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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The study investigated the hypothesis that delayed cerebral injury after transient cerebral ischemia is associated with vasoconstriction and decreased cerebral oxygenation. Eight chronically instrumented, late gestation fetal sheep were subjected to 30 min of cerebral ischemia in utero. Cortical impedance (CI) and electrocorticogram (ECoG) were recorded to determine the time course of cellular dysfunction. Histologic outcome was assessed 4 d postischemia. Changes in cerebral vascular tone and oxygenation were observed during and for 4 d after the insult using near infrared spectroscopy to measure changes in total cerebral Hb ([tHb]), oxyhemoglobin ([Hbo2]), and oxidized cytochrome aa3 ([Cyto2]). Results are expressed as mean +/- SEM. CI increased transiently during ischemia; then a delayed increase commenced 17.5 +/- 2.3 h postischemia and peaked at 42.3 +/- 2.4 h. ECoG was depressed during and after the insult. Seizures started 13.6 +/- 3.0 h postinsult and persisted for 25.4 +/- 3.2 h. Increases in [tHb] indicated two periods of cerebral vasodilation: immediately after early reperfusion, lasting 2.3 +/- 0.4 h and peaking to 20 +/- 2.0 mumol.L-1; and a later phase, commencing 12.8 +/- 2.0 h postischemia, peaking to 43 +/- 4.0 mumol.L-1 and lasting 43.1 +/- 5.2 h. [Hbo2] was relatively elevated (18 +/- 3.0 mumol.L-1) during d 4 postischemia, demonstrating a delayed increase in mean cerebral oxygen saturation. [Cyto2] fell during the insult (-0.7 +/- 0.2 mumol.L-1); and, commencing at 28-30 h postischemia, fell progressively to reach a minimum of -5.0 +/- 2.8 mumol.L-1 at 78-80 h postischemia. A greater fall in [Cyto2] was related to worse cerebral injury (p < 0.05). Delayed cerebral injury is accompanied by vasodilation and increased mean cerebral oxygen saturation, although a progressive fall in [Cyto2] might indicate a fall in mitochondrial oxygenation, cell loss, or changes in tissue optical characteristics.
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PMID:Delayed vasodilation and altered oxygenation after cerebral ischemia in fetal sheep. 882 85

Pilocarpine injection into rodents leads to the development of chronic limbic seizures that follow an initial status epilepticus and a seizure-free interval. It has been proposed that a decreased efficacy of the mechanisms that buffer the extracellular concentration of K+ ([K+]o) leads to an increase in seizure susceptibility. Therefore, we analyzed the changes in [K+]o associated with the synchronous activity induced by 4-aminopyridine (4AP) in hippocampal slices obtained from control and pilocarpine-treated rats. At all recording sites (i.e. stratum radiatum of the CA1 and CA3 subfields, and hilus of the dentate gyrus), the amplitude of GABA-mediated synchronous field potentials induced by 4AP, as well as the associated [K+]o increases, were significantly reduced in slices obtained from the pilocarpine-treated rats. In the control group, the field-potential amplitudes reached 1 mV (i.e. 1.7 +/- 0.3 mV in CA1, 0.93 +/- 0.2 mV in CA3, and 1.03 +/- 0.12 mV in the hilus; mean +/- SEM), while the accompanying rises in [K+]o exceeded 4 mM (i.e. 4.17 +/- 0.15 mM in CA1, 4.04 +/- 0.12 mM in CA3, 4.04 +/- 0.11 mM in the hilus) from a baseline of 3.25 mM. The corresponding values in slices from the pilocarpine-treated group were rarely greater than 0.4 mV (i.e. 0.3 +/- 0.09 mV in CA1, 0.27 +/- 0.03 mV in CA3 and 0.38 +/- 0.06 mV in the hilus), and larger than 3.6 mM (i.e. 3.63 +/- 0.04 mM in CA1, 3.64 +/- 0.03 mM in CA3 and 3.60 +/- 0.04 mM in the hilus) from a similar baseline value. With pilocarpine, the rate of occurrence of the GABA-mediated potential significantly decreased from 0.035 to 0.016 s-1. Since the rises in [K+]o decreased rather than increased and their overall duration was unchanged (possibly reflecting cell loss), we conclude that a modification of [K+]o buffering capacity is unlikely to account for the appearance of in vivo seizures in the pilocarpine model of epilepsy.
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PMID:Extracellular potassium elevations in the hippocampus of rats with long-term pilocarpine seizures. 883 Mar 21

