Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Systemic injection of kainic acid (KA) does not cause neuronal pathology in limbic structures in rat brain prior to postnatal day (PND) 21. The present study tested if the development of the pathogenic response is associated with the maturation of a link between seizure activity and polyamine metabolism. Pathology was assessed with histological techniques and with the binding of [3H]Ro5-4864, a ligand for the peripheral type benzodiazepine binding sites (PTBBS), a marker of glial cell proliferation. In agreement with previous results, peripherally administered kainate at doses sufficient to induce intense behavioral seizures produced a loss of Nissl staining in hippocampus after PND 21 but not at earlier ages. The pattern of neuronal damage observed after PND 21 resembled that found in adult animals: extensive losses of Nissl staining in area CA3 of hippocampus and in piriform cortex, more modest effects in CA1 and sparing of the granule cells of the dentate gyrus. Similarly, no increase in [3H]Ro5-4864 binding as a result of KA administration was observed in hippocampus and piriform cortex until PND 21. Ornithine decarboxylase (ODC) activity and putrescine levels were high in the neonatal brain and decreased to reach adult values by PND 21. KA-induced seizure activity did not significantly alter both variables until PND 21. After PND 21, ODC activity and putrescine levels markedly increased 16 h after KA-induced seizure activity in hippocampus and piriform cortex. The magnitude of the effects increased between PND 21 and PND 30, at which point the changes in both parameters were comparable to those found in adults. Polyamines stimulate the activity of the calcium-dependent proteases calpain in brain fractions and may increase calpain-mediated proteolysis in situ. In accord with this, kainate-induced breakdown of spectrin, a preferred substrate of calpain, measured 16 h after KA injection followed a developmental curve parallel to that for kainate-induced increases in putrescine levels. These results indicate that the onset of vulnerability to seizure activity triggered by kainic acid is correlated with the development of an ODC/polyamine response to the seizures and further support a critical role for the ODC/polyamine pathway in neuronal pathology following a variety of insults.
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PMID:Seizure activity-induced changes in polyamine metabolism and neuronal pathology during the postnatal period in rat brain. 133 Mar 69

The induction of ornithine decarboxylase (ODC) in adult CNS and the resulting changes in polyamine levels are often observed under conditions associated with activation of NMDA receptors, calpain stimulation and spectrin degradation. The present study was directed at evaluating the links between these two sets of events. We measured the effects of an acute treatment of adult rats with difluoromethylornithine (DFMO), an irreversible inhibitor of ODC, on biochemical alterations following kainate-induced seizure activity. Beside ODC activity and polyamine levels, we assayed the in situ spectrin degradation and the in vitro binding of 3H-Ro5-4864, a ligand for the peripheral benzodiazepine binding sites which is a good marker of glial proliferation, at various time intervals following systemic kainic acid (KA) injection. Kainate-induced seizure activity was followed by a transient increase in ODC activity, a long-lasting increase in putrescine levels and spectrin degradation, and a delayed increase in 3H-Ro5-4864 binding, mainly in hippocampus and piriform cortex. Treatment of the animals with DFMO markedly reduced the increase in putrescine levels up to 7 days after KA injection. It also reduced the increase in spectrin breakdown observed at 16 h but not at 4 and 7 days after KA injection. Finally, it did not modify the increase in 3H-Ro5-4864 binding measured 4 and 7 days after KA injection. The levels of putrescine were positively correlated with the extent of spectrin proteolysis in KA-treated animals whether or not they were treated with DFMO, at 16 h but not at 7 days after KA injection. The results indicate that the extent of spectrin breakdown observed shortly after KA-induced seizure activity is causally related to the changes in ODC activity and putrescine levels. Although the data are consistent with the idea that putrescine could be a marker for acute pathology, they do not support a role for polyamines in delayed neurotoxicity.
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PMID:Changes in polyamine levels and spectrin degradation following kainate-induced seizure activity: effect of difluoromethylornithine. 158 35

