Anticonvulsant properties of the cerebrospinal fluid during activation of the antiepileptic system of the brain

Cerebrospinal fluid (CSF) was obtained after 30-40 sessions of daily electrical stimulation of the cat cerebellum vermis. The intraventricular injection of CSF (10 microliters) to Wistar rats increased the latent period of initial seizure manifestations, significantly reduced the number of animals with seizures and reduced the severity of seizures induced by korazol injection (40 mg/kg). Analogous seizure changes were observed in rats after intraventricular injection of CSF (10 microliters) from cats subject to 3-10 electroshock seizure fits. Intraventricular injection of CSF (250 microliters) obtained from cats after electroshock to cats with strychnine-induced epileptic foci in the brain cortex led to the suppression of the epileptic activity. The conclusion was made that different ways of antiepileptic system activation cause the accumulation of endogenous antiepileptic substances in CSF.     

α-Guanidinoglutaric Acid, an Endogenous Convulsant, as a Novel Nitric Oxide Synthase Inhibitor

Abstract: The effects of α-guanidinoglutaric acid (GGA), the levels of which were increased in the cobalt-induced epileptic focus tissue in the cerebral cortex of cats, on brain nitric oxide synthase (NOS) activity were observed. GGA inhibited NOS activity in a linear mixed manner ( K _i = 2.69 µ M ) and was as effective as N ^G-monomethyl- l -arginine (MeArg; K _i = 3.51 µ M ), a well-known NOS inhibitor. Although MeArg was synthesized by substituting the guanidino nitrogen of l -arginine (Arg), GGA was a non-guanidino nitrogen-substituted guanidino compound. On the other hand, Arg, which is an endogenous NOS substrate, elevates the threshold of seizures induced by GGA. There is evidence that GGA is an endogenous, potent, and non-guanidino nitrogen-substituted NOS inhibitor and that suppression of nitric oxide biosynthesis may be involved in GGA-induced convulsions. Therefore, GGA may be a useful tool in elucidating the chemical nature of NOS and the physiological function of nitric oxide.     

Enhanced Susceptibility to Spontaneous Seizures of Noda Epileptic Rats by Loss of Synaptic Zn2+

Zinc homeostasis in the brain is associated with the etiology and manifestation of epileptic seizures. Adult Noda epileptic rats (NER, >12-week-old) exhibit spontaneously generalized tonic-clonic convulsion about once a day. To pursue the involvement of synaptic Zn²⁺ signal in susceptibility to spontaneous seizures, in the present study, the effect of zinc chelators on epileptogenesis was examined using adult NER. Clioquinol (CQ) and TPEN are lipophilic zinc chelotors, transported into the brain and reduce the levels of synaptic Zn²⁺. The incidence of tonic-clonic convulsion was markedly increased after i.p. injection of CQ (30–100 mg/kg) and TPEN (1 mg/kg). The basal levels of extracellular Zn²⁺ measured by ZnAF-2 were decreased before tonic-clonic convulsion was induced with zinc chelators. The hippocampal electroencephalograms during CQ (30 mg/kg)-induced convulsions were similar to those during sound-induced convulsions in NER reported previously. Exocytosis of hippocampal mossy fibers, which was measured with FM4-64, was significantly increased in hippocampal slices from CQ-injected NER that did not show tonic-clonic convulsion yet. These results indicate that the abnormal excitability of mossy fibers is induced prior to epileptic seizures by injection of zinc chelators into NER. The incidence of tonic-clonic convulsion induced with CQ (30 mg/kg) was significantly reduced by co-injection with aminooxyacetic acid (5–10 mg/kg), an anticonvulsant drug enhancing GABAergic activity, which did not affect locomotor activity. The present paper demonstrates that the abnormal excitability in the brain, especially in mossy fibers, which is potentially associated with the insufficient GABAergic neuron activity, may be a factor to reduce the threshold for epileptogenesis in NER.     

