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C Shin

Publications and source records attributed to C Shin.

At least 19 recordsLinked to original sources

NMDA-receptor mediated electrical epileptogenesis in the organotypic culture of rat hippocampus.

Extracellular field recordings were made in CA1 in the hippocampal explant cultures in oxygenated artificial cerebrospinal fluid. Schaffer collaterals were stimulated with 1-s trains of 60 Hz pulses every 10 min. Seizures were reliably elicited with progressive lengthening over 1-2 h. D-APV, an N-methyl-D-aspartate (NMDA) antagonist, stereoselectively blocked the development of seizures. Thus we have demonstrated that in vitro epileptogenesis occurs in hippocampal explant cultures through NMDA receptor mediated mechanisms.

2-Amino-5-phosphonovalerate

Antiepileptogenic effects of conventional anticonvulsants in the kindling model of epilespy.

We sought to determine whether the clinically effective anticonvulsant drug valproate exhibited antiepileptogenic properties in the kindling model (we use the term anticonvulsant to mean suppression of seizure, and antiepileptogenic to mean suppression of development of epilepsy). We compared and contrasted valproate with two other anticonvulsant drugs, phenobarbital and carbamazepine. We investigated the effects of these drugs on the development of kindling, that is, the number of stimulation-induced afterdischarges required to induce enhanced seizure susceptibility in rats. Valproate exhibited powerful antiepileptogenic effects as evident in a dose-dependent increase in the number of afterdischarges required to induce kindling. These effects were not due to retained valproate or an active metabolite merely masking the expression of kindled seizures. By contrast, carbamazepine was devoid of any antiepieptogenic effects despite exhibiting marked anticonvulsant effects. Like valproate, phenobarbital exhibited both antiepileptogenic and anticonvulsant properties, but its antiepileptogenic properties were significantly less pronounced. The antiepileptogenic effects of valproate and phenobarbital strengthen the candidacy of these agents for the clinical studies needed to investigate pharmacological prevention of the development of epilepsy in high-risk groups.

Action Potentials

Differential expression of immediate early genes in the hippocampus in the kindling model of epilepsy.

Kindling is a phenomenon in which brief afterdischarges (ADs) evoked by periodic electrical stimulation of the brain eventually result in generalized clonic motor seizures. Once present, the enhanced sensitivity to electrical stimulation is lifelong. The mechanism by which brief ADs produce this long-lasting effect may involve a change in gene expression. To begin to investigate changes in gene expression that occur during kindling, we used in situ hybridization histochemistry to examine the time course of expression of mRNAs of the immediate early genes (IEGs) c-fos, c-jun, NGFI-A, and c-myc within the dorsal hippocampus of rats following a kindling AD. Three principal findings resulted from this study. First, the expression of all mRNAs except c-myc was significantly increased (P less than 0.05) within discrete neuronal populations. Second, the time course of expression of the IEGs differed markedly within the same neuronal population. Third, for a given IEG, the time course and anatomic pattern of expression were strikingly different among different neuronal populations of the hippocampus. The prolonged and distinctly different patterns of IEG expression suggest that target genes are differentially regulated in these neuronal populations for prolonged periods following a kindling AD.

Animals

Inhibition of muscarinic-coupled phosphoinositide hydrolysis by N-methyl-D-aspartate is dependent on depolarization via channel activation.

The intent of this work was to elucidate the mechanism by which N-methyl-D-aspartate (NMDA) receptor agonists inhibit a second messenger system, namely, the stimulation of phosphoinositide (PI) hydrolysis activated by muscarinic cholinergic receptor agonists. NMDA inhibited cholinergic stimulation of PI hydrolysis in a dose- and time-dependent manner. NMDA exerts this effect indirectly through channel activation, because both MK-801 and N-[1-(2-thienyl)cyclohexyl]piperidine (TCP) prevented this action. Prevention of the NMDA effect by removal of sodium, but not calcium, from the incubation buffer suggested that depolarization may be the responsible mechanism. Depolarization alone proved sufficient to inhibit cholinergic activation of PI hydrolysis, because both veratridine and an elevated extracellular potassium level inhibited cholinergic stimulation of PI hydrolysis. The effect of NMDA appeared to require sodium flux through NMDA channels rather than through voltage-dependent sodium channels, because tetrodotoxin failed to inhibit the effect of NMDA. In correlative electrophysiologic experiments, NMDA profoundly inhibited evoked excitatory postsynaptic potentials and population action potentials of CA1 neurons, an effect almost certainly due to depolarization. The dose and time course of the electrophysiologic effects correlated well with the biochemical effects. Taken together, the data support the assertion that NMDA receptor activation inhibits PI hydrolysis by depolarization mediated by sodium flux through NMDA channels.

