Kainic acid-induced excitotoxic hippocampal neurodegeneration in C57BL/6 mice: B cell and T cell subsets may contribute differently to the pathogenesis (original) (raw)
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Kathmandu University medical journal (KUMJ)
Neurodegenerative disease is a progressive loss of neurons from the central nervous system (CNS). Various conditions have been implicated for such conditions including ageing, inflammation, stress and genetic predisposition. Recently, studies have linked neurodegeneration with inflammation. Some studies have suggested the harmful effect of immune response while others have argued its neuroprotective role in neurodegeneration of the CNS. However, the precise role of inflammation and immune cells in such condition is still not clear. To investigate the role of lymphocytes in neurodegeneration of the CNS and determine the underlying mechanism. We have used 4-7 days old mouse pups (C57Bl6) to prepare organotypic slice cultures which were cultured for 13-15 days prior to experiment. To induced cell death kainic acid was used and considered as an in vitro model for neurodegeneration. Lymphocytes were obtained from peripheral lymph nodes of 5-10 weeks old adult mouse which were used in the...
Journal of Neuroimmunology, 2004
Kainic acid (KA)-induced hippocampal injury is a good model for studying human neurodegenerative diseases. To investigate the roles of immune cells and age related changes in neurodegeneration, we used this model to assess reactions in young and middle-aged wild-type and CD4/CD8(À / À) mice by intranasal administration of KA. We found that CD4/CD8-deficiency resulted in a significant reduction of the severity of clinical signs and pathological changes in KA-treated young, but not in KA-treated middle-aged mice. Middle-aged wild-type mice had a similar reaction to KA insult as young and middle-aged CD4/CD8(À / À) mice. CD4/CD8(À / À) mice exhibited decreased locomotor and rearing activities as they approached to middle-aged state, which was not seen in wild-type mice. In addition, CD4/CD8deficiency and increased age prevented KA-induced increase of both locomotor and rearing activities. The results suggest that a decline of immunological function is associated with aging, and both of them may contribute to the relative resistance to KA-induced neurotoxicity.
Journal of Neuroscience, 2012
The excitotoxic effects of kainic acid (KA) in the mouse hippocampus is strain dependent. Following KA administration, the large majority of hippocampal pyramidal cells die in the FVB/N (FVB) mouse, while the pyramidal cells of the C57BL/6 (B6) strain are largely spared. We generated aggregation chimeras between the sensitive FVB and the resistant B6 strains to investigate whether intrinsic or extrinsic features of a neuron confer cell vulnerability or resistance to KA. The constitutive expression of transgenic green fluorescence protein (GFP) or -galactosidase expressed from the ROSA26 locus was used to mark cells in FVB or B6 mice, respectively. These makers enable the identification of cells from each parental genotype while TUNEL (terminal deoxynucleotidyl transferase-mediated biotinylated dUTP nick end labeling)-staining labeled dying cells. The analysis of the percentage of dying cells in FVB-GFP 7 B6-ROSA chimeras yielded an intriguing mix of both intrinsic and extrinsic factors in the readout of cell phenotype. Thus, normally resistant B6-ROSA pyramidal neurons demonstrated an increasing sensitivity to KA, in a linear fashion, when the percentage of FVB-GFP cells was increased, either across chimeras or in different regions of the same chimera. However, the death of B6-ROSA pyramidal cells never exceeded ϳ70% of the total amount of B6 neurons regardless of the amount of FVB cells in the chimeric hippocampus. In a similar manner, FVB-GFP cells show lower amounts of cell death in chimeras that are colonized by B6-ROSA cells, but again, are never fully rescued. These data indicate that both intrinsic and extrinsic factors modulate the sensitivity of hippocampal pyramidal cells to kainic acid.
Repeated kainic acid administration and hippocampal neuronal degeneration
Prague medical report, 2005
Many animal models have been established to study the mechanisms leading to excitotoxicity. One of the more commonly used models is kainic acid (KA) induced excitotoxicity. Upon administration of KA in rodents, KA produces acute status epilepticus and neuronal damage. The aim of the study was to examine the morphologic alteration in the hippocampus of mature rats, after repeated KA administration. The first group was given KA repeatedly in six doses (10 mg/1000 g), each second day. The second group was given KA i.p. repeatedly in six smaller doses (5 mg/1000 g), each second day. The third group (control animals) received corresponding volumes of the normal saline (5 or 10 mg/1000 g respectively). Animals were transcardially perfused; serial sections were stained with Fluoro-Jade B and DNA-specific dye bis-benzimide (Hoechst). In CA1 region of the first group many degenerating cells were observed. The CA2 region was not as much affected as CA1. In the CA3 region no degenerating cells...