The effects of kainate (KA)-induced epileptic seizures on the binding properties of hippocampal glutamate receptors, on the modulation of DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/quisqualate receptor by phospholipase A2 (PLA2), and on the formation of long-term potentiation (LTP) were studied in hippocampal membranes and hippocampal slices. Systemic administration of KA (10 mg/kg; 15 hr survival) produced specific changes in the binding properties of the AMPA/quisqualate receptors and its regulation. Whereas the binding of various ligands to the N-methyl-D-aspartate receptors was not modified by KA treatment, there was a significant decrease in the maximal number of binding sites for [3H]AMPA. In addition, the increase in [3H]AMPA binding elicited by PLA2 treatment of hippocampal, but not cerebellar, membranes was markedly decreased after KA injection. LTP was also substantially reduced in area CA1 of hippocampal slices from KA-treated animals. The loss of LTP was not due to changes in postsynaptic responses elicited by the bursts that trigger the potentiation effect, thus suggesting that KA treatment disrupts processes that follow N-methyl-D-aspartate receptor activation. Systemic administration of KA was associated with calpain activation as the amount of spectrin breakdown products was increased severalfold in hippocampus but not in cerebellum. Pretreatment of telencephalic membranes with calpain greatly reduced the PLA2-induced increase in [3H]AMPA binding. The results provide evidence in favor of an essential role of PLA2 in the development of LTP and suggest that the order of activation of different calcium-dependent processes is critical for producing the final changes underlying LTP.
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PMID:Modulation of DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/quisqualate receptors by phospholipase A2: a necessary step in long-term potentiation? 184 14

Systemic injection of kainic acid (KA) in adult rat elicits a pattern of neuronal pathology which exhibits several features of human temporal lobe epilepsy. KA-induced seizure activity is accompanied by the activation of the calcium-dependent protease calpain in limbic structures. In the present study, we evaluated the spatio-temporal activation of calpain after the onset of seizure activity by immunohistochemistry using an antibody for the spectrin breakdown product (sbdp) generated by calpain-mediated spectrin proteolysis. In addition, we compared the changes in sbdp immunoreactivity with those in immunoreactivity to subunits of the Glu/AMPA receptors (GluR1 and GluR2/3). One hour after seizure onset, sbdp accumulation was observed in selected interneurons in stratum oriens and in the hilus of the dentate gyrus. By 4 h, sbdp immunoreactivity was prominent in dendritic fields of the hippocampus as well as in neurons in thalamus and piriform cortex. By 8 h, sbdp immunoreactivity had disappeared from interneurons but was localized in pyramidal cell bodies in hippocampus. Intense labeling of cell bodies and dendritic fields persisted until 5 days following KA treatment. Changes in GluR subunit immunoreactivity were mirror images of those seen for sbdp. In general, increased sbdp immunoreactivity in dendritic fields was associated with decreased GluR1 immunoreactivity. However, increased sbdp immunoreactivity in neuronal perikarya was also associated with increased GluR immunoreactivity. These results indicate that calpain activation following seizure onset exhibits a specific spatio-temporal pattern, with activation in restricted interneurons preceding widespread activation in pyramidal neurons. Calpain activation also precedes neuronal pathology and could thus represent an initial trigger for neuronal pathology. Finally, the results suggest that calpain activation produces rapid alterations in GluR subunit properties which could be involved in the hyperexcitability observed following seizure activity.
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PMID:Regional distribution and time-course of calpain activation following kainate-induced seizure activity in adult rat brain. 883 50

