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)

Kindling, an animal model of epilepsy, results in an increased volume of the hilus of the dentate gyrus and sprouting of the mossy fiber pathway in the hippocampus. Our previous studies have revealed that chronic infusion of neurotrophins can regulate not only seizure development, but also these kindling-induced structural changes. Kindling, in turn, can alter the expression of neurotrophins and their receptors. We previously showed that intraventricular administration of a synthetic peptide that interferes with nerve growth factor stability and thus its binding to TrkA and p75(NTR) receptors suppressed kindling and sprouting. However, the precise involvement of TrkA, p75(NTR), and downstream signaling effectors of neurotrophins on kindling, sprouting and hilar changes are unknown. One of these downstream effectors is Ras. In the present study, we find that intraventricular infusion of the synthetic peptide Reo3Y, which binds to p65/p95 receptors and causes a rapid inactivation of Ras protein, impairs development of perforant path kindling, reduces the growth in afterdischarge duration, blocks kindling-induced mossy fiber sprouting in area CA3 of hippocampus and in inner molecular layer of the dentate gyrus, and prevents kindling-induced increases in hilar area. These results are consistent with a mediation of neurotrophin effects on kindling, hilar area, and axonal sprouting via Trk receptors, and suggest important roles for Ras in kindling and in kindling-induced structural changes.
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PMID:A ligand of the p65/p95 receptor suppresses perforant path kindling, kindling-induced mossy fiber sprouting, and hilar area changes in adult rats. 1283 69

Recent in vitro and in vivo studies have shown that glucocorticoids have a profound influence on the survival of hippocampal neurones, and that the depletion of glucocorticoids as a result of adrenalectomy (ADX) reduces nerve growth factor levels in the hippocampus. It is also believed that ADX is associated with the seizure susceptibility of the Mongolian gerbil. In the present study, the choronological changes of c-jun immunoreactivity were investigated after ADX in the hippocampal formations in the seizure-prone gerbil model. In the sham hippocampus, c-jun immunoreactivity was not observed in the neurones of the hippocampus proper and dentate gyrus. C-jun immunoreactive neurones appeared 3 h after ADX in the neurones of the CA1 area and dentate gyrus, and these immunoreactivities peaked 24 h after ADX and then gradually decreased. These results suggest that, in the adrenalectomized gerbil, c-jun may be expressed in the neurones of the hippocampus in compensation for glucocorticoid deficit. The result of enhanced c-jun expression of the hippocampal formation provides anatomical support for the hypothesis that c-jun may play a role in the reduction of seizure activity.
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PMID:The enhanced expression of c-Jun immunoreactivity in the adrenalectomized gerbil hippocampus. 1296 31

Gene expression profiles in several brain regions of adult male rats were evaluated following a d-amphetamine (AMPH) exposure paradigm previously established to produce AMPH neurotoxicity. Escalating doses of AMPH (5-30 mg/kg) were given over the course of 16 h per day in an 18 degrees C environment for 2 days. This paradigm produces neurotoxicity but eliminates or minimizes the hyperthermia and seizure activity that might influence gene expression in a manner unrelated to the neurotoxic effects of AMPH. The expression of 1185 genes was monitored in the striatum, parietal cortex, piriform cortex and posteriolateral cortical amygdaloid nucleus (PLCo) using cDNA array technology, and potentially significant changes were verified by RT-PCR. Gene expression was determined at time points after AMPH when neurodegeneration was beginning to appear (16 h) or maximal (64 h). Expression was also determined 14 days after AMPH to find long-term changes in gene expression that might be biomarkers of a neurotoxic event. In the parietal cortex there was a two-fold increase in neuropeptide Y precursor protein mRNA whereas nerve growth factor-induced receptor protein I-A and I-B mRNA decreased 50% at 16 h after the end of AMPH exposure. Although these changes in expression were not observed in the PLCo, insulin-like growth factor binding protein 1 mRNA was increased two-fold in the PLCo at 16 and 64 h after AMPH. Changes in gene expression in the cortical regions were all between 1.2- and 1.5-fold 14 days after AMPH but some of these changes, such as annexin V increases, may be relevant to neurotoxicity. Gene expression was not affected by more than 1.5-fold at the time points in the striatum, although 65% dopamine depletions occurred, but the plasma membrane-associated dopamine transporter and dopamine D2 receptor were decreased about 40% in the substantia nigra at 64 h and 14 days post-AMPH. Thus, the 2-day AMPH treatment produced a few changes in gene expression in the two-fold range at time points 16 h or more after exposure but the majority of expression changes were less than 1.5-fold of control. Nonetheless, some of these lesser fold-changes appeared to be relevant to the neurotoxic process.
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PMID:Selective changes in gene expression in cortical regions sensitive to amphetamine during the neurodegenerative process. 1518 10