Neuroscience, 2001
AbstractÐThe role of interleukin-6 in hippocampal tissue damage after injection with kainic acid, a rigid glutamate analogue inducing epileptic seizures, has been studied by means of interleukin-6 null mice. At 35 mg/kg, kainic acid induced convulsions in both control (75%) and interleukin-6 null (100%) mice, and caused a signi®cant mortality (62%) only in the latter mice, indicating that interleukin-6 de®ciency increased the susceptibility to kainic acid-induced brain damage. To compare the histopathological damage caused to the brain, control and interleukin-6 null mice were administered 8.75 mg/kg kainic acid and were killed six days later. Morphological damage to the hippocampal ®eld CA1±CA3 was seen after kainic acid treatment. Reactive astrogliosis and microgliosis were prominent in kainic acid-injected normal mice hippocampus, and clear signs of increased oxidative stress were evident. Thus, the immunoreactivity for inducible nitric oxide synthase, peroxynitrite-induced nitration of proteins and byproducts of fatty acid peroxidation were dramatically increased, as was that for metallothionein I 1 II, Mn-superoxide dismutase and Cu/Zn-superoxide dismutase. In accordance, a signi®cant neuronal apoptosis was caused by kainic acid, as revealed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling and interleukin-1b converting enzyme/Caspase-1 stainings. In kainic acid-injected interleukin-6 null mice, reactive astrogliosis and microgliosis were reduced, while morphological hippocampal damage, oxidative stress and apoptotic neuronal death were increased. Since metallothionein-I 1 II levels were lower, and those of inducible nitric oxide synthase higher, these concomitant changes are likely to contribute to the observed increased oxidative stress and neuronal death in the interleukin-6 null mice.
European Journal of Neuroscience, 2006
We assessed inbred, outbred and hybrid mouse strains for susceptibility to seizures and neurodegeneration induced by systemic administration of kainic acid (KA). Each strain showed a unique pattern of susceptibility to seizures as assessed by the dose necessary to induce continuous tonic clonic seizures, progression through six seizure levels, the number of mice that failed to satisfy seizure criteria, and seizure-induced mortality. In general, the C57BL ⁄ 6, ICR, FVB ⁄ N, and BALB ⁄ c strains were resistant to seizures while the C57BL ⁄ 10, DBA ⁄ 2 J, and F1 C57BL ⁄ 6*CBA ⁄ J strains were vulnerable. Neuronal cell death was quantified in four subfields of the hippocampus: CA3, the hilus of the dentate gyrus, CA1, and the dentate granule cell layer. Neurodegeneration was also semiquantitatively assessed in other brain regions including the neocortex, striatum, thalamus, hypothalamus and amygdala. Although there was variability in the extent of cell death within strains, there were significant differences in the amount of hippocampal cell death between strains and also different patterns of neurodegeneration in affected brain areas. In general, the C57BL ⁄ 6, C57BL ⁄ 10, and F1 C57BL ⁄ 6*CBA ⁄ J strains were resistant to neurodegeneration while the FVB ⁄ N, ICR and DBA ⁄ 2 J strains were vulnerable. The BALB ⁄ c strain was unique in that neurodegeneration was confined to the hippocampus. Consistent with previous findings, the resistant neurodegeneration phenotype was dominant in an F1 cross of resistant and vulnerable inbred strains. Our results, using a large number of mouse strains, definitively demonstrate that a mouse strain's seizure phenotype is not related to its neurodegeneration phenotype.
Molecular Brain Research, 2001
Apoptosis results from the activation of a programmed cellular cascade involving several mechanisms. In the present study, we have investigated the implication of three molecules of this cascade, p53, Bax and caspase-3, in neuronal death induced by kainic acid (KA) administration in mouse hippocampus. Using immunocytochemistry, western blot and quantification of enzyme activity, we observed in p531 / 1 and p532 / 2 animals that KA induced neuronal death by both p53-dependent and independent pathways. Moreover, apoptosis (labeled by TUNEL) and the increase of bax and caspase-3 protein expression after the neurotoxic insult appeared to clearly depend on p53 expression.
