The expression of the c-fos and krox-24 (immediate early genes: IEGs) and the BDNF (late response gene) were investigated by convulsants such as kainate (KA, 200 micrometer), N-methyl-D-aspartate (NMDA, 10 mM), glutamate (GLU, 2 mM), and picrotoxin (PTX, 20 micrometer in the rat C6 glioma cells. In addition, the changes of their expression patterns were investigated by the anticonvulsants such as a NMDA antagonist MK-801, phenytoin, phenobarbiw, diazepam, and newer antiepileptic drugs like felbamate and gabapentin. NMDA induced c-fos and krox-24 expromiom were decreased spatially by the anticonvulsants. KA, NMDA, GLU, and PTX-induced BDNF expression were increased by the anticonvulsants. These results imply the molecular basis of the anticonvulsant action mechanism lies in differential and coordinated transcriptional regulation of IEGs.
Animals ; Anticonvulsants* ; Brain-Derived Neurotrophic Factor ; Convulsants ; Diazepam ; Dizocilpine Maleate ; Genes, Immediate-Early* ; Glioma ; Glutamic Acid ; Kainic Acid ; N-Methylaspartate ; Phenytoin ; Picrotoxin ; Rats

OBJECTIVEStriatum may be involved in depressive disorders according to the neuroimaging analysis and clinical data. However, no animal model at present supported the possible role of striatum in the pathogenesis of depression. In the present study, we have investigated the depressive-like behavior in mice recently intoxicated with 3-nitropropionic acid (3-NP), a widely known toxin that selectively damages the striatum in the brain.

METHODSMouse model was made with subacute systemic 3-NP treatment, and the depressive-like behavior was measured using the duration of immobility during forced swimming test (FST).

RESULTSWhen the mice at day 15 post-intoxication just totally recovered from motor deficits, the duration of immobility in FST was significantly longer than that in controls. The depressive-like behavior was not due to the fatigue or general sickness following 3-NP intoxication and could be reversed by the antidepressant, desipramine hydrochloride. In two successive FST in 24 h interval, the depressive-like behavior could be observed again in subsequent FST (at day 16 post-intoxication), and the mice presented a normal "learned helplessness".

CONCLUSIONA novel depression animal model could be established in mice during the initial period of recovery from 3-NP intoxication. The depression-like behavior might occur independently without involvement of cognitive defects, and the striatal lesions may underlie the depression-like behavior attributable to 3-NP intoxication.

Animals ; Convulsants ; toxicity ; Corpus Striatum ; drug effects ; Depression ; chemically induced ; Disease Models, Animal ; Mice ; Motor Activity ; drug effects ; Nitro Compounds ; toxicity ; Propionates ; toxicity

INTRODUCTIONThe need for the rational development of newer and adjuvant drugs to treat epilepsy has prompted this study of the potential anticonvulsant effect of amlodipine.

METHODSThe acute effect was studied in mice in single doses of 1 mg/kg, 2 mg/kg and 4 mg/kg of amlodipine and the chronic effect was studied in doses of 1 mg/kg and 4 mg/kg (administered daily for 21 days) using the maximal electroshock seizure and pentylenetetrazole-induced seizure models of epilepsy. Sodium valproate and normal saline were used as the standard and control, respectively.

RESULTSFor the acute study, in the maximal electroshock seizure model, the administration of 1 mg/kg of amlodipine resulted in the complete abolition of seizures in 33 percent of the mice, and this was increased to 67 percent with the administration of 4 mg/kg. In the pentylenetetrazole-induced seizure model, the administration of 1 mg/kg and 2 mg/kg amlodipine protected 33 percent of the animals from mortality, and 67 percent were protected with the administration of 4 mg/kg. For the chronic study, in the maximal electroshock seizure model, the administration of 1 mg/kg amlodipine resulted in the complete abolition of seizures in 40 percent of the mice and in 60 percent, with the administration of 4 mg/kg. In the pentylenetetrazole-induced seizure model, 50 percent of the mice were protected from mortality with 1 mg/kg amlodipine and 60 percent, with 4 mg/kg amlodipine.

CONCLUSIONThese findings indicate that amlodipine may be a good candidate as an add-on therapy for epilepsy.

Amlodipine ; therapeutic use ; Animals ; Anticonvulsants ; therapeutic use ; Calcium Channel Blockers ; therapeutic use ; Convulsants ; toxicity ; Disease Models, Animal ; Electroshock ; adverse effects ; Female ; Male ; Mice ; Mice, Inbred Strains ; Pentylenetetrazole ; toxicity ; Seizures ; drug therapy ; etiology ; prevention & control ; Time Factors ; Valproic Acid ; therapeutic use

OBJECTIVEMeasuring the serum concentrations of adrenocorticotropic hormone (ACTH) and cortisol in epileptic seizures during sleep to investigate their link to the EEG changes.