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family that mediates synaptic plasticity and excitability in the CNS. Recent evidence has shown that increased BDNF levels can lead to hyperexcitability and epileptiform activities, while suppression of BDNF function in transgenic mice or by antagonist administration retards the development of seizures. However, several groups, including our own, have reported that increasing BDNF levels by continuous intrahippocampal infusion inhibits epileptogenesis. It is possible that the continuous administration of BDNF produces a down-regulation of its high-affinity TrkB receptor, leading to a decrease of neuronal responsiveness to BDNF. If so, then animals should respond differently to bolus injections of BDNF, which presumably do not alter Trk expression, compared with continuous infusion. To test this hypothesis, we compared the effects of intrahippocampal BDNF continuous infusion and bolus injections on kindling induction. We showed that continuous infusion of BDNF inhibited the development of behavioral seizures and decreased the level of phosphorylated Trks or TrkB receptors. In contrast, multiple bolus microinjections of BDNF accelerated kindling development and did not affect the level of phosphorylated Trks or TrkB receptors. Our results indicate that different administration protocols yield opposite effects of BDNF on neuronal excitability, epileptogenesis and Trk expression. Unlike nerve growth factor and neurotrophin-3, which affect mossy fiber sprouting, we found that BDNF administration had no effect on the mossy fiber system in naive or kindled rats. Such results suggest that the effects of BDNF on epileptogenesis are not modulated by its effect on sprouting, but rather by its effects on excitability.
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PMID:The effects of brain-derived neurotrophic factor (BDNF) administration on kindling induction, Trk expression and seizure-related morphological changes. 1518 2

Activity-dependent brain-derived neurotrophic factor (BDNF) expression is Ca2+-dependent, yet little is known about the Ca2+ channel contributions that might direct selective expression of the multiple BDNF transcripts. Here, effects of pilocarpine-induced seizure activity on total BDNF expression and on the individual sensitivity of BDNF transcripts to glutamate receptor and Ca2+ channel blockers were evaluated using hippocampal slice cultures and in situ hybridization of transcript-specific cRNA probes directed against mRNAs for the four 5' exons (I-IV) of the BDNF gene. mRNAs for nerve growth factor (NGF) and tyrosine kinase B (trkB) also were studied. Pilocarpine (5 mM) induced a dose- and time-dependent increase in total BDNF (exon V) mRNA expression in the dentate granule cells and CA3-CA1 pyramidal cells with maximal effects at 6 and 24 h, respectively. Increases were blocked by co-treatment with the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainate 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX: 25 microM) and the N-methyl-d-aspartic acid receptor antagonist 2-amino-5-phosphonovaleric acid (APV; 25 microM), whereas the L-type voltage sensitive Ca2+ channel blocker nifedipine (20 microM) was without detectable effect. Maximal NGF and trkB mRNA expression was induced by pilocarpine at 4 and 12 h, respectively. For the individual BDNF transcripts, APV blocked pilocarpine-induced increases in transcript II, whereas nifedipine blocked increases in transcripts I and III. Transcript IV levels were not altered by treatment. These results indicate that transcript II makes the greatest contribution to pilocarpine effects on total BDNF mRNA content in this model and provides evidence for regional and Ca2+ channel-specific differences in activity-dependent regulation of the different BDNF transcripts in hippocampus.
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PMID:Differential expression of brain-derived neurotrophic factor transcripts after pilocarpine-induced seizure-like activity is related to mode of Ca2+ entry. 1518 16