Nuclear factor kappa B-mediated kainate neurotoxicity in the rat and hamster hippocampus
Neuroscience, 1999
Administration of the excitotoxin kainate produces seizure activity and selective neuronal death in various brain areas. We examined the degeneration pattern of hippocampal neurons following systemic injections of kainate in the hamster and the rat. As reported, treatment with kainate resulted in severe neuronal loss in the hilus and CA3 in the rat. While the hilar neurons were also highly vulnerable to kainate in the hamster, neurons in the CA1 area, but not CA3, were highly sensitive to kainate. In both animals, immunoreactivity to anti-p50 nuclear factor kappa B antibody was increased in nuclei of the hilar neurons within 4 h following administration of kainate. Kainate treatment also increased the nuclear factor kappa B immunoreactivity in hamster CA1 neurons and rat CA3 neurons 24 h later. Neurons showing intense nuclear factor kappa B signal were stained with acid fuchsin. Kainate also increased DNA binding activity of p50 and p65 nuclear factor kappa B in the nuclear extract of the hippocampal formation as analysed by electrophoretic mobility shift assay in the hamster, suggesting that activation of nuclear factor kappa B may contribute to kainate-induced hippocampal degeneration. Administration of 100 nmol dizocilpine maleate 3 h prior to kainate attenuated kainate-induced activation of nuclear factor kappa B and neuronal death in CA1 in the hamster. The present study provides evidence that the differential vulnerability of neurons in the rat and the hamster hippocampus to kainate is partly mediated by mechanisms involving N-methyl-d-aspartate-dependent activation of nuclear factor kappa B. ᭧ 1999 IBRO. Published by Elsevier Science Ltd.
Degeneration of hippocampal CA3 pyramidal cells induced by intraventricular kainic acid
The Journal of Comparative Neurology, 1980
Degeneration of hippocampal CA3 pyramidal cells was investigated by light and electron microscopy after intraventricular injection of the potent convulsant, kainic acid. Electron microscopy revealed evidence of pyramidal cell degeneration within one hour. The earliest degenerative changes were confined to the cell body and proximal dendritic shafts. These included an increased incidence of lysosomal structures, deformation of the perikaryal and nuclear outlines, some increase in background electron density, and dilation of the cisternae of the endoplasmic reticulum accompanied by detachment of polyribosomes. Within the next few hours the pyramidal cells atrophied and became electron dense. Then these cells became electron lucent once more as ribosomes disappeared and their membranes and organelles broke up and disintegrated. Light microscopic changes correlated with these ultrastructural observations. The dendritic spines and the initial portion of the dendritic shaft became electron dense within four hours and degenerated rapidly, whereas the intermediate segment of the dendrites swelled moderately and became more electron lucent. No degenerative changes were evident in pyramidal cell axons and boutons until one day after kainic acid treatment.
IL-12p35 deficiency alleviates kainic acid-induced hippocampal neurodegeneration in C57BL/6 mice
Neurobiology of Disease, 2004
The role of IL-12 in excitotoxic neurodegeneration of brain is largely unknown. To address this issue, we used the model of kainic acid (KA)induced hippocampal injury in IL-12p35 knockout (KO) mice, a wellcharacterized model for human neurodegenerative diseases. After KA treatment, hippocampal neurodegeneration was significantly less severe in the IL-12p35 KO mice than in wild-type mice as demonstrated by reduced pathological changes and astrogliosis. One day after KA treatment, levels of F4/80 and CD86 expression on microglia were significantly lower in IL-12p35 KO mice than in wild-type mice analyzed by flow cytometry, indicating that IL-12p35 deficiency resulted in lower levels of microglial activation. Five days after KA treatment, CD86 expression on microglia of wild-type mice was still higher, whereas F4/80 expression in wild-type mice decreased and was similar to that in IL-12p35 KO mice. Because microglial activation is necessary for KA-induced neurodegeneration, the lower level of microglial activation in the absence of IL-12p35 may alleviate hippocampal injury in KO mice. In summary, this study indicates that IL-12 may play a critical role in excitotoxin-induced brain injury.