METHODSPre-surgical evaluation was performed by video-EEG monitoring using 24 channel recording. Thirty six epilepsy patients could be attributed to two groups: 28 patients had spontaneous seizures, and the other 8 patients whose seizures were induced by bemegride. Another 11 persons with confirmed psychogenic non-epileptic seizures (PNES) served as control group. Blood samples were obtained at five points: wake (08:00 a.m.), sleep (00:00 a.m.), and shortly before, during and after an epileptic seizure. The serum ACTH and cortisol were measured and analyzed by chemiluminescent immunoassay.

RESULTSThe levels of ACTH and cortisol in serum underwent significant changes: declining below the average sleep-level shortly before seizures, increasing during seizures, and far above the average wake-level after seizures (P < 0.001). Such changes did not occur in the control group (P > 0.05). The ACTH and cortisol levels had no significant difference between spontaneous group and bemegride-induced group (P > 0.05).

CONCLUSIONThe serum concentrations of ACTH and cortisol during sleep seizures are linked with pre-ictal and ictal EEG changes in epilepsy patients.

Action Potentials ; physiology ; Adolescent ; Adrenocorticotropic Hormone ; blood ; Adult ; Bemegride ; pharmacology ; Biomarkers ; blood ; Cerebral Cortex ; metabolism ; physiopathology ; Convulsants ; pharmacology ; Electroencephalography ; Epilepsy ; blood ; physiopathology ; Evoked Potentials ; physiology ; Humans ; Hydrocortisone ; blood ; Hypothalamo-Hypophyseal System ; metabolism ; physiopathology ; secretion ; Pituitary-Adrenal System ; metabolism ; physiopathology ; secretion ; Sleep Wake Disorders ; blood ; physiopathology ; Up-Regulation ; physiology ; Wakefulness ; physiology

OBJECTIVEA sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) method has been developed and validated for the determination of brucine and strychnine in rat plasma.

METHODSamples were extracted by ethyl acetate-n-butanol (7: 3). Chromatographic separation was operated on ZORBAX XDB-C18 column with gradient elution of acetonitrile-methanol-water (0.05% acetic acid and 10 nmol x L(-1) ammonium formate contained), followed by LC-MS/MS in positive electrospray ionization. Quantification was carried out on multiple reaction monitoring (MRM) of the transition m/z 395.2/324.2, m/z 335.2/184.2 and m/z 199.1/171.1 for brucine, strychnine and tacrine (internal standard), respectively.

RESULTThe method was linear in the range of 0.195-100 and 0.07840 microg x L(-1) for brucine and strychnine, with coefficient correlation 0.994 and 0.996 respectively. The recoveries of extraction were 78.9% - 102.4% for brucine and 95.2% - 106.1% for strychnine. Precision, accuracy, stability and matrix effect of the analytes met the requirement. The method was applied to a pharmacokinetic study of brucine and strychnine after cutaneous administration of Semen Strychni niosome gel. The C(max) were (26.20 +/- 5.81) and (12.50 +/- 3.00) microg x L(-1) while the AUC(0-infinity), were (193.75 +/- 39.43) and (98.25 +/- 28.54) microg x h x L(-1) of the two components.

CONCLUSIONWe conclude that the niosomes may reduce the systemic exposures and prolong the local release of brucine and strychnine.

Administration, Cutaneous ; Analgesics ; analysis ; pharmacokinetics ; Animals ; Chromatography, Liquid ; Convulsants ; analysis ; pharmacokinetics ; Female ; Gels ; chemistry ; Liposomes ; chemistry ; Male ; Plants, Medicinal ; chemistry ; Rats ; Rats, Sprague-Dawley ; Seeds ; chemistry ; Semen ; chemistry ; Specific Pathogen-Free Organisms ; Strychnine ; analogs & derivatives ; analysis ; pharmacokinetics ; Strychnos nux-vomica ; chemistry ; Tandem Mass Spectrometry

OBJECTIVENumerous studies have described both motor defects and cognitive impairments in several strains of rodents following 3-nitropropionic acid (3-NP) intoxication. In the present study, we investigated spatial recognition memory in Kunming mice that just recovered from motor defects induced by 3-NP.

METHODSMouse model was made by systemic subacute 3-NP treatment, and spatial recognition memory was measured through the Y-maze Test, a simple two-trial recognition test.

RESULTS(1) On day 15 following 3-NP treatment, affected Kunming mice did not show motor defects in the Rotarod test and presented normal gait again. (2) In the following Y-maze test after 1h interval, the percentage (90.0%) of mice showing novel arm preference in 3-NP treatment group was significantly higher than the random chance level (50%), although it was only slightly higher than that (83.3%) in control group. On day 45 after 3-NP treatment, mice failed to choose unfamiliar novel arm as first choice, and the same occured in the control group. (3) For both post-intoxicated (on day 15 and day 45 following 3-NP treatment) and control groups, the duration in the novel arm and the frequency of entering it, were longer and higher compared with familiar start and other arms. For these mice that recently recovered from motor defects following 3-NP intoxication, no spatial memory deficits were observed through Y-maze Test.

