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)

Norepinephrine turnover rates were estimated in the hypothalamus-thalamus, midbrain, pons-medulla and telencephalon of genetically epilepsy-prone rats (GEPR). In each of these 4 brain areas the endogenous norepinephrine levels were significantly lower in the GEPR than in control animals. In the hypothalamus-thalamus, midbrain and telencephalon the calculated norepinephrine turnover rates were also significantly lower in GEPRs than in control. These studies confirm and extend earlier observations relating seizures in the GEPR to decrements in central nervous system noradrenergic function.
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PMID:Abnormalities in norepinephrine turnover rate in the central nervous system of the genetically epilepsy-prone rat. 669 49

The authors investigated the value of high-dose thiopental (TH) therapy after 16-min complete global brain ischemia (GBI) in three groups of pigtailed monkeys, using a neck cuff model of GBI with 96 h intensive care postischemia (PI). Control group (n18): Normotension was restored within 2 min PI; paralysis/controlled ventilation was maintained for 48 h PI with 50% N2O/O2. Thiopental loading group (n13): Control treatment plus TH-loading with 90 mg/kg iv given from 5 to 65 min PI (mean peak TH plasma level 130 micrograms/ml). Thiopental anesthesia group (n14): Control treatment plus TH anesthesia with 90 mg/kg iv given over 12 h PI (sustained TH plasma levels of 25-35 micrograms/ml and EEG burst suppression). Norepinephrine requirement for blood pressure control PI was greater in the TH groups than in the control group (P less than 0.05). Lidocaine was needed for control of arrhythmias in the TH loading group. There was no significant difference in mortality or neurologic outcome between the groups. At 96 h PI seven of 11 animals were awake in the control group, compared with seven of 12 and six of 12 in the two TH groups. Neurologic deficit scores (NDS) for the survivors at 96 h PI were 23 +/- 6% (mean +/- SD) (n10) in the control group, compared with 25 +/- 9% (n11) and 26 +/- 12% (n10) in the two TH groups (NDS 100% = brain death, 0% = normal). Seizures PI (in 1-2 of each group) were associated with worse neurologic deficits.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Thiopental treatment after global brain ischemia in pigtailed monkeys. 669 50

The functions of the putative noradrenergic innervation of cerebral microvessels from the nucleus locus ceruleus remain ambiguous. Although most evidence indicates that such innervation does not have a major role in the control of cerebral blood flow, there are increasing indications that it modulates transport and permeability functions of the blood-brain barrier. In this study we investigated the effect of unilateral chemical lesioning of the locus ceruleus on the leakage of radioiodinated human serum albumin across the blood-brain barrier. Experiments were performed in awake and restrained rats under steady-state conditions and during drug-induced systemic arterial hypertension, and in anesthetized and paralyzed rats during bicuculline-induced seizures. Both hypertension and seizures are known to be associated with increased leakage of macromolecules across the blood-brain barrier. Albumin leakage into norepinephrine-depleted forebrain structures ipsilateral to the locus ceruleus lesion was compared with that of the contralateral side. There were no side-to-side differences in blood-brain barrier permeability to albumin under steady-state conditions, the stress of restraint, or angiotensin-induced hypertension, or after isoproterenol administration. Norepinephrine-induced hypertension and seizures, however, caused significant increases in albumin leakage into forebrain structures ipsilateral to the lesion. These results suggest that noradrenergic innervation of cerebral microvessels from the locus ceruleus helps preserve the integrity of the blood-brain barrier during pathophysiological states associated with hypertension and increased circulating catecholamines.
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PMID:The protective influence of the locus ceruleus on the blood-brain barrier. 674 91

L-Huperzine-A (Hup-A), a natural cholinesterase inhibitor (ChEI) derived from the Chinese herb Huperzia serrata, was administered systemically (i.p.) or locally through the microdialysis probe into the rat cortex. Systemic Hup-A significantly increased acetylcholine (ACh) levels above baseline at doses of 0.1, 0.3, and 0.5 mg/kg; the increases were 54%, 129%, and 220%, respectively. Norepinephrine (NE) and dopamine (DA) levels were also increased 121% and 129% above baseline at 0.3 mg/kg, and 143% and 153% at 0.5 mg/kg. Peak cholinesterase (ChE) inhibition was 23% at 60 min with the 0.3 mg/kg dose. Huperzine-A, perfused through the microdialysis probe, produced a maximal increase of ACh levels of 3090% and 7790% at concentrations of 5 and 50 microM. The ACh increase seen at both concentrations lasted at least 6 hr. At the 5-microM dose, NE and DA were increased by 214% and 386%; at the 50-microM dose, NE and DA were increased by 216% and 1141%. There were no changes of 5-HT levels. With local administration (via the probe), both doses produced facial-forelimb seizures that lasted throughout the perfusion. Our results show that Hup-A is a potent inhibitor of ChE which penetrates into the brain and produces a dose-dependent increase of ACh, NE, and DA in rat cortex. This effect is seen with both systemic and local intracerebral administration, suggesting cortical as well as subcortical effects of the drug.
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PMID:Second generation cholinesterase inhibitors: effect of (L)-huperzine-A on cortical biogenic amines. 750 Mar 84