The cellular distribution of calpain activation and glutamate receptor 1 (GluR1) subunits of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and their alterations following kainic acid-induced seizure were evaluated during postnatal development using antibodies specific for spectrin breakdown product and the C-terminus of GluR1 subunits. In the first postnatal week, most brain regions exhibited high levels of calpain activity that progressively decreased during the following weeks. The highest levels of spectrin breakdown product immunoreactivity were observed in the somata and proximal dendrites of hippocampal pyramidal cells, non-pyramidal neurons in stratum oriens, and cortical neurons. In general, during the first two postnatal weeks, kainic acid treatment induced a decrease in spectrin breakdown product immunoreactivity in neuronal cell bodies and an increase in dendritic fields. Obvious elevation in spectrin breakdown product immunoreactivity in selective non-pyramidal cells in stratum oriens started at postnatal day 14, and was further evidenced by postnatal day 21. Likewise, massive calpain activation in subpopulations of neurons in some thalamic nuclei, amygdala, and pyriform cortex was observed after the third postnatal week. GluR1 subunits were highly expressed throughout the forebrain in the first postnatal week, further increased during the second postnatal week, decreased thereafter, and reached adult levels after postnatal day 21. In cortex, intense GluR1 immunostaining was found in the somata and proximal processes of pyramidal and non-pyramidal neurons, with the non-pyramidal neurons in layers IV through VI exhibiting the densest immunolabelling. In the first two postnatal weeks, the somata of hippocampal pyramidal neurons exhibited intense GluR1 immunostaining that became more dendritic in the subsequent developmental period. While hilar cells exhibited a similar developmental pattern as CA regions, the molecular layer of dentate gyrus exhibited weak immunoreactivity from postnatal day 7 to postnatal day 14. The early increase in GluR1 immunoreactivity in hippocampal pyramidal layer following kainic acid treatment occurred throughout the developmental period, while the later decrease in CA regions, amygdala, and pyriform cortex was observed only in postnatal day 21 animals. The combined immunocytochemical studies of spectrin breakdown product localization and GluR1 expression indicate that calpain activation might play an important role in synaptic formation, developmental regulation of synaptic plasticity, and neuronal vulnerability to excitotoxicity during postnatal development. Moreover, calpain-mediated modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors might underlie these processes.
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PMID:Developmental changes in calpain activity, GluR1 receptors and in the effect of kainic acid treatment in rat brain. 933 Mar 73

The implications of increased calpain-mediated proteolysis during epileptic seizures are still unclear, and in this study we investigate the effect of the continuous perfusion of calpain inhibitor I on picrotoxin-induced seizures in chronic freely moving rats. Continuous intrahippocampal microperfusion of 500 microM calpain inhibitor I had no effect on basal EEG, but doubled (P < 0.05) average seizure duration, and increased more than five-fold (P < 0.01) the total seizure time and three-fold (P < 0.01) the seizure offset time compared to picrotoxin alone, in each individual rat. However, seizure type and onset time were not modified by calpain inhibitor I. These results indicate that a calpain-mediated mechanism may be responsible for seizure offset, probably through AMPA glutamate receptors internalization and further degradation.
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PMID:Calpain inhibitor I retards seizure offset in the hippocampus of freely moving rats. 1021 61

Glutamate receptor overactivation contributes to neuron death after stroke, trauma, and epileptic seizures. Exposure of cultured rat hippocampal neurons to the selective glutamate receptor agonist N-methyl-d-aspartate (300 microm, 5 min) or to the apoptosis-inducing protein kinase inhibitor staurosporine (300 nm) induced a delayed neuron death. In both cases, neuron death was preceded by the mitochondrial release of the pro-apoptotic factor cytochrome c. Unlike staurosporine, the N-methyl-d-aspartate-induced release of cytochrome c did not lead to significant activation of caspase-3, the main caspase involved in the execution of neuronal apoptosis. In contrast, activation of the Ca(2+)-activated neutral protease calpain I was readily detectable after the exposure to N-methyl-d-aspartate. In a neuronal cell-free apoptosis system, calpain I prevented the ability of cytochrome c to activate the caspase cascade by inhibiting the processing of procaspase-3 and -9 into their active subunits. In the hippocampal neuron cultures, the inhibition of calpain activity restored caspase-3-like protease activity after an exposure to N-methyl-d-aspartate. Our data demonstrate the existence of signal transduction pathways that prevent the entry of cells into a caspase-dependent cell death program after the mitochondrial release of cytochrome c.
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PMID:Activation of calpain I converts excitotoxic neuron death into a caspase-independent cell death. 1082 77

