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)

The subcellular distribution of amino acids was compared in brains of genetically seizure-susceptible (SS) and genetically seizure-resistant (SR) rats. The total taurine content (mumol/brain) in the P2B, or synaptosomal, fraction in SS rats was only 37% of that of SR rats. Glutamate, glutamine, glycine, alanine, and gamma-aminobutyric acid (GABA) contents were unaltered. No alterations in total content were found in other subcellular fractions for the amino acids studied. SS animals that had never been stimulated to audiogenic seizure had decreased concentrations of taurine (nmol/mg protein) in the P2, P2B, and P2C fractions as compared with SR animals. These fractions contain crude synaptosomes, enriched synaptosomes, and enriched mitochondria, respectively. Phosphoethanolamine concentrations were also decreased in the P2B fractions, but concentrations of other amino acids were unaltered, as compared with SR animals. Twenty-four hours after the intracerebroventricular injection of taurine (6 mumol) in SS animals that had never been convulsed, taurine concentrations were significantly increased in whole brain homogenate and P2 and P2B fractions as compared with SS animals not given taurine. This treatment left unaltered the concentrations of glutamate, glutamine, GABA, and glycine in brain homogenate and P2 fraction. Because decreases in taurine concentration were seen in animals that had not been convulsed, these alterations are intrinsic to the SS strain and are not a consequence of convulsive activity. In view of the antiepileptic action of taurine, and the fact that an impairment of taurine transport in the brain of SS rats had previously been demonstrated, we suggest that a defect in the biochemistry of taurine is partially responsible for the seizure susceptibility of the SS rat.
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PMID:Subcellular distribution of neuroactive amino acids in brains of genetically epileptic rats. 647 8

The relationship between seizure propensity and the vascular anatomy of the anterior cerebral arteries, or stroke induced by unilateral ligation of the common carotid artery, was investigated utilizing well differentiated colonies of seizure-prone (SP) and non-seizure-prone (NSP) gerbils. Twenty SP and 20 NSP gerbils were perfused with a latex dye and the vascular patterns of the anterior cerebral arteries (ACA) were analyzed. In addition, 30 SP and 30 NSP gerbils were subjected to unilateral ligation of the common carotid artery and the number developing stroke (determined by clinical observation as well as by microscopic examination of the brain) was recorded. We found that in all animals the ACAs formed a fused-central vessel which vascularized the olfactory bulbs, as well as two lateral vessels (rostral arteries) that vascularized a previously undescribed nasal plexus. Neither the vascular pattern of the ACA, nor the frequency of occurrence of stroke following unilateral ligation was related to seizure propensity.
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PMID:Brain vasculature and induced ischemia in seizure-prone and non-seizure-prone gerbils. 705 30

D, L-3-hydroxy-3-ethyl-3-phenylpropanamide (HEPP) is a synthetic drug with anticonvulsant effects in a variety of seizure models. HEPP pharmacokinetics was studied after single 50 mg kg-1 intravenous (i.v.), intraperitoneal (i.p.), and oral (PO) administration in male albino Wistar rats. The plasma concentration against time curves showed a biphasic decay pattern with a similar distribution phase and the same terminal rate constant (beta = 0.22 h-1) by all three routes. The apparent volume of distribution at steady state (Vss = 0.80 L kg-1) indicates that HEPP is extensively distributed in extracellular tissues. This finding agrees very well with its low binding to plasma protein (mean bound fraction = 19.3 +/- 1.1%). The systemic clearance (Cl) was very low (3.30 mL min-1 kg-1). The bioavailability after IP and PO administration was 0.80 and 0.60 respectively. In the pharmacokinetic-pharmacodynamic studies a direct relationship was found between the protective effect of HEPP against pentylenetetrazole (PTZ) induced seizures and its concentration in plasma and/or brain. The concentrations at half-maximal effect (EC50) with 95% confidence interval (Cl) were 70.6 (66-75.5) micrograms mL-1 in serum and 60.1 (55.4-65.1) micrograms g-1 in brain. There was a rapid uptake of HEPP into the brain, and after the distributive phase, the disappearances in plasma and brain were almost parallel [C(serum) = 109 e-0.25t, r2 = 0.95; C(brain) = 38 e-2.53t + 91 e-0.21t, r2 = 0.93], with a C(brain)/C(plasma) ratio of 1.1.
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PMID:Disposition kinetics of HEPP in rats after intravenous, oral, and intraperitoneal administration. Correlation of plasma and brain levels with the anticonvulsant effect. 778 49

