24 h of recovery, especially in areas vulnerable to hypoxic-ischemic injury, such as the thalamus and hippocampus. At 72 h of recovery, although IGFBP2 and type 1 IGF receptor mRNA levels remain suppressed, gene expression of both IGF-I and IGFBP5 was activated in reactive astrocytes.Therefore, during the critical growth period in rats, the transcriptional levels of all IGF system components are extremely sensitive to metabolic perturbations associated with cerebral hypoxia-ischemia. The immediate decrease in IGF-I gene expression may be partially responsible for the impending neuronal death and selective vulnerability of myelinogenesis during the perinatal period.

Animals↗

PubMed2003

Vulnerability of human neurons to T cell-mediated cytotoxicity.

Axonal and neuronal loss occurs in inflammatory diseases of the CNS such as multiple sclerosis. The cause of the loss remains unclear. We report that polyclonally activated T cells align along axons and soma of cultured human neurons leading to substantial neuronal death. This occurs in an allogeneic and syngeneic manner in the absence of added Ag, requires T cells to be activated, and is mediated through cell contact-dependent mechanisms involving FasL, LFA-1, and CD40 but not MHC class I. Activated CD4(+) and CD8(+) T cell subsets are equally neuronal cytotoxic. In contrast to neurons, other CNS cell types (oligodendrocytes and astrocytes) are not killed by T cells. These results demonstrate for the first time the high and selective vulnerability of human neurons to T cells, and suggest that when enough activated T cells accumulate in the CNS, neuronal cytotoxicity can result through Ag-independent non-MHC class I mechanisms.

Antibodies, Blocking↗

PubMed1980

Pathogenesis of human poliovirus infection in mice. I. Clinical and pathological studies.

Human poliovirus infection in mice was studied to determine the similarities to human poliomyelitis, the selective vulnerability of neurons to infection, the role of the immune response in age-dependent susceptibility, and possible viral persistence. Mice inoculated intracerebrally (ic) with the Lansing type 2 poliovirus developed a disease with clinical, pathological, and age-dependent features resembling human poliomyelitis. Adult mice had a shorter incubation period (50% paralysis, Day 8 vs. Day 13) and a higher incidence of paralysis (97% vs. 79%) than newborns. Only paralyzed animals had pathologic changes in the spinal cord, and these corresponded to the degree of paralysis. Fluorescent antibody staining showed that selective infection of neurons was most intense in the anterior horn motor neurons of the spinal cord. There was no extraneural virus replication and no systemic neutralizing antibody response. Cyclophosphamide immunosuppression enhanced rather than diminished disease, indicating that maturation of immune responses did not explain the relative resistance of newborns to paralysis.

Animals↗

PubMed1987

Synthesis of acetylcholine from choline derived from phosphatidylcholine in a human neuronal cell line.

Cholinergic neurons are unique among cells since they alone utilize choline not only as a component of major membrane phospholipids, such as phosphatidylcholine (Ptd-Cho), but also as a precursor of their neurotransmitter acetylcholine (AcCho). It has been hypothesized that choline-phospholipids might serve as a storage pool of choline for AcCho synthesis. The selective vulnerability of cholinergic neurons in certain neurodegenerative diseases (e.g., Alzheimer disease, motor neuron disorders) might result from the abnormally accelerated liberation of choline (to be used as precursor of AcCho) from membrane phospholipids, resulting in altered membrane composition and function and compromised neuronal viability. However, the proposed metabolic link between membrane turnover and AcCho synthesis has been difficult to demonstrate because of the heterogeneity of the preparations used. Here we used a population of purely cholinergic cells (human neuroblastoma, LA-N-2), incubated in the presence of [methyl-3H]methionine to selectively label PtdCho synthesized by methylation of phosphatidylethanolamine, the only pathway of de novo choline synthesis. PtdCho, purified by thin-layer chromatography, contained 90% of the label incorporated into lipids, demonstrating that LA-N-2 cells contained phosphatidylethanolamine N-methyltransferase. Three peaks of radioactive material that cochromatographed with authentic Ac-Cho, choline, and phosphocholine were observed when the water-soluble metabolites of the [3H]PtdCho were purified by high-performance liquid chromatography. Their identities were ascertained by subjecting them to enzymatic modifications with acetylcholinesterase, choline oxidase, and alkaline phosphatase, respectively. The results demonstrate that AcCho can be synthesized from choline derived from the degradation of endogenous PtdCho formed de novo by methylation of phosphatidylethanolamine.

Acetylcholine↗

PubMed1992

Why are nigral catecholaminergic neurons more vulnerable than other cells in Parkinson's disease?

Although the cause of neuronal death in Parkinson's disease remains unknown, a hyperoxidation phenomenon has been implicated as a potential cytotoxic mechanism. Catecholaminergic neurons containing neuromelanin, an autoxidation byproduct of catecholamines, are more vulnerable in Parkinson's disease than nonmelanized catecholaminergic neurons. High levels of CuZn superoxide dismutase mRNA have been observed in the substantia nigra, suggesting that high levels of oxygen free radicals are indeed produced in the structure. Catecholaminergic neurons surrounded by a low density of glutathione peroxidase cells are more susceptible to degeneration in Parkinson's disease than those well protected against oxidative stress. The nigral content in iron, a compound that exacerbates the production of free radicals in catecholaminergic neurons, is increased in Parkinson's disease. Altogether these data suggest that hyperoxidation may participate in the selective vulnerability of catecholaminergic neurons in Parkinson's disease.