Tissue Distribution, Metabolism, Anticonvulsant Efficacy, and Effect on Brain Amino Acid Levels of the Glia-Selective γ-Aminobutyric Acid Transport Inhibitor 4,5,6,7-Tetrahydroisoxazolo[4,5-c]pyridin-3-ol in Mice and Chicks

Using tritium-labelled 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol (THPO) its tissue distribution and metabolism were investigated in adult mice and 4-day-old chicks after systemic administration of the drug. It was found not to be significantly metabolized in the brain since metabolites of THPO corresponding to only approximately 8% of the parent compound could be detected 30 min after administration of the drug intramuscularly in mice. In the liver, however, THPO was found to be metabolized to a considerable extent. In chicks THPO metabolites were found in the brain but they accounted for less than 35% of the radioactivity. The brain concentration of THPO in mice and chicks corresponded to respectively 10 and 50% of the dose injected intramuscularly and the tissue level was essentially constant for at least 3 h after injection. Following systemic administration of THPO to mice and chicks the contents of aspartate, glutamate, glutamine, and gamma-aminobutyric acid (GABA) in whole brain and in synaptosomes was determined. It was found that only GABA contents were affected being increased in synaptosomes from mice and decreased in whole brain in chicks. Doses of THPO, which in chicks but not in mice led to brain levels that were sufficient to inhibit glial GABA uptake, were found to protect chicks but not mice against isonicotinic acid hydrazide-induced seizures. The findings are compatible with the notion that THPO exerts its anticonvulsant activity by inhibition of astrocytic GABA uptake.     

Glutathione and gamma-glutamyl transpeptidase in the adult female rat brain after intraventricular injection of LHRH and somatostatin

Glutathione content and glutamyl transpeptidase activity in different regions of adult female rat brain were determined at 10 and 30 min following intraventricular injection of LHRH and somatostatin. Hypothalamic glutathione levels were significantly elevated at 10 and 30 min after a single injection of a 0.1 micrograms dose of LHRH. On the contrary, glutathione levels significantly decreased in the hypothalamus, cerebral cortex and cerebellum at 10 and 30 min after 0.5 or 1 microgram dose. However, significant decrease in brain stem glutathione was evident at 30 min after 0.5 microgram and 10 min after the 1 microgram dose. Somatostatin at doses of 0.5 microgram and 1 microgram significantly decreased glutathione levels in all four brain regions both at 10 and 30 min following injection into the 3rd ventricle. Gamma-glutamyl transpeptidase activity in the hypothalamus and cerebral cortex was significantly elevated after intraventricular injection of LHRH. However, a significant increase in gamma-glutamyl transpeptidase activity in cerebellum and brain stem was seen only with 0.5 and 1 micrograms doses of LHRH. Somatostatin also significantly increased gamma-glutamyl transpeptidase activity in hypothalamus, cerebral cortex, brain stem and cerebellum. The decrease in glutathione levels with corresponding increase in gamma-glutamyl transpeptidase activity after intraventricular administration of LHRH and somatostatin suggests a possible interaction between glutathione and hypothalamic peptides.     

Epilepsy-like convulsive seizures induced by cholera toxin administration into amygdaloid complex and lateral ventricle

Epilepsy-like convulsive seizures have been induced by cholera toxin administration into the rat amygdaloid complex and lateral ventricle. Between the 8th and 48th h following the administration, rhythmic spike discharges (1–3 spikes/s) were electroencephalographically observed bilaterally in the amygdaloid complexes, and rats exhibited abnormal behaviors such as running, jumping, tail lifting, rearing, vocalization, aggressive behavior, facial twitching and increased salivation. During these stages, high voltage spikes were intermittently observed with generalized convulsive seizures. Duration of the seizure was 1–2 min and the incidence was 0–6 times/h. At 48 h after the administration or thereafter, convulsive seizures disappeared and electroencephalographic abnormalities were gradually normalized. Occasional rhythmic spike discharges, however, were observed more than 168 h after the administration. Intraventricularly administered cholera toxin also induced the same type of convulsive seizures. Cyclic AMP content in the rat cerebrum from toxin-treated animals was significantly higher than that found in controls. The present results clearly indicate that cholera toxin administered intraventricularly as well as into the amygdaloid complexes of the rats induces epileptic attack-like convulsive seizures 8–48 h after the administration and this effect of the toxin is most likely to be related to the increase of cerebral cyclic AMP content.     