Systemically administered (-)nicotine (0.2-1.2 mg/kg, s.c.) significantly increased the release of acetylcholine (ACh), norepinephrine (NE) and dopamine (DA) in rat cortex. The lowest dose of (-)nicotine examined (0.2 mg/kg, s.c.) also significantly elevated extracellular serotonin (5-HT) levels, and the maximal increases of extracellular ACh (122% at 90 min post injection) and DA levels (249% at 120 min post-injection) were observed following this dose. In contrast, the maximal increase of NE release (157% at 30 min post-injection) was observed following the highest dose of (-)nicotine injected (1.2 mg/kg, s.c.). This higher dose consistently produced generalized seizures. Repeating the (-)nicotine (0.58 mg/kg, s.c.) injection four hours after the first administration significantly elevated extracellular NE levels and also appeared to increase DA and ACh release. In addition, extracellular ACh and DA levels increased significantly in the dialysate after (-)nicotine was administered directly to the neocortex through the microdialysis probe membrane. Norepinephrine levels appeared to be elevated in the cortex following local administration as well.
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PMID:Effects of local and repeated systemic administration of (-)nicotine on extracellular levels of acetylcholine, norepinephrine, dopamine, and serotonin in rat cortex. 756 73

Rats subjected to structural brain damage induced by sustained convulsions triggered by systemic administration of pilocarpine (PILO) are a useful model for investigation of the mechanisms essential for seizure generation and spread in rodents. After PILO administration, three distinct phases are observed: (a) an acute period of 1-2 days' duration corresponding to a pattern of repetitive limbic seizures and status epilepticus; (b) a seizure-free (silent) period characterized by a progressive return to normal EEG and behavior of 4-44 days' duration; and (c) a period of spontaneous recurrent seizures (SRS) starting 5-45 days after PILO administration and lasting throughout the animal's life. PILO (320-350 mg/kg intraperitoneally, i.p.) was administered to rats, and the content of hippocampal monoamines and amino acids was measured in the acute, silent, and SRS periods by liquid chromatography. Norepinephrine (NE) level was decreased during all periods whereas dopamine (DA) content was increased. Serotonin (5-hydroxytryptamine, 5-HT) was increased only in the acute period. Utilization rate measurement of monoamines showed increased NE consumption and decreased DA consumption during all phases. 5-HT utilization rate was increased only in the acute period. Amino acid content showed a decrease in aspartate (ASP) and glutamate (GLU) concentrations associated with increased gamma-aminobutyric acid (GABA) level during the acute period. The silent phase was characterized by a decrease in glycine (GLY) and GABA levels and an increase in GLU concentration. The SRS period showed an increase in all amino acid concentrations. These findings show important neurochemical changes in the course of establishment of an epileptic focus after brain damage induced by status epilepticus triggered by pilocarpine.
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PMID:Spontaneous recurrent seizures in rats: amino acid and monoamine determination in the hippocampus. 811 29

Noradrenaline (NA) and dopamine (DA) levels in six brain regions of stimulated and nonstimulated El (El[s] and El[ns]) mice and their maternal ddY mice were determined at various ages and various times after a convulsion. The NA levels in the striatum and hippocampus of 12-week-old El[s] and El[ns] mice were lower than in ddY mice, and remained lower in 23-week-old El[s] mice, but not in El[ns] mice. DA levels were lower in the striatum of El[s] mice than in El[ns] and ddY mice at 16 and 23 weeks of age. NA levels decreased during seizure in the striatum and hippocampus of El[s] mice, and returned to preconvulsive levels 1 hr after convulsion in the striatum and 30 min in the hippocampus. DA levels in the striatum of El[s] mice decreased during convulsion and increased from 1 to 10 min after convulsion. These changes suggest that the NAergic systems in the striatum and hippocampus and the DAergic system in the striatum have important roles in relation to seizure susceptibility in El mice.
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PMID:Age- and seizure-related changes in noradrenaline and dopamine in several brain regions of epileptic El mice. 847 54