We examined metallothionein (MT)-induced neuroprotection during kainic acid (KA)-induced excitotoxicity by studying transgenic mice with MT-I overexpression (TgMT mice). KA induces epileptic seizures and hippocampal excitotoxicity, followed by inflammation and delayed brain damage. We show for the first time that even though TgMT mice were more susceptible to KA, the cerebral MT-I overexpression decreases the hippocampal inflammation and delayed neuronal degeneration and cell death as measured 3 days after KA administration. Hence, the proinflammatory responses of microglia/macrophages and lymphocytes and their expression of interleukin (IL)-1, IL-6, IL-12, tumor necrosis factor-alpha and matrix metalloproteinases (MMP-3, MMP-9) were significantly reduced in hippocampi of TgMT mice relative to wild-type mice. Also by 3 days after KA, the TgMT mice showed significantly less delayed damage, such as oxidative stress (formation of nitrotyrosine, malondialdehyde, and 8-oxoguanine), neurodegeneration (neuronal accumulation of abnormal proteins), and apoptotic cell death (judged by TUNEL and activated caspase-3). This reduced bystander damage in TgMT mice could be due to antiinflammatory and antioxidant actions of MT-I but also to direct MT-I effects on the neurons, in that significant extracellular MT presence was detected. Furthermore, MT-I overexpression stimulated astroglia and increased immunostaining of antiinflammatory IL-10, growth factors, and neurotrophins (basic fibroblastic growth factor, transforming growth factor-beta, nerve growth factor, brain-derived neurotrophic factor, glial-derived neurotrophic factor) in hippocampus. Accordingly, MT-I has different functions that likely contribute to the increased neuron survival and improved CNS condition of TgMT mice. The data presented here add new insight into MT-induced neuroprotection and indicate that MT-I therapy could be used against neurological disorders.
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PMID:Metallothionein reduces central nervous system inflammation, neurodegeneration, and cell death following kainic acid-induced epileptic seizures. 1561 85

In this report, we provide direct demonstration that the neurotrophin nerve growth factor (NGF) is released in the extracellular space in an activity-dependent manner in its precursor form (proNGF) and that it is in this compartment that its maturation and degradation takes place because of the coordinated release and the action of proenzymes and enzyme regulators. This converting protease cascade and its endogenous regulators (including tissue plasminogen activator, plasminogen, neuroserpin, precursor matrix metalloproteinase 9, and tissue inhibitor metalloproteinase 1) are colocalized in neurons of the cerebral cortex and released upon neuronal stimulation. We also provide evidence that this mechanism operates in in vivo conditions, as the CNS application of inhibitors of converting and degrading enzymes lead to dramatic alterations in the tissue levels of either precursor NGF or mature NGF. Pathological alterations of this cascade in the CNS might cause or contribute to a lack of proper neuronal trophic support in conditions such as cerebral ischemia, seizure and Alzheimer's disease or, conversely, to excessive local production of neurotrophins as reported in inflammatory arthritis pain.
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PMID:Activity-dependent release of precursor nerve growth factor, conversion to mature nerve growth factor, and its degradation by a protease cascade. 1661 25