褪黑素对谷氨酸钠致痫大鼠海马5-羟色胺水平的影响

目的观察褪黑素(Melatonin,MT)对谷氨酸钠(Glutamate,Glu)致痫大鼠海马5-羟色胺(5-hydroxytryptamine,5-HT)水平的影响,研究其抑制癫痫的作用机制。方法40只健康雄性SD大鼠随机分为4组(每组10只),分别为生理盐水对照组(NS组);谷氨酸钠致痫组(Glu组);褪黑素 谷氨酸钠组(MT Glu组);Luzidole 褪黑素 谷氨酸钠组(Luz MT Glu组)。观察并记录大鼠行为学及脑电图改变,用免疫组织化学方法检测大鼠海马内5-HT含量变化。结果行为学观察和EEG显示,NS组无痫样发作和痫样放电,Glu组和Luz MT Glu组痫样发作重(Ⅲ-Ⅴ级),脑电图显示频发高幅的痫样波,TM Glu组无或仅有轻微发作(0-Ⅱ级),脑电图上无或偶见散在单个微小痫样波;免疫组织化学分析结果显示,Glu组和Luz MT Glu组大鼠海马内5-HT含量与对照组比较均减少,差异性明显(P<0.05),MT Glu组较Glu组和Luz MT Glu组5-HT含量升高,差异性明显(P<0.05)。结论MT对谷氨酸钠致痫大鼠痫样发作程度、痫样放电有抑制作用,其机制之一是经由其特异性的膜受体,通过某种机制增强5-HT作用,进而发挥抑痫效应。     

State of the antioxidant system during induction in rats of primary generalized epileptic activity

Antioxidation system in the brain and blood of rats with generalized bemegride-induced epileptic activity was studied. Antioxidation enzyme activity (superoxide dismutase, glutathione peroxidase and glutathione reductase) and alpha-tocopherol content were determined at an early convulsive stage, immediately after generalized seizures and 10-15 min after seizure. Antioxidation enzyme activity and alpha-tocopherol level in the brain homogenate and blood remained unchanged at any stages of investigation. It is suggested that the increased level of lipid peroxidation products in the brain and blood of rats upon the development of bemegride-induced epileptic activity is not related to the decrease in antioxidation system activity. The effect is mediated by the activation of the reaction initiating free radical brain lipid transformations.     

Diazepam and chlormethiazole attenuate the development of hyperthermia in an animal model of the serotonin syndrome

The serotonin (5-HT) syndrome is the most serious toxic interaction of antidepressants, but no pharmacotherapy has yet been established. In the present study, we created an animal model of the 5-HT syndrome by intraperitoneally injecting rats with clorgyline (2 mg/kg) and 5-hydroxy-L-tryptophan (5-HTP) (100 mg/kg) and evaluated the effectiveness of potent 5-HT(2A) receptor antagonists and GABA-enhancing drugs, including diazepam and chlormethiazole. The rectal temperature of the rats was measured, and the noradrenaline (NA) and 5-HT levels in the anterior hypothalamus were measured by microdialysis. In the group pre-treated with saline, the rectal temperature increased to more than 40 degrees C, and all of the animals died within 90 min after administration. Pre-treatment with potent 5-HT(2A) receptor antagonists prevented the development of hyperthermia and death in the rats. Pre-treatment with diazepam, 10 and 20mg/kg, and chlormethiazole, 50 and 100mg/kg, attenuated the development of hyperthermia. Although neither of these drugs completely prevented the rats from dying, they prolonged their survival time. Regardless of the type of therapeutic agents, the concentration of 5-HT increased to about 1100-fold the pre-administration level. The NA levels in the saline group increased to about 16-fold the pre-administration levels, but the increase was significantly lower in the rats that survived as a result of drug therapy. These results suggest that GABA-mimetic drugs may be effective against the 5-HT syndrome, although they have a somewhat weaker effect than the potent 5-HT(2A) receptor blockers, and that not only is 5-HT activity increased in the brain in the 5-HT syndrome, but the NA system is also enhanced.     

Plasma free 5-hydroxytryptamine (5-HT): Evidence of an increase induced by LM 5008, a potent 5-HT uptake inhibitor

When 5-HT platelet uptake was inhibited in rats by single or repeated oral administration of 4-[2-(3-indolyl)ethyl]piperidine (LM 5008), 5-hydroxy-indole-acetic acid (5-HIAA) and 5-HT platelet concentration decreased. An oral administration of LM 5008 (10 mg/kg) to rats whose platelets were previously labeled with tritiated 5-HT provoked an increase in plasma free 5-HT and 5-HIAA. The maximum rise in 5-HT occured at 15 min while that of 5-HIAA appeared later (30 min). Concurrently urinary excretion of 5-HT was dramatically increased (about 5 times the control value) which indicates that 5-HT metabolism was not stimulated. According to the similarity between blood platelets and tryptaminergic neurons, plasma free 5-HT variations appeat to reflect changes of the neurotransmitter level into the synaptic cleft. Moreover, the excess of plasma free 5-HT induced by LM 5008 could improve 5-HT effects on vascular tone and pain.     