(R)-(+)-2-Amino-4-(4-fluorophenyl)-5-[1-[4-(4-fluorophenyl)-4-oxobutyl]+ ++pyrrolidin-3-yl]thiazole (NRA0045), a novel thiazole derivative, has high affinities for the human cloned dopamine D4.2, D4.4 and D4.7 receptors, with Ki values of 2.54, 0.55 and 0.54 nM, respectively. NRA0045 is approximately 91-fold more potent at the dopamine D4.2 receptor, compared with human cloned dopamine D2L receptor. NRA0045 also has high affinities for the serotonin (5-HT)2A receptor (Ki = 1.92 nM) and alpha-1 adrenoceptor (Ki = 1.40 nM) but weak affinities (IC50 values are approximately 1 microM) for six other neurotransmitter receptors (adenosine1, 5-HT1A, 5-HT1C, dopamine transporter, alpha2A and alpha2A) and negligible affinities (IC50 values are over 10(-5) M) for 42 other receptors, including neurotransmitters and hormones, ion channels and second messenger systems. Locomotor hyperactivity induced by methamphetamine (1 mg/kg i.p.) in mice was dose-dependently antagonized by NRA0045 (ED50 = 0.5 mg/kg i.p. and 1.9 mg/kg p.o., respectively). Methamphetamine (10 mg/kg i.p.)-induced stereotyped behavior in mice was dose-dependently antagonized by NRA0045, whereas NRA0045 did not exceed 50% inhibition even at the highest dose given (30 mg/kg i.p.). Catalepsy was dose-dependently and significantly induced by NRA0045 in rats, whereas NRA0045 did not exceed 50% induction even at the highest dose given (30 mg/kg i.p.). Thus NRA0045 blocks behaviors associated with activation of the mesolimbic/mesocortical dopaminergic neurons more selectively than behaviors associated with nigrostriatal dopaminergic neurons. In rats, tryptamine-induced clonic seizure, a 5-HT2 receptor-mediated behavior, was also dose-dependently inhibited by NRA0045 (ED50 = 1.7 mg/kg i.p.). Norepinephrine-induced lethality is regarded as being induced through the alpha-1 adrenoceptor. NRA0045 dose-dependently antagonized norepinephrine-induced lethality in rats (ED50 = 0.2 mg/kg i.p.). Thus NRA0045 may have a unique antipsychotic activity with regard to dopamine D4 and 5-HT2A receptors and alpha-1 adrenoceptor antagonistic activities, without producing the extrapyramidal side effects.
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PMID:In vitro and in vivo characterization of the dopamine D4 receptor, serotonin 5-HT2A receptor and alpha-1 adrenoceptor antagonist (R)-(+)-2-amino-4-(4-fluorophenyl)-5-[1-[4-(4-fluorophenyl)-4-oxobutyl] pyrrolidin-3-yl]thiazole (NRA0045). 922 39

This study examined brain regional neurotransmitter level changes as a function of seizure duration following soman intoxication. Rats, implanted with cortical electrodes and pretreated with HI-6, received a convulsant dose of soman. At selected times after seizure onset the EEG recording electrodes were removed and the animal was killed. Spinal cord cholinesterase (ChE) activity was rapidly and maximally depressed, while brain acetylcholine (ACh) levels showed elevations as early as 3 min after soman treatment and reached significantly high levels at time of seizure onset. Norepinephrine (NE) levels decreased starting 5 min after seizure onset and continued to decline. Levels of dopamine (DA) and of its metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid were elevated as early as 5 min after seizure onset and thereafter. The brain levels of aspartate were markedly decreased at and after 20 min of seizures; levels of glutamate were depressed at 80 min in the cortex. Levels of gamma-aminobutyric acid (GABA) were significantly increased in the cortex starting at 20 min after seizure onset, and in the striatum and hippocampus at 80 min after onset. The levels of glutamine, glycine and taurine were not changed at any time studied. These findings are consistent with the notion that inhibition of ChE and elevation of ACh initiate the seizure process, resulting in secondary changes in DA turnover and release of NE, and later changes in excitatory (aspartate, glutamate) and inhibitory (GABA) amino acid transmitters.
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PMID:Neurochemical mechanisms in soman-induced seizures. 928 39

Fish venoms can be lethal for Vertebrates. The effect depends of dose and subject, more than incriminated fish. The most constant symptom is a violent pain; but the serious pharmacological effects are respiratory and heart failure with marked hypotension and cardiac perturbations, neurologic damage, such as seizure and coma. Experimentation is difficult due to venom instability. Activity is lost by distilled water, lyophilisation in buffers, several successive freezing and defreezing. In addition, when venom is broken, other pharmacological effects are evidenced, for instance, with Synanceia verrucosa venom, hypertensive phase takes the place of hypotension. It is difficult to distinguish toxin effect from this of denaturation products of the toxin. Noradrenaline is present in Synanceia venom, and it seems that acetylcholine exists in some venom, at least when diluted in saline solution. Other biological active products are present. Purified toxins allow pharmacological investigations. Stonefish venom is better studied, because venomous glands contain relatively high venom quantity. Stonustoxin from Synanceia horrida exerts its action through NO-synthase liberation, and its primary action can be attributed to its potent vasorelaxant activity, causing a rapid, marked and irreversible hypotension. Trachynilysin, from Synanceia trachynis, causes massive release and depletion of acetylcholine and damage to nerve and muscle fibres, which can account for the inhibition of neuromuscular function, and skeletal paralysis. But the used doses are not compatible with respiratory arrest. Verrucotoxin from Synanceia verrucosa activates potassium channels dependent from ATP; this can explain damage, and probably neurologic and respiratory distress.
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PMID:[Pharmacological properties of fish venoms]. 975 86


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