Opioid peptide release in the hippocampus was shown to be increased immediately following amygdala kindling stimulation in freely moving rats using microdialysis combined with a universal opioid peptide radioimmunoassay (RIA). Extracellular opioid peptide levels were elevated (55% above basal levels) within the first 10 min after electrical stimulation-induced partial seizures in previously nonkindled animals. Fully kindled rats showed lower extracellular opioid peptide levels (40% reduction) during the interictal period [16 +/- 2.1 days (mean +/- SEM) after the last stage V seizure], in comparison with values obtained from the sham-kindled group under basal conditions. However, opioid peptide release in fully kindled rats increased above 152% of interictal levels within the first 20 min after onset of fully kindled seizures, attaining peak levels equal to that of the partial kindled group and returning to prestimulation conditions 40-60 min following the ictal events. The majority of the immunoreactive material recovered from the hippocampus within the first 20 min following partial and generalized kindled seizures coeluted with dynorphin-A (1-6), dynorphin-A (1-8), and Leu-enkephalin by HPLC/RIA analysis. It is proposed that the enhanced opioid peptide release in hippocampus induced by amygdala kindling stimulation might be associated with either enhanced excitability or seizure suppression as seizure susceptibility fluctuates. The reduced interictal opioid peptide levels may also underlie some interictal behavioral disturbances.
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PMID:Amygdala kindling modifies extracellular opioid peptide content in rat hippocampus measured by microdialysis. 900 48

Tiagabine (TGB) is a novel antiepileptic drug whose anticonvulsant effects are due to inhibition of gamma-aminobutyric acid (GABA) transport mediated by the GABA transporter-1. We have previously shown that TGB is effective in acute amygdala kindled seizures, and consequently we wanted to test the hypothesis that TGB also could suppress the development of kindling epileptogenesis. Rats had stereotaxically implanted stimulating/recording electrodes in the basolateral amygdala and recording electrode in the contralateral occipital cortex. Rats were divided in three groups (n = 8 for each group) intraperitoneally (i.p.) administered vehicle, TGB 7.3 micromol/kg and TGB 24.3 micromol/kg, respectively, 30 min before stimulation. TGB dose-dependently suppressed the development of the behavioral seizure score and afterdischarge (AD) duration recorded from the amygdala and cortex. Vehicle treated animals displayed at the 16th stimulation an average behavioral score of 4.7 +/- 0.2 (mean +/- SEM) compared to 3.9 +/- 0.2 in the 7.3 micromol/kg TGB treated group and 1.4 +/- 0.3 in the 24.3 micromol/kg TGB treated group. Amygdaloid AD in controls on the 16th stimulation was 92 +/- 10 s compared to 56 +/- 12 s in group 2 and 25 +/- 3 s in group 3. Cortical AD was at the same time 92 +/- 10, 55 +/- 13 and 20 +/- 5 s, respectively. Groups 2 and 3 required four and seven further stimulations, respectively, without TGB administration to reach the AD level in the control group. At the 17th stimulation, rats in group 1 were administered TGB 24.3 micromol/kg and displayed an average behavioral score of 0.5 +/- 0.2. Amygdaloid and cortical AD were both 6 +/- 1 s. Tiagabine 24.3 micromol/kg suppresses both the kindling process and the expression of the fully kindled seizure.
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PMID:Tiagabine exerts an anti-epileptogenic effect in amygdala kindling epileptogenesis in the rat. 922 9

The effect of flunarizine (FLU) and sodium valproate (SV) alone and in combination were examined for their effects on seizure thresholds elicited by cortical stimulation in conscious rats. Two different pharmacodynamic parameters could be distinguished viz, the threshold for localised seizures (TLS) defined as the current (mu A) required to elicit forelimb clonus and the threshold for generalised seizure (TGS), defined as the current (mu A) required to elicit vigorous clonic activity without a tonic component. In preliminary neuro-behavioral studies on rats, the most favourable combination was FLU 10 mg/kg i.p. and SV 200 mg/kg i.p., which produced anticonvulsant efficacy with minimal neurotoxicity. With FLU alone, SV alone and the combination of FLU and SV, the mean % change +/- SEM from baseline values over a period of 6 h were for TLS: 3.8 +/- 0.8, 23.9 +/- 3.7, and 29.8 +/- 2.1; and for TGS 5.5 +/- 0.7, 15.6 +/- 2.7 and 190.9 +/- 22.7 respectively, indicating that FLU alone had no effect on TLS or TGS, SV significantly elevated TLS but had no effect on TGS and the combination of FLU plus SV produced a synergistic elevation of both TLS and TGS-the intensity of effect being more on TGS than on TLS. This model provides a new dimension to the profiling of two anticonvulsant agents with different mechanisms of anticonvulsant activity and offers predictive criteria for protective effects on clinical manifestations of partial or generalised tonic clonic seizure.
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PMID:Synergistic effect of flunarizine and sodium valproate on seizure thresholds elicited by cortical stimulation in conscious rats. 951 92