CONCLUSIONKunming mice used in our assays might possess resistance to cognitive impairment induced by 3-NP, which is consistent with previous findings in Swiss EPM-M1 mice.

Animals ; Behavior, Animal ; Convulsants ; toxicity ; Male ; Maze Learning ; drug effects ; Memory Disorders ; etiology ; Mice ; Mice, Inbred Strains ; Motor Activity ; drug effects ; Movement Disorders ; etiology ; Nitro Compounds ; toxicity ; Poisoning ; complications ; etiology ; Propionates ; toxicity ; Recovery of Function ; drug effects ; physiology ; Rotarod Performance Test ; Time Factors

This study is to examine the sedative, hypnotic and anticonvulsive effects of an adenosine analogue, WS090501. The spontaneous locomotor activity was recorded by open field equipment, and the EEG of rats was recorded by polyphysiograph. Pentylenetetrazol (PTZ)-induced seizure model was used. The spontaneous locomotor activity was decreased by WS090501 at various doses (0.06, 0.13, and 0.25 mg x kg(-1)), and the decreasing rate was 28.4%, 47.1% and 61.2% respectively. Furthermore, the effect of WS090501 on spontaneous locomotor activity of mice can be antagonized by DPCPX, a selective adenosine A1R antagonist, but cannot be antagonized by SCH58261, a selective adenosine A2AR antagonist. The NREM sleep was significantly increased by WS090501 (0.05 and 0.2 mg x kg(-1)), and the increasing rate was 27.6% and 102.8%, respectively, at 6th hour after administration. The REM sleep decreased significantly at the higher dose. PTZ induced serious convulsion in mice. The latency of convulsion was prolonged, and the number of seizure and mortality decreased after administration of WS090501. These results show that WS090501 has potent sedative, hypnotic and anticonvulsive effects, which may be mediated through adenosine A1R.
Adenosine ; analogs & derivatives ; antagonists & inhibitors ; pharmacology ; Adenosine A1 Receptor Antagonists ; pharmacology ; Adenosine A2 Receptor Antagonists ; pharmacology ; Animals ; Anticonvulsants ; antagonists & inhibitors ; pharmacology ; Convulsants ; Electroencephalography ; Hypnotics and Sedatives ; antagonists & inhibitors ; pharmacology ; Male ; Mice ; Mice, Inbred ICR ; Motor Activity ; drug effects ; Pentylenetetrazole ; Pyrimidines ; pharmacology ; Rats ; Rats, Wistar ; Seizures ; chemically induced ; prevention & control ; Sleep ; drug effects ; Triazoles ; pharmacology ; Xanthines ; pharmacology

Accumulating data have revealed that abnormal activity of the mTOR (mammalian target of rapamycin) pathway plays an important role in epileptogenesis triggered by various factors. We previously reported that pretreatment with perifosine, an inhibitor of Akt (also called protein kinase B), abolishes the rapamycin-induced paradoxical increase of S6 phosphorylation in a rat model induced by kainic acid (KA). Since Akt is an upstream target in the mTOR signaling pathway, we set out to determine whether perifosine has a preventive effect on epileptogenesis. Here, we explored the effect of perifosine on the model of temporal epilepsy induced by KA in rats and found that pretreatment with perifosine had no effect on the severity or duration of the KA-induced status epilepticus. However, perifosine almost completely inhibited the activation of p-Akt and p-S6 both acutely and chronically following the KA-induced status epilepticus. Perifosine pretreatment suppressed the KA-induced neuronal death and mossy fiber sprouting. The frequency of spontaneous seizures was markedly decreased in rats pretreated with perifosine. Accordingly, rats pretreated with perifosine showed mild impairment in cognitive functions. Collectively, this study provides novel evidence in a KA seizure model that perifosine may be a potential drug for use in anti-epileptogenic therapy.
Animals ; Anticonvulsants ; pharmacology ; Brain ; drug effects ; pathology ; Convulsants ; toxicity ; Disease Models, Animal ; Epilepsy, Temporal Lobe ; chemically induced ; pathology ; Kainic Acid ; toxicity ; Male ; Neurons ; drug effects ; pathology ; Phosphorylcholine ; analogs & derivatives ; pharmacology ; Protein Kinase Inhibitors ; pharmacology ; Proto-Oncogene Proteins c-akt ; antagonists & inhibitors ; Rats ; Rats, Sprague-Dawley ; Status Epilepticus ; chemically induced ; pathology