In this study, we have investigated the expression of the nuclear transcription factor (c-Fos, NFkB), growth factors (nerve growth factor--NGF, brain-derived neurotrophic factor--BDNF), peptides (enkephalin, galanin) and glutamate transporter (AA 504-523 rat EAAC1) in 6 dogs sacrificed immediately after seizure attack during encephalomyelitis due to canine distemper virus (CDV) (as assessed by clinical examination, RT-PCR and viral RNA detection either in blood or brain tissue and CDV immunohistochemistry in brain slices). In all these CDV affected dogs, the observed neurological signs included untreatable seizures, leading to cluster seizure activity and status epilepticus. In the inter-ictal phase abnormal mentation, postural and gait deficits and sometimes involuntary movements such as myoclonus were recorded. The same investigation was carried out in 5 control dogs affected by different disorders, all characterized by the absence of seizures. Brains were dissected out immediately after euthanasia and fixed; sections collected from the dorsal hippocampus were processed for immunohistochemistry. By comparing hippocampus sections obtained from dog with and without seizure, the following regulations were observed. A strong up-regulation of glutamate transporter throughout the cell layers was found together with the onset of nuclear Fos and NFkB-IR in the pyramidal cell layer X. Among the investigated peptides, we observed a slight increase in enkephalinergic fibers and a strong up-regulation of mu-opioid receptors, whereas galanin-IR seemed to be weaker. Finally, both NGF and BDNF expression was strongly up-regulated. BDNF-IR was mainly localized in the apical dendrite in pyramidal neurons. To our knowledge, these data offer the first indication that molecular events described in experimental kindling also occur during spontaneous pathology in animal species sharing close similarities to human neuropathology.
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PMID:A molecular study of hippocampus in dogs with convulsion during canine distemper virus encephalitis. 1676 33

In our previous studies, we demonstrated that intraperitoneal (i.p.) injections with the neurotransmitter/neuromodulatory peptide Cholecystokinin-8 (CCK-8) stimulate the synthesis of the neurotrophin nerve growth factor (NGF) resulting in the structural and functional recovery of neuronal damage. This neurotrophin-mediated neuroprotective action of CCK-8 has opened a new perspective for a better understanding of the CCK neurobiological and pharmacological properties. To explore the possible beneficial effects of the CCK-induced increase of neurotrophin availability in brain, we compared the effects of i.p. CCK-8 in healthy rats and in a chemical kindling model using a subconvulsive dose of pentylenetetrazol (PTZ). Behavioural changes were monitored during treatment and classified according to a six-point scale. After 3 weeks of treatment (12 trials), the PTZ group of rats manifested generalized clonic-tonic seizures (Class 5 behaviour). For this reason, this time point was chosen to compare the effects of CCK-8 treatment on the expression of NGF, the brain derived neurotrophin factor (BDNF) and their receptors in the septum and hippocampus. We found that repeated i.p. injections with CCK-8 in adult rats result in: (1) an increase of NGF and BDNF protein and mRNA levels in the septum and hippocampus; (2) a down-regulation of TrkA and p75NTR and an up-regulation of TrkB; (3) reduced susceptibility to develop chemical kindling; (4) recovery of the PTZ-induced changes in the expression of neurotrophin receptors in the septal and hippocampal tissues. This data clearly indicates that CCK-induced variation of neurotrophin synthesis in brain is able to influence the susceptibility to develop seizures in adult rats most probably by counteracting the progressive neuronal dysfunction and/or damage.
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PMID:CCK-8 induces NGF and BDNF synthesis and modulates TrkA and TrkB expression in the rat hippocampus and septum: Effects on kindling development. 1696 63

Some epidemiological studies concerning gender differences in Alzheimer's disease (AD) support the higher prevalence and incidence of AD in women, while most studies using animal models of aging have included only male subjects. It is still uncommon for aged males and females to be compared in the same study. In the present study, we investigated how age and gender influence the excitotoxic neurodegeneration by treating C57BL/6 mice (aged females and males as well as adult females and males) with kainic acid (KA) intranasally. Clinical signs, behavioural changes, pathological changes and astrocyte proliferation were tested; and the levels of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) were measured after KA treatment. The results showed that aged female mice were more sensitive to KA-induced excitotoxicity as demonstrated by severer seizure activity, increased locomotion and rearing in open-field test, prominent hippocampal neuronal damage, enhanced astrocyte proliferation compared with aged males, adult females and adult male mice. In addition, higher BDNF level in hippocampus of aged female mice was observed. These results denote the disparity of aging and gender in KA-induced hippocampal neurodegeneration and aged female mice are more sensitive to the excitotoxicity.
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PMID:Gender differences in susceptibility to kainic acid-induced neurodegeneration in aged C57BL/6 mice. 1834 45


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