Prolonged cerebral hypothermia is neuroprotective if started within a few hours of hypoxia-ischemia. However, delayed seizure activity is one of the major clinical indicators of an adverse prognosis after perinatal asphyxia. The aim of this study was to determine whether head cooling delayed until after the onset of postasphyxial seizures may still be neuroprotective. Unanesthetized near-term fetal sheep in utero received 30 min of cerebral ischemia induced by bilateral carotid artery occlusion. Eight and one-half hours later, they received either cooling (n = 5) or sham cooling (n = 13) until 72 h after the insult. Intrauterine cooling, induced by circulating cold water through a coil around the fetal head, was titrated to reduce fetal extradural temperature from 39.4+/-0.1 degrees C to between 30 and 33 degrees C. Cerebral ischemia led to the delayed development of intense epileptiform activity from 6 to 8 h postinsult, followed by a marked secondary rise in cortical impedance (a measure of cytotoxic edema) and in carotid blood flow. Cerebral cooling markedly attenuated the secondary rise in impedance and reduced carotid blood flow (p < 0.001). After 5 d recovery, there was no significant difference in loss of parietal EEG activity relative to baseline in the hypothermia compared with the control group (-12.5+/-1.4 versus -15.2+/-1.2 dB, mean +/- SEM, NS) or in parasagittal cortical neuronal loss (82+/-9 versus 90+/-5%, NS). In conclusion, delayed prolonged head cooling begun after the onset of postischemic seizures was not neuroprotective. These data highlight the importance of intervention in the latent phase, after reperfusion but before the onset of secondary injury.
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PMID:Cerebral hypothermia is not neuroprotective when started after postischemic seizures in fetal sheep. 1047 41

Although serine proteases and their receptors are best known for their role in blood coagulation and fibrinolysis, the CNS expresses many components of an extracellular protease signaling system including the protease-activated receptor-1 (PAR1), for which thrombin is the most effective activator. In this report we show that activation of PAR1 potentiates hippocampal NMDA receptor responses in CA1 pyramidal cells by 2.07 +/- 0.27-fold (mean +/- SEM). Potentiation of neuronal NMDA receptor responses by thrombin can be blocked by thrombin and a protein kinase inhibitor, and the effects of thrombin can be mimicked by a peptide agonist (SFLLRN) that activates PAR1. Potentiation of the NMDA receptor by thrombin in hippocampal neurons is significantly attenuated in mice lacking PAR1. Although high concentrations of thrombin can directly cleave both native and recombinant NR1 subunits, the thrombin-induced potentiation we observe is independent of NMDA receptor cleavage. Activation of recombinant PAR1 also potentiates recombinant NR1/NR2A (1.7 +/- 0.06-fold) and NR1/NR2B (1.41 +/- 0.11-fold) receptor function but not NR1/NR2C or NR1/NR2D receptor responses. PAR1-mediated potentiation of recombinant NR1/NR2A receptors occurred after activation with as little as 300 pm thrombin. These data raise the intriguing possibility that potentiation of neuronal NMDA receptor function after entry of thrombin or other serine proteases into brain parenchyma during intracerebral hemorrhage or extravasation of plasma proteins during blood-brain barrier breakdown may exacerbate glutamate-mediated cell death and possibly participate in post-traumatic seizure. Furthermore, the ability of neuronal protease signaling to control NMDA receptor function may also have roles in normal brain development.
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PMID:Potentiation of NMDA receptor function by the serine protease thrombin. 1084 28