Calcium↗

PubMed2006

Irreversible translation arrest in the reperfused brain.

Irreversible translation arrest occurs in reperfused neurons that will die by delayed neuronal death. It is now recognized that suppression of protein synthesis is a general response of eukaryotic cells to exogenous stressors. Indeed, stress-induced translation arrest can be viewed as a component of cell stress responses, and consists of initiation, maintenance, and termination phases that work in concert with stress-induced transcriptional mechanisms. Within this framework, we review translation arrest in reperfused neurons. This framework provides a basis to recognize that phosphorylation of the alpha subunit of eukaryotic initiation factor 2 is the initiator of translation arrest, and a key marker indicating activation of neuronal stress responses. However, eIF2 alpha phosphorylation is reversible. Other phases of stress-induced translation arrest appear to contribute to irreversible translation arrest specifically in ischemic vulnerable neuron populations. We detail two lines of evidence supporting this view. First, ischemia, as a stress stimulus, induces irreversible co-translational protein misfolding and aggregation after 4 to 6 h of reperfusion, trapping protein synthesis machinery into functionally inactive protein aggregates. Second, ischemia and reperfusion leads to modifications of stress granules (SGs) that sequester functionally inactive 48S preinitiation complexes to maintain translation arrest. At later reperfusion durations, these mechanisms may converge such that SGs become sequestered in protein aggregates. These mechanisms result in elimination of functionally active ribosomes and preclude recovery of protein synthesis in selectively vulnerable neurons. Thus, recognizing translation arrest as a component of endogenous cellular stress response pathways will aid in making sense of the complexities of postischemic translation arrest.

Animals↗

PubMed1994

c-fos protein expression and ischemic changes in neurons vulnerable to ischemia/hypoxia, correlated with basic fibroblast growth factor immunoreactivity.

Injuries to the brain induce rapid expression of c-fos and c-jun proto-oncogenes in neurons. The protein products (Fos and Jun) of these cellular immediate early genes are thought to regulate target genes that participate in fundamental biological responses. In recent studies of rat brain infarct we demonstrated that gliosis and angiogenesis, two of the fundamental biological responses, are related to neuronal expression of basic fibroblast growth factor (bFGF). In the present study, we explore the linkage between c-fos and bFGF genes by comparing the temporal and spatial domains of Fos and bFGF immunoreactivities (IR) in brain infarct and in transient global ischemia. We demonstrate colocalization of Fos-IR and ischemic changes in neurons at infarct periphery and in regions of "selective vulnerability" beginning 3 hours post-infarction and lasting up to 1-2 weeks. These are: cortical neurons in layers II-III and V, interneurons in hippocampal formation, cerebellar Purkinje cells, and many subcortical nuclei and brainstem nuclei. bFGF-IR appears 12-24 hours later than Fos-IR in the same region but in non-ischemic neurons and the expression persists beyond 2 weeks. Persistent and not transient c-fos expression appears to be associated with ischemic neuronal death, although some of these neurons may survive beyond 2 weeks postinfarction.

Animals↗

PubMed1983

Resistance of hippocampal CA-1 interneurons to 20 min of transient cerebral ischemia in the rat.

The aim of this morphological study was to determine the vulnerability of hippocampal interneurons to ischemia in the adult rat. Two types of interneurons situated in the CA-1 stratum orients were investigated, the larger basket cells close to stratum pyramidale and the smaller basket cells close to the alveus. Male Wistar rats were subjected to 20 min of transient cerebral ischemia by means of 4-vessel occlusion and perfusion fixed 1, 2, 4, or 21 days later. In both Golgi-impregnated and in routinely stained sections the pyramidal cells and interneurons in the hippocampal CA-1 region were examined and counted. The study clearly demonstrated the selective vulnerability of the CA-1 pyramidal cells, as no ischemic cell damage to or loss of interneurons was found.

Animals↗

PubMed2002

Environmental risk factors and Parkinson's disease: selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat.