The molecular mechanisms mediating degeneration in response to neuronal insults, including damage evoked by prolonged seizure activity, show substantial variability across laboratories and injury models. Here we investigate the extent to which the proportion of cell death occurring by apoptotic vs. necrotic mechanisms may be shifted by changing the temporal parameters of the insult. In initial studies with continuous seizures (status epilepticus, SE), signs of apoptotic degeneration were most clearly observed when SE occurred following a long latency (>86 min) after injection of kainic acid as compared with a short-latency SE (<76 min). Therefore, in this study we directly compared short- with long-latency SE for the expression of molecular markers for apoptosis and necrosis in an especially vulnerable brain region (rhinal cortex). Molecular markers of apoptosis (DNA fragmentation, cleavage of ICAD, an inhibitor of "caspase-activated DNase" (CAD), and prevalence of a caspase-generated fragment of alpha-spectrin) were detected following long-latency SE. Short-latency SE resulted in expression of predominantly necrotic features of cell death, such as "non-ladder" pattern of genomic DNA degradation, prevalence of a calpain-generated alpha-spectrin fragment, and absence of ICAD cleavage. Silver staining revealed no significant difference in the extent and spatial distribution of degeneration between long- or short-latency SE. These data indicate that the latency to onset of SE determines the extent to which apoptotic or necrotic mechanisms contribute to the degeneration following SE. The presence of a long latency period, during which multiple brief seizure episodes may occur, favors the occurrence of apoptotic cell death. It is possible that the absence of such "preconditioning" period in short-latency SE favors predominantly necrotic profile.
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PMID:Latency to onset of status epilepticus determines molecular mechanisms of seizure-induced cell death. 1496 39

AMPA receptor-elicited excitotoxicity is manifested as both a type of programmed cell death termed dark cell degeneration and edematous necrosis, both of which are linked to increased intracellular Ca2+ concentration. The appearance of marked cytoskeletal changes in response to abusive AMPA receptor activation, coupled with increased intracellular Ca2+ concentration suggests activation of various destructive enzymes such as calpains, a family of Ca2+-dependent cysteine proteases. Since calpains and AMPA have been linked to both necrotic cell death and programmed cell death, we sought to determine the role of calpains in mediating both types of AMPA-mediated toxicity in Purkinje neurons of the cerebellum. These studies employed immunohistochemistry for cytoskeletal breakdown products of calpain activity coupled with confocal microscopy and pharmacological interventions with calpain and AMPA receptor antagonists. The present study identifies an early involvement of calpains in mediating AMPA-induced dark cell degeneration, but not edematous necrosis, based upon the effectiveness of AMPA to generate calpain-derived alpha-spectrin cleavage products in cerebellar Purkinje neurons that express dark cell degeneration, and the effectiveness of calpain antagonists, PD150606 and MDL28170, to attenuate AMPA-induced dark cell degeneration. Moreover, the AMPA receptor antagonist CNQX, a proven inhibitor of AMPA-elicited dark cell degeneration, also blocked AMPA-induced increases in alpha-spectrin, further suggesting interplay between abusive AMPA receptor activation, calpain activation and dark cell degeneration. Since AMPA-induced dark cell degeneration possesses morphological changes that resemble those that occur following brain ischemia in vivo, hypoglycemia, or extended seizure episodes, the involvement of calpains as mediators of cell death is potentially far reaching and has widespread therapeutic implications in numerous CNS disorders.
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PMID:Involvement of calpain in AMPA-induced toxicity to rat cerebellar Purkinje neurons. 1718 64

Under normal physiological conditions, synaptic vesicle endocytosis is regulated by phosphorylation and Ca(2+)-dependent dephosphorylation of endocytic proteins such as amphiphysin and dynamin. To investigate the regulatory mechanisms that may occur under the conditions of excessive presynaptic Ca(2+) influx observed preceding neural hyperexcitation, we examined hippocampal slices following high-potassium or high-frequency electrical stimulation (HFS). In both cases, three truncated forms of amphiphysin I resulted from cleavage by the protease calpain. In vitro, the binding of truncated amphiphysin I to dynamin I and copolymerization into rings with dynamin I were inhibited, but its interaction with liposomes was not affected. Moreover, overexpression of the truncated form of amphiphysin I inhibited endocytosis of transferrin and synaptic vesicles. Inhibiting calpain prevented HFS-induced depression of presynaptic transmission. Finally, calpain-dependent amphiphysin I cleavage attenuated kainate-induced seizures. These results suggest that calpain-dependent cleavage of amphiphysin I inhibits synaptic vesicle endocytosis during neural hyperexcitation and demonstrate a novel post-translational regulation of endocytosis.
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PMID:Truncations of amphiphysin I by calpain inhibit vesicle endocytosis during neural hyperexcitation. 1754 3


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