The morphology of the rolandic spike, the trough between the rolandic spike and the following slow wave, and of the slow wave itself was quantitatively studied in 43 children, classified into five clinical groups: (a) functional with epilepsy benign focal epilepsy of childhood with centrotemporal spikes (BECT) with oropharyngeal seizures or (b) BECT with unilateral or generalized seizures or (c) functional without epilepsy, and (d) organic with or (e) without epilepsy. The morphologic features of the rolandic spike-and-wave complex were identical in the five clinical categories. Thus, a quantitative description of the rolandic spike-and-wave complex can be given that is valid for the 43 children of the present study, although they represent a heterogeneity of associated clinical syndromes. The rolandic spike appeared to be not a spike but a sharp wave with a mean duration of 88 ms. In contrast to the opinion of several investigators, the morphology of the rolandic spike does not provide a clue to its "epileptogenicity" or to the presence or absence of an organic cerebral lesion in the individual child. In clinical practice, additional information (background activity of the EEG, computed tomography (CT) scan, or magnetic resonance imaging (MRI) of the brain) is needed to determine the significance of rolandic spikes occurring in the EEG of a child with respect to the probability of a cerebral lesion and the prognosis in relation to epileptic seizures.
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PMID:Identical morphology of the rolandic spike-and-wave complex in different clinical entities. 850 86

The effect of N(G)-nitro-L-arginine (NNA), an inhibitor of nitric oxide (NO) synthase on L-cysteine- induced neurotoxicity was investigated in mice. When L-cysteine (1, 2.5, 5 or 10 micromol/brain) was injected intracerebroventricular (i.c.v.) in mice, severe tonic seizures were observed for over 20 s in the treated mice in a dose-dependent manner. However, the tonic seizures induced by L-Cysteine were prevented by pretreatment with N(G)-nitro-L-arginine. Although L-cysteine (0.5, 1, 2.5, 5, 10 micromol/brain, i.c.v.) also caused a wild running (WR), NNA did not affect behavior. These results suggest that an overproduction of NO may be involve in the development of tonic seizures but not WR induced by L-cysteine.
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PMID:Preventive effect of N(G)-nitro-L-arginine against L-cysteine-induced seizures in mice. 859 72

The epileptogenic and neurodegenerative effects of dendrotoxin K, from Dendroaspis polylepis, a specific blocker of a non-inactivating, voltage-sensitive K+ channel, were studied after focal injection into one dorsal hippocampus in rats. Administration of 35 pmol dendrotoxin K elicited motor seizures and bilateral electrocortical discharges after a latent period (5.3 +/- 2.1 min), in all of the treated animals (n = 6). At 24 h, histological examination of brain (n = 5) coronal sections (10 microns; n = 6 per brain) detected bilateral damage to the hippocampal formation which extended 300 microns rostral and caudal to the injection tract. Quantitation of the damage revealed significant bilateral neuronal cell loss in the CA1 and CA4 pyramidal cell layer relative to the corresponding brain regions of rats (n = 3) injected with bovine serum albumin (105 pmol), which per se was ineffective in all respects. Dendrotoxin K (35 pmol) also caused a significant loss of CA3 pyramidal neurons and dentate gyrus granule cells ipsilateral to the site of toxin injection. In one out of six rats, a lower dose (3.5 pmol) of dendrotoxin K produced convulsive behaviour and electrocortical seizures but after a longer latency and these were accompanied by significant neuronal loss in the CA1, CA3 and CA4 pyramidal cell layer ipsilateral to the injected side. The lowest dose (0.35 pmol; n = 6 rats) of dendrotoxin K used failed to induce seizures and did not cause hippocampal damage (n = 6 rats). Systemic (i.p.) treatment with dizocilpine maleate (3 mg/kg) or LY 274614 (5 mg/kg i.p.), two N-methyl-D-aspartate receptor antagonists (given 15 min beforehand), prevented dendrotoxin K (35 pmol)-induced motor seizures and electrocortical epileptogenic discharges in 100% of the animals (n = 6 per group) treated. Similarly, these antagonists minimized the damage typically produced in the rat hippocampus, with no significant neuronal loss being observed. By contrast, NBQX (30 mg/kg, i.p. given 15 min previously), a non-N-methyl-D-aspartate antagonist, failed to prevent seizures normally evoked by dendrotoxin K (35 pmol; n = 6 rats); also, this treatment was unable to abolish CA1 pyramidal cell loss but minimized the loss in hippocampal sectors distant to the site of dendrotoxin K injection. However, complete protection against motor and electrocortical seizures and hippocampal damage was afforded by GYKI 52466 (10 mg/kg i.p.; n = 6 rats), a more effective non-N-methyl-D-aspartate receptor antagonist. These findings differ from the reported lack of protection by N-methyl-D-aspartate and non-N-methyl-D-aspartate receptor antagonists to rats receiving intra-hippocampal injection of alpha-dendrotoxin; this difference may stem from the ability of alpha-dendrotoxin to block predominantly a slowly inactivating K+ current whereas dendrotoxin K inhibits a non inactivating variant. In conclusion, the present data on dendrotoxin K, together with the previously described pattern of neurotoxicity for alpha-dendrotoxin, show that these homologues act via different mechanisms and, thus, can be used effectively as complementary tools to study seizures and neuronal cell death.
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PMID:N-methyl-D-aspartate and non-N-methyl-D-aspartate receptors mediate seizures and CA1 hippocampal damage induced by dendrotoxin-K in rats. 886 35