Environmental toxicants and, in particular, pesticides have been implicated as risk factors in Parkinson's disease (PD). The purpose of this study was to determine if selective nigrostriatal degeneration could be reproduced by systemic exposure of mice to the widely used herbicide paraquat. Repeated intraperitoneal paraquat injections killed dopaminergic neurons in the substantia nigra (SN) pars compacta, as assessed by stereological counting of tyrosine hydroxylase (TH)-immunoreactive and Nissl-stained neurons. This cell loss was dose- and age-dependent. Several lines of evidence indicated selective vulnerability of dopaminergic neurons to paraquat. The number of GABAergic cells was not decreased in the SN pars reticulata, and counting of Nissl-stained neurons in the hippocampus did not reveal any change in paraquat-treated mice. Degenerating cell bodies were observed by silver staining, but only in the SN pars compacta, and glial response was present in the ventral mesencephalon but not in the frontal cortex and cerebellum. No significant depletion of striatal dopamine followed paraquat administration. On the other hand, enhanced dopamine synthesis was suggested by an increase in TH activity. These findings unequivocally show that selective dopaminergic degeneration, one of the pathological hallmarks of PD, is also a characteristic of paraquat neurotoxicity. The apparent discrepancy between pathological (i.e., neurodegeneration) and neurochemical (i.e., lack of significant dopamine loss) effects represents another important feature of this paraquat model and is probably a reflection of compensatory mechanisms by which neurons that survive damage are capable of restoring neurotransmitter tissue levels.

1-Methyl-4-phenylpyridinium↗

PubMed2005

Changes of endogenous antioxidant enzymes during ischemic tolerance acquisition.

The purpose of this study was to investigate the role of superoxide dismutase (SOD) and catalase (CAT) in brain ischemic tolerance induced by ischemic preconditioning. Forebrain cerebral ischemia was induced in rat by four vessel occlusion. The activities of the antioxidant enzymes CuZn-SOD, Mn-SOD and CAT were measured in the hippocampus, striatum and cortex after 5 min of ischemia used as a preconditioning and subsequent reperfusion, by spectrophotometric methods. In all ischemia-reperfusion groups (5 h, 1 and 2 days of reperfusion), CuZn-SOD activities were found to be increased if compared to the sham operated controls. The increase was significant (P < 0.05) in all reperfusion groups, particularly after 5 h of reperfusion (3 times) in all studied brain regions; the largest increase was detected in the more vulnerable hippocampus and striatum. Very similar changes were found in Mn-SOD activity. The activity of CAT was increased too, but reached the peak of postischemic activity 24 h after ischemia. Our attempt to understand the mechanisms of increased SOD and CAT activities by application of protein synthesis inhibitor cycloheximide showed that this increase was caused by de novo synthesis of enzymes during first hours after ischemia. Our findings indicate that both major endogenous antioxidant enzymes SOD and CAT are synthesized as soon as 5 h after ischemia. In spite of significant upregulation of these enzymes a large number of neurons in selectively vulnerable CA1 region of hippocampus undergoes to neurodegeneration within 7 days after ischemia.

Animals↗

PubMed1996

Vesicular dysfunction during experimental thiamine deficiency is indicated by alterations in dopamine metabolism.

Experimental and clinical studies indicate that catecholamines play an important role in the neurobehavioural symptomatology of thiamine deficiency. Given the cerebral region-selective vulnerability and the behavioural impairment commonly encountered in thiamine deficiency, we undertook to investigate regional catecholamine metabolism in the brains of pyrithiamine-induced thiamine-deficient rats. Dopamine metabolism was unaffected in the striatum. In contrast, other regions also known to be involved in sensory processing and intellectual function (e.g., frontal cortex, hypothalamus, thalamus), but having a greater noradrenergic input, had increased levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and decreased levels of other dopaminergic metabolites including noradrenaline. In these regions levels of the vesicular amine transporter, defined by tetrabenazine-sensitive [3H]ketanserin binding, were also decreased. Our data suggest a region-selective vesicular dysfunction resulting in intraneuronal release, and subsequent degradation, of dopamine. These disruptions of dopamine and consequently noradrenaline metabolism may account for certain neurobehavioural deficits commonly encountered in thiamine deficiency.

Adrenergic Uptake Inhibitors↗

PubMed1989

Health needs of older adults displaced to Sudan by war and famine: questioning current targeting practices in health relief.

The high rates of death, disability and illness and the scarcity of resources associated with relief operations for victims of oppression, war and famine have led to some support systems of triage for health and nutritional care in relief. Two vulnerable groups have often been given priority for targeting in health relief--young children and their mothers. This paper reports the findings of a study of the health needs of another vulnerable group, older adults, among those who had been recently displaced to Sudan in 1984-1985 by the war and famine in Tigray region of Ethiopia. The study attempted to determine the extent to which morbidity events and migration affected the life-style of older adults and the socio-economic support mechanisms which were available to them. The findings indicate that older adults (those over 45 years of age) were a very small proportion of the population and that over half of those aged 60 years and over (defined as 'elderly' in this paper) had been left behind in Tigray. This may well indicate that disability, illness or both, forced many older adults, particularly those most in need, to remain in Tigray. Among older adults living in Sudan, high levels of minor disability, social isolation and total economic dependency indicated vulnerability, but older adults had not been specifically considered in health policies and plans. Their primary needs were basic--for cloth, food, shelter, transport, seeds, oxen and farming tools. We conclude that priority in relief should be to support individuals, families and entire communities by adequately providing for basic needs. Furthermore, international relief agencies should give equal consideration to those who remain in their homes and those who migrate for assistance. This approach would take into consideration quality of life, not just the number of lives saved among those who reach the camps and shelters, and would assume responsibility for 'Health for All', not just for selected 'vulnerable groups'.

Aged↗