Animals

Induction of c-fos mRNA expression by afterdischarge in the hippocampus of naive and kindled rats.

Periodic induction of focal electrical seizure [afterdischarge (AD)] is an absolute prerequisite for the development of kindling, an animal model of complex partial epilepsy. Once established, it is a permanent condition. The mechanism(s) that translate ADs, which last tens of seconds, into life-long alterations in the CNS is unclear. Cellular immediate-early genes have been implicated in the conversion of short-term stimuli to long-term alterations in cellular phenotypes by regulating target gene expression. We have investigated the contribution of one such early gene, c-fos, to this process. The relationship between ADs and expression of c-fos gene in the rat hippocampus, a key structure in kindling development, was studied by analysis of mRNA levels. The low constitutive expression of c-fos mRNA in the hippocampus was not altered by kindling. There was an "all-or-none" relationship between induction of c-fos and the duration of AD. The threshold for induction was approximately 30 s of AD. Above-threshold ADs induced c-fos in both naive and kindled animals to the same extent and with identical temporal profiles. Although the expression of c-fos is unchanged with kindling, c-fos may nonetheless contribute to many long-term changes of kindling, both adaptive and epileptogenic.

Animals

Sensorineural hearing loss: a reversible effect of valproic acid.

We report 2 patients over the age of 70 who, while on valproate (VPA) for complex partial seizures, developed sensorineural hearing loss. Following discontinuation of VPA for nonaudiologic reasons, the patients reported improved hearing which was confirmed by audiometry. These findings represent VPA-induced sensorineural hearing loss, possibly in preexisting presbycusis.

Aged

Intravenous phenytoin is an effective anticonvulsant in the kindling model.

We reexamined the efficacy of the clinically effective anticonvulsant drug phenytoin in the kindling model. We investigated the effects of varying doses of intravenous phenytoin on serum concentrations and on several indexes of stimulation-evoked kindled seizures. Intravenous phenytoin produced a dose-dependent increase in serum phenytoin concentration and powerfully suppressed both limbic and clonic motor seizures. Although focal afterdischarge threshold was elevated to some extent, the most profound effect of phenytoin was limitation of seizure propagation. Variable and low serum concentrations of intraperitoneal or oral phenytoin may explain previous findings that phenytoin is only partly effective or ineffective against kindled seizures. Together with previous results with other drugs, the excellent correlation among drugs effective against human and kindled seizures strengthens the validity of this model. We suggest that the efficacy of experimental anticonvulsant drugs be established in the kindling model before initiation of clinical trials for partial and secondarily generalized seizures.

Animals

Microinjection of a benzodiazepine into substantia nigra elevates kindled seizure threshold.

The purpose of these experiments was to initiate investigations of the brain site(s) at which the benzodiazepines exert their anticonvulsant effect. We examined the effects of microinjections of clonazepam into substantia nigra (SN) on seizure threshold in the kindling model. We also examined the distribution of microinjected [3H]methylclonazepam with autoradiographic methods. Microinjection of clonazepam bilaterally into substantia nigra pars reticulata (SNR), but not nearby, produced a 75% elevation of generalized seizure threshold. Quantitative analysis of autoradiographic studies indicated that the vast majority of [3H]methylclonazepam was distributed within 400 micron of the injection cannula tip; even optimally placed injections did not result in drug access throughout the entire SN. The data demonstrate that local application of an anticonvulsant benzodiazepine to the substantia nigra alone is sufficient to suppress seizures. We suggest that the substantia nigra is one site at which systemically administered benzodiazepines act to suppress seizures.

Animals

The role of substantia nigra in the development of kindling: pharmacologic and lesion studies.