1. Earlier optimization of structure-activity relationships in a novel series of 4-(benzoylamino)-benzopyrans, led to the discovery of SB-204269 (trans-(+)-6-acetyl-4S-(4-fluorobenzoylamino)-3,4-dihydro-2, 2-dimethyl-2H-benzo[b]pyran-3R-ol, hemihydrate), a potent orally-active anticonvulsant in the mouse maximal electroshock seizure threshold (MEST) test. 2. Studies have now been undertaken to determine the effects of SB-204269 in a range of seizure models and tests of neurological deficits in rats. In addition, the compound has been evaluated in a series of in vitro mechanistic assays. 3. SB-204269 proved to be an orally-effective anticonvulsant agent, at doses (0.1-30 mg Kg-1) devoid of overt behavioural depressant properties, in models of both electrically (MEST and maximal electroshock (MEST)) and chemically (i.v. pentylenetetrazol (PTZ) infusion)-evoked tonic extension seizures. However, the compound did not inhibit PTZ-induced myoclonic seizures at doses up to 30 mg kg-1, p.o. 4. SB-204269 also selectively reduced focal electrographic seizure activity in an in vitro elevated K+ rat hippocampal slice model at concentrations (0.1-10 microM) that had no effect on normal synaptic activity and neuronal excitability. 5. In all of these seizure models, SB-204269 was equivalent or better than the clinically established antiepileptic drugs carbamazepine and lamotrigine, in terms of anticonvulsant potency and efficacy. 6. Unlike SB-204269, the corresponding trans 3S,4R enantiomer, SB-204268, did not produce marked anticonvulsant effects, an observation in accord with previous findings for other related pairs of trans enantiomers in the benzopyran series. 7. In the rat accelerating rotarod test, a sensitive paradigm for the detection of neurological deficits such as sedation and motor incoordination, SB-204269 was inactive even at doses as high as 200 mg kg-1, p.o. This was reflected in the excellent therapeutic index (minimum significantly effective dose in the rotarod test/ED50 in the MES test) for SB-204269 of > 31, as compared to equivalent values of only 7 and 13 for carbamazepine and lamotrigine, respectively. 8. At concentrations (> or = 10 microM) well above those required to produce anticonvulsant activity in vivo (i.e. 0.1 microM in brain), SB-204269 did not interact with many of the well known mechanistic targets for established antiepileptic drugs (e.g. Na+ channels or GABAergic neurotransmission). Subsequent studies have shown that the anticonvulsant properties of SB-204269 are likely to be mediated by a novel stereospecific binding site present in the CNS. 9. The overall efficacy profile in rodent seizure models, together with a minimal liability for inducing neurological impairment and an apparently unique mechanism of action, highlight the therapeutic potential of SB-204269 for the treatment of refractory partial and generalized tonic-clonic seizures.
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PMID:Profile of SB-204269, a mechanistically novel anticonvulsant drug, in rat models of focal and generalized epileptic seizures. 928 3