The present study examines the effect of tiagabine (a selective inhibitor of GABA transporter 1, GAT-1), SNAP-5114 (a semi-selective inhibitor of rat GAT-3/mouse GAT4) and NNC 05-2045 (a non-selective GABA uptake inhibitor) in modulating GABA levels in the hippocampus and thalamus. Anticonvulsant effects of the same compounds were assessed (after intranigral administration) after maximal electroshock (MES) in juvenile rats. Anticonvulsant effects were also tested after intraperitoneal (i.p.) administration against audiogenic seizures in DBA/2 mice and against pentylentetrazole (PTZ)-induced tonic convulsions or MES in NMRI mice. Tiagabine (30 microM, perfused through the microdialysis probe in halothane anaesthetized rats) increased GABA levels to (% basal+/-SEM) 645+/-69 in the hippocampus and 409+/-61 in the thalamus. SNAP-5114 (100 microM) increased GABA levels in the thalamus (% basal+/-SEM) to 247+/-27 but had no effect on hippocampal GABA-levels. NNC 05-2045 (100 microM) increased GABA levels both in the hippocampus (% basal+/-SEM, 251+/-51) and in the thalamus (298+/-27). All compounds protected against tonic hindlimb extension (THE) in juvenile male rats after intranigral administration. Sound induced convulsions in DBA/2 mice were dose-dependently inhibited by all compounds (administered intraperitoneal, i.p.) with ED(50) values of 1, 6 and 110 micromol/kg, for tiagabine, NNC 05-2045 and SNAP-5114, respectively. Tiagabine and NNC 05-2045 but not SNAP-5114 protected against PTZ-induced tonic convulsions whereas only NNC 05-2045 protected against MES-induced tonic convulsions in NMRI mice. However, tiagabine and NNC 05-2045 exerted a synergistic effect in the MES model. These findings substantiate and extend previous findings of different effects of selective versus non-selective GABA uptake inhibitors in animal models of epilepsy.
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PMID:GABA-level increasing and anticonvulsant effects of three different GABA uptake inhibitors. 1097 24

The androgen receptor (AR) plays a central role in mediating androgen action. Since the hippocampus is a target of steroid modulation, we studied the expression of AR mRNAs in hippocampal tissue specimens from patients undergoing epilepsy surgery (n=42). AR mRNA expression was in the same order of magnitude than in prostate tissue, known for its high expression of AR. AR mRNA concentrations showed no significant difference in AR mRNA expression between men (49.3+/-8.0 arbitrary units (aU); mean+/-SEM) and women (54.3+/-11.2 aU) and no sex-specific hippocampal lateralization pattern was observed. No relationship could be detected between duration of epilepsy, individual seizure frequency, age of the patients and the expression levels of AR. The high expression of AR in the hippocampus suggests that this human brain area is an important target for androgen action.
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PMID:Androgen receptor mRNA expression in the human hippocampus. 1104 78

We have utilized cultured neuronal networks grown on microelectrode arrays to demonstrate rapid, reliable detection of a toxic compound, trimethylolpropane phosphate (TMPP). Initial experiments, which were performed blind, demonstrated rapid classification of the compound as a convulsant, a finding consistent with previous whole animal neurobehavioral studies. TMPP (2-200 microM) reorganized network spike activity into synchronous, quasi-periodic burst episodes. Integrated burst amplitudes invariably increased, reflecting higher spike frequencies within each burst. The variability of network burst parameters, quantified as coefficients of variation (CVs), was decreased. Mean CVs for burst duration, interburst interval, and burst rate were lowered by 42+/-13, 58+/-5.5, and 62+/-1.8%, respectively (mean+/-SEM, n=8 cultures, 197 channels). These changes in network activity paralleled the effects induced by bicuculline, a known disinhibitory and seizure-inducing drug, and confirmed classification of TMPP as a potential epileptogenic compound. Simple pharmacological tests permit exploration of mechanisms underlying observed activity shifts. The EC(50) for GABA inhibition of network activity was increased from 2.8 to 7.0 microM by 20 microM TMPP and to 20.5 microM by 200 microM TMPP. Parallel dose-response curves suggest that TMPP acts by a competitive antagonism of GABA inhibition, and are consistent with reported patch-clamp analysis of TMPP-induced reduction of inhibitory postsynaptic current amplitudes. The potency of TMPP in generating epileptiform activity in vitro was comparable to concentrations reported for in vivo studies. TMPP and bicuculline produced both increases and decreases in burst rate depending on native spontaneous bursting levels. These results demonstrate a need for multivariate analysis of network activity changes to yield accurate predictions of compound effects.
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PMID:Characterization of acute neurotoxic effects of trimethylolpropane phosphate via neuronal network biosensors. 1154 45


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