The role of substantia nigra (SN) in the development of kindling was investigated. Microinjection of gamma-vinyl gamma-aminobutyric acid (GVG), a gamma-aminobutyric acid (GABA) transaminase inhibitor, into the SN bilaterally retarded kindling development by 77%. GVG injected dorsal to the SN did not alter the kindling rate. By contrast, lesions of the SN, whether by thermocoagulation or by microinjected neurotoxin, N-methyl-D,L-aspartate, facilitated kindling development by 27-44%. Thermocoagulative lesions dorsal to the SN did not affect the rate of kindling development. Thus these two manipulations, each presumed to suppress the activity of the SN, resulted in opposite effects on kindling development. We interpret the pharmacologic findings to indicate that the intact SN can powerfully facilitate kindling development. However, the SN is not vital for kindling development, since kindling can be established after destruction of a considerable portion of SN. Whether the increased rate of kindling development following SN lesions is due solely to the absence of SN remains unclear.

Aminocaproates

Stimulation of substantia nigra pars reticulata enhances dentate granule cell excitability.

We studied the effects of electrical and chemical stimulation of the substantia nigra (SN) on the dentate granule cell (DGC) response to perforant path stimulation. Studies were carried out in both pentobarbital anesthetized and awake freely moving rats. Chemical stimulation was achieved by microinjection of N-methyl-D,L-aspartate (NMDA), an excitatory amino acid. Electrical preconditioning stimulation applied to the area of the SN, but not dorsal to SN, increased the excitability of DGCs. Intracerebral microinjection of NMDA into the contralateral SN pars reticulata (SNR), but not into SN pars compacta or cerebral peduncle, also produced a marked and reversible enhancement of DGC excitability. In both instances, the increased DGC excitability consisted of increased amplitude of the perforant path evoked population spike without change in the slope of the population excitatory postsynaptic potential (pEPSP). We interpret the data to indicate that increasing the output of the SNR increases the excitability of the DGCs, a limbic neuronal population regulating information transfer through hippocampal pathways. Together with our previous finding that decreasing the output of SNR suppressed limbic seizures, these data demonstrate that the SNR exerts a powerful influence on limbic system excitability. Delineating the anatomic pathway mediating this influence could provide valuable insight into the mechanisms underlying basal ganglia-limbic interactions in both physiologic and pathologic conditions.

Action Potentials

Anti-seizure and anti-epileptogenic effect of gamma-vinyl gamma-aminobutyric acid in amygdaloid kindling.

We examined the effects of systemic administration of gamma-vinyl gamma-aminobutyric acid (GVG), a gamma-aminobutyric acid (GABA) transaminase inhibitor, on the kindling model of epilepsy in rats. GVG (1200 or 1500 mg/kg) approximately doubled the number of stimulations required for kindling development. GVG also suppressed both generalized motor seizures and electrographic after discharges in previously fully kindled animals. These results further support the idea that enhanced GABAergic neurotransmission suppresses both seizures and epileptogenesis. The results also suggest that GVG may be an effective anti-seizure and anti-epileptogenic agent in humans.

Aminocaproates

Changes in dynorphin, enkephalin and cholecystokinin content of hippocampus and substantia nigra after amygdala kindling.

Amygdaloid kindling of rats produced an increase in hippocampal Met5-enkephalin-Arg6-Gly7-Leu8 and cholecystokinin immunoreactivities and simultaneously a decrease in dynorphin A1-8 content. In substantia nigra Met5-enkephalin-Arg6-Gly7-Leu8 was increased and no change was observed in dynorphin A1-8 content. These data suggest that specific alterations of neuropeptides in limbic and extrapyramidal circuits are prominent manifestations of the kindling process or kindled seizures.

Amygdala

High-resolution computed tomography in multiple sclerosis.