The epileptogenic and neurodegenerative effects of dendrotoxin K (DTx-K), from Dendroaspis polylepsis, a specific blocker of a noninactivating, voltage-sensitive K+ channel, were studied after focal injection into one dorsal hippocampus in rats pretreated with the 21-aminosteriod U-74389G, a scavenger of free oxygen radicals. Administration of 35 pmol DTx-K elicited in all of the treated animals (n = 6) motor seizures and bilateral electrocortical (ECoG) discharges after a latent period of approximately 5 min. At 24 h, histological examination of brain (n = 6) coronal sections (10 microns; n = 6 per brain) detected bilateral damage to the hippocampal formation. Quantitation of damage revealed significant bilateral neuronal cell loss in the CA1 and CA4 pyramidal cell layer and dentate gyrus granule cell layer relative to the corresponding brain regions of rats (n = 6) injected with bovine serum albumin (300 ng), which per se was ineffective in all respects. DTx-K (35 pmol) also caused a significant loss of CA3 pyramidal neurons ipsilateral to the site of toxin injection. Systemic (i.p.) administration of U-74389G (5 mg/kg given 30 min beforehand) delayed the onset of motor and ECoG seizures and reduced the number of epileptogenic discharges typically observed in rats receiving an injection of DTx-K (35 pmol) alone. Similarly, this treatment prevented the damage inflicted to the hippocampus by the toxin and in no instance was significant neuronal loss observed. At variance with these results, pretreatment with U-74389G (up to 10 mg/kg i.p.) failed to prevent seizures and CA1 hippocampal damage evoked by intra-hippocampal injection of alpha-DTx (35 pmol), a DTx-K homologue which preferentially inhibits a slowly inactivating, voltage-dependent K+ conductance in nerve cells. In conclusion, the present data support a role for free oxygen radicals in mediating hippocampal damage induced by DTx-K, but not alpha-DTx, and confirm the original deduction that these DTx homologues are complementary neurobiological tools to study mechanisms of seizures and neuronal death.
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PMID:Seizures and hippocampal damage produced by dendrotoxin-K in rats is prevented by the 21-aminosteroid U-74389G. 929 17

Shiverer (shi) mice, which are neurologically mutant, lack a large portion of the gene for the myelin basic proteins (MBPs), have virtually no myelin in their central nervous system (CNS), and shiver, undergo seizures, and die early. At least five types of MBPs (21.5, 18.5, 17.3, 17.2 and 14.0 kDa) are known to be generated through alternative splicing from a single MBP gene. We have produced transgenic shi mice carrying a cDNA encoding mouse 14-kDa MBP isoform, the most abundant form of MBPs, under control of a mouse MBP gene promoter, and showed that expression of the 14-kDa MBP can restore CNS myelination. To test whether the 17.2-kDa MBP isoform, one of the minor components of MBPs, can also elicit myelination in homozygous shi mutants, we produced seven independent transgenic shi mice carrying cDNA encoding the mouse 17.2-kDa MBP isoform, and the transcription of which was driven by a mouse MBP gene promoter. The axons in the cerebellum of one transgenic line, which exhibited the highest expression of transgene-derived mRNA ( approximately 50% of the level of total MBP mRNA in the normal mouse brain), were myelinated. This mouse exhibited nearly normal behavior. These findings indicate that the 17.2-kDa MBP isoform, even when the only 17.2-kDa MBP isoform is present, has the ability to elicit CNS myelination in transgenic shi mice. This transgenic strategy will be useful for elucidating the role of each type of MBP isoform in CNS myelinogenesis.
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PMID:Overexpression of a minor component of myelin basic protein isoform (17.2 kDa) can restore myelinogenesis in transgenic shiverer mice. 951 36

This review examines interactions in the mammalian central nervous system (CNS) between carnosine and the endogenous transition metals zinc and copper. Although the relationship between these substances may be applicable to other brain regions, the focus is on the olfactory system where these substances may have special significance. Carnosine is not only highly concentrated in the olfactory system, but it is also contained in neurons (in contrast to glia cells in most of the brain) and has many features of a neurotransmitter. Whereas the function of carnosine in the CNS is not well understood, we review evidence that suggests that it may act as both a neuromodulator and a neuroprotective agent. Although zinc and/or copper are found in many neuronal pathways in the brain, the concentrations of zinc and copper in the olfactory bulb (the target of afferent input from sensory neurons in the nose) are among the highest in the CNS. Included in the multitude of physiological roles that zinc and copper play in the CNS is modulation of neuronal excitability. However, zinc and copper also have been implicated in a variety of neurologic conditions including Alzheimer's disease, Parkinson's disease, stroke, and seizures. Here we review the modulatory effects that carnosine can have on zinc and copper's abilities to influence neuronal excitability and to exert neurotoxic effects in the olfactory system. Other aspects of carnosine in the CNS are reviewed elsewhere in this issue.
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PMID:Interactions between carnosine and zinc and copper: implications for neuromodulation and neuroprotection. 1095 Oct 99


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