The lactam of alpha-guanidinoglutaric acid (1-amidino-2-pyrrolidone-5-carboxylic acid)

alpha-Guanidinoglutaric acid (alpha-GGA) has been reported to occur in the cerebral cortex after epileptic seizures. No physical characteristics of alpha-GGA have been given. A practical procedure for the preparation of alpha-GGA is reported here. alpha-GGA forms a lactam in aqueous solution at 80 degrees C. It is proposed to substitute this lactam, 1-amidino-2-pyrrolidone-5-carboxylic acid (pAGlu), for pyroglutamic acid (pGlu) at the N-terminal position in neuropeptides to modify their biological characteristics. L(+)-Glutamic acid was reacted with S-methylisothiourea (I) at pH 10 in aqueous solution to form L(-)-alpha-guanidinoglutaric acid: mp 165-168 degrees C, [alpha]22D = -22.7 (C = 4, 2 M HCl). alpha-GGA reacted promptly with excess reagent to form a salt, S-methylisothiourea-alpha-guanidinoglutarate: mp 209-210 degrees C, [alpha]22D = -13.0 (C = 4, 2 M HCl). I was removed from the salt with aqueous picric acid, since I readily formed an insoluble picrate, S-methylisothiourea picrate (mp 225-228 degrees C). Alternatively, the salt was added to a cation exchange column, and the alpha-GGA was eluted with molar ammonium acetate buffer, pH 9.5. Its lactam, 1-amidino-2-pyrrolidone-5-carboxylic acid, mp 248-249 degrees C, [alpha]22D = +2.1 (C = 4, 2 M HCl), formed a picrate (mp 196-199 degrees C).     

褪黑素对谷氨酸钠致痫大鼠海马5-色胺水平的影响

目的观察褪黑素（Melatonin,MT）对谷氨酸钠（Glutamate,Glu）致痫大鼠海马5-羟色胺（5-hydroxytryptamine,5-HT）水平的影响,研究其抑制癫痫的作用机制。方法40只健康雄性SD大鼠随机分为4组（每组10只）,分别为生理盐水对照组（NS组）;谷氨酸钠致痫组（Glu组）;褪黑素＋谷氨酸钠组（MT＋Glu组）;Luzidole＋褪黑素＋谷氨酸钠组（Luz＋MT＋Glu组）。观察并记录大鼠行为学及脑电图改变,用免疫组织化学方法检测大鼠海马内5-HT含量变化。结果行为学观察和EEG显示,NS组无痫样发作和痫样放电,Glu组和Luz＋MT＋Glu组痫样发作重（Ⅲ—Ⅴ级）,脑电图显示频发高幅的痫样波,TM＋Glu组无或仅有轻微发作（0-Ⅱ级）,脑电图上无或偶见散在单个微小痫样波;免疫组织化学分析结果显示,Glu组和Luz＋MT＋Glu组大鼠海马内5-HT含量与对照组比较均减少,差异性明显（P〈0．05）,MT＋Glu组较Glu组和Luz＋MT＋Glu组5-HT含量升高,差异性明显（P〈0．05）。结论MT对谷氨酸钠致痫大鼠痫样发作程度、痫样放电有抑制作用,其机制之一是经由其特异性的膜受体,通过某种机制增强5-HT作用,进而发挥抑痫效应。     

Effects of acute and chronic administration of the serotonin1A agonist buspirone on serotonin synthesis in the rat brain

The effects of acute and chronic administration of buspirone, a serotonin 5-HT1A agonist, on the 5-HT synthesis rates in various rat brain structures were investigated using alpha-[14C]methyl-L-tryptophan (alpha-[14C]MTrp) and an autoradiographic method. In the acute treatment study, buspirone (10 mg/kg) was injected subcutaneously 30 min before alpha-[14C]MTrp administration (30 microCi over 2 min) into a femoral vein. In the chronic treatment study, buspirone was given in a sustained fashion (10 mg/kg/day) for 14 days using an osmotic minipump implanted subcutaneously. Rats were killed 60 and 150 min after alpha-[14C]MTrp administration (two-time point method). A single dose of buspirone induced a significant decrease of 5-HT synthesis throughout the brain with the exception of the pineal body. However, the chronic treatment with buspirone did not induce significant differences in 5-HT synthesis in the brain. There was no significant difference in plasma free tryptophan concentration between any of the groups. The unaltered 5-HT synthesis rates in the chronic treatment study likely reflect a normalization of this parameter due to a desensitization of 5-HT1A autoreceptors on the cell body of 5-HT neurons, which has been previously shown to occur following long-term treatment with 5-HT1A agonists.     

The γ-Aminobutyrate Content of Nerve Endings (Synaptosomes) in Mice After the Intramuscular Injection of γ-Aminobutyrate-Elevating Agents: A Possible Role in Anticonvulsant Activity

Abstract: The intramuscular administration of L-cycloserine, gabaculine, and aminooxyacetic acid caused significant, time-dependent increases in the γ-aminobutyric acid (GABA) content of both whole brain and synaptosomalenriched preparations obtained from the tissue, a linear relationship being observed between the two parameters. In contrast, the administration of hydrazine resulted in a large increase in whole brain GABA level, with little change in the synaptosomal GABA content. The key factor in these different responses appeared to be the degree of inhibition of glutamic acid decarboxylase by the drugs. Pretreatment of mice with the GABA-elevating agents resulted in a delay in the onset of seizures, which was related directly to the increase in synaptosomal GABA content. Although the seizures were delayed, they occurred while the GABA content of nerve endings (synaptosomes) was above that in preparations from untreated animals. The decrease in GABA content at the onset of seizures, expressed as a percentage of the level at the time of injection of the convulsant agent, was, however, reasonably constant. A hypothesis to explain these results is proposed.     

Correlation of behavioral and neurochemical effects of acute administration of cocaine in rats.

Effects of cocaine were investigated on spontaneous motor activity (SMA) and stereotypy as well as on the concentrations of norepinephrine (NE), dopamine (DA), serotonin (5-HT) and acetylcholine (ACh) in the discrete brain areas, such as the caudate nucleus (CN), diencephalon-midbrain (DM) and pons-medulla (PM) in rats up to 90–120 min following its injection in single doses (15–20 mg/kg, i.p.). After cocaine administration, the SMA was increased usually reaching its peak between 10–20 min, and then decreased gradually. Stereotypy and its components gradually increased to their maximum at about 50–60 min and remained at that level during rest of 120 min sessions. NE levels slightly increased in the DM and PM at 10 min post-drug after which they were decreased at 20 min. DA levels in the CN and DM were increased markedly at 20 min post-drug and decreased at 40 min. 5-HT levels in DM and PM decreased gradually up to 20 min, then began to increase. ACh level in the CN was gradually increased at 40 min and then decreased. It appears that cocaine-induced hyperactivity and stereotypy followed release of NE and DA after their accumulation in the respective brain areas.     

癫痫病人脑电信号的奇异谱

癫痫是一种常见的神经系统疾患,其唯一客观证据为脑电图的癫痫样发放。在癫痫发作间期,仅有偶发的很难辨别的癫痫样放电,为了正确诊断癫痫病,往往需要医生长时间监测病人的脑电信号,在对脑电信号进行相空间重构,进而对其进行奇异系统分析,发现癫痫病人无论在癫痫发作前、发作中、发作后,其脑电信号的奇异谱曲线不存在噪声平台,明显区别于正常人。是否可以认为脑电信号的奇异谱正代表着大脑的一种基本状态,癫痫患者在未发作时,大脑的基本状态已经处于异常。无论如休,奇异系统分析方法使得可以利用很短的一段脑电数据诊断癫痫。无疑为癫痫病人的临床诊断提供了一条简单、有效的途径。     

Effects of acute and chronic administrations of phencyclidine on the levels of serotonin and 5-hydroxyindoleacetic acid in discrete brain areas of mouse

The effects of phencyclidine (PCP) on the levels of serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in discrete brain areas of mouse were investigated. Following a single administration, PCP significantly increased at 60 min the level of 5-HT but not 5-HIAA in the cortex. However, acute administration of PCP induced no changes of 5-HT and 5-HIAA levels in other brain areas investigated. On the other hand, chronic treatment of PCP produced a significant increase the striatal 5-HT and 5-HIAA levels by about 30% and 20%, respectively. These increased levels were gradually returned to the control levels, and there was no difference of these