Eighty-five patients were classified as having definite (n = 34), probable (n = 18), or possible (n = 33) multiple sclerosis using the criteria of Poser. Each patient had an enhanced computed tomographic examination, and most had cerebrospinal fluid and evoked response studies at the same time. Abnormalities including focal decreased brain density, abnormal enhancement, and cerebrospinal fluid space enlargement were found in 62% of patients (85% of those with definite, 39% of those with probable, and 52% of those with possible multiple sclerosis), and abnormal enhancing areas were demonstrated in 29% (44% of those with definite, 17% of those with probable, and 21% of those with possible disease). In the subgroup of patients with definite multiple sclerosis and recent clinical exacerbation (within the prior 8 weeks), abnormal enhancement was present in 89%. There was a strong correlation between clinical exacerbation and abnormal contrast enhancement. Cerebrospinal fluid studies (IgG, white blood cell count, total protein) had no correlation with exacerbation or abnormal enhancement. Maps of low-density and enhancing areas were similar to those previously described in postmortem studies. Computed tomography thus provides an in vivo, objective, and anatomically specific map of the brain parenchyma and the integrity of the blood-brain barrier that is useful in research studies evaluating the treatment of multiple sclerosis. It is also useful in patients in whom the diagnosis of multiple sclerosis is suspected but not certain on the basis of clinical and laboratory evaluation.

Adult

gamma-Aminobutyric acid and benzodiazepine receptors in the kindling model of epilepsy: a quantitative radiohistochemical study.

Quantitative radiohistochemistry was utilized to study alterations of gamma-aminobutyric acid (GABA) and benzodiazepine receptors in the kindling model of epilepsy. The radioligands used for GABA and benzodiazepine receptors were [3H] muscimol and [3H]flunitrazepam, respectively. GABA receptor binding was increased by 22% in fascia dentata of the hippocampal formation but not in neocortex or substantia nigra of kindled rats. Within fascia dentata, GABA receptor binding was increased to an equivalent extent in stratum granulosum and throughout stratum moleculare; no increase was found in dentate hilus or stratum lacunosummoleculare or stratum radiatum of CA1. The increased binding was present at 24 hr but not at 28 days after the last kindled seizure. The direction, anatomic distribution, and time course of the increased GABA receptor binding were paralleled by increased benzodiazepine receptor binding. Unexpectedly, GABA receptor-mediated enhancement of benzodiazepine receptor binding was slightly attenuated in fascia dentata of kindled compared to control rats. The anatomic distribution of the increased GABA receptor binding is consistent with a localization to somata and dendritic trees of dentate granule cells. We suggest that increased GABA and benzodiazepine receptor binding may contribute to enhanced inhibition of dentate granule cells demonstrated electrophysiologically in kindled animals.

Animals

The kindling model of epilepsy: a critical review.

Kindling is an animal model of epilepsy induced by electrical stimulation of the brain. This model has attracted the interest of many neuroscientists, in part because it involves a robust, permanent modification of brain function. This report will describe the kindling phenomenon and critically review current understanding of the underlying mechanisms. The review will carefully consider whether this model accurately reflects analogous processes in humans. The review will consider some hypotheses inspired by the kindling studies which may be relevant to human epilepsy.

Acetylcholine

Evidence implicating substantia nigra in regulation of kindled seizure threshold.

We studied the effects of microinjected drugs and brainstem lesions on motor and limbic seizures in the kindling model of epilepsy. The duration of motor seizures was determined by timing the colonic and tonic movements of the extremities. The duration of limbic seizures was determined by measuring afterdischarge recorded on the electroencephalogram. Bilateral microinjection of a gamma-aminobutyric acid (GABA) agonist, muscimol, into the area of the substantia nigra (SN) markedly suppressed both motor and limbic seizures induced by stimulation of amygdala, olfactory structures, or lateral entorhinal cortex. Microinjection of saline did not suppress seizures. The suppressive effect of muscimol: (i) dissipated after several hours and was dependent on dose; (ii) was due to an elevation of the seizure threshold, since typical seizures could be elicited with electrical current far exceeding the threshold; and (iii) exhibited spatial specificity since muscimol injections 1 to 2 mm dorsal to the SN or into neocortex did not suppress the seizures. The actions of muscimol were probably mediated by its GABA agonist properties, since microinjection of an irreversible inhibitor of GABA transaminase (gamma-vinyl GABA) into the area of the SN also suppressed kindled seizures. Destruction of brainstem structures was produced by microinjection of the neurotoxin, N-methyl-D,L-aspartate. Seizures were markedly suppressed in animals with bilateral destruction of the SN but not in animals in which the SN was spared bilaterally. We interpret the data to indicate that the SN is the site at which the GABA agonists and lesions act to raise the threshold for kindled seizures. The suppression of limbic seizures indicates that this brainstem nucleus can regulate the intrinsic neuronal excitability of hemispheric sites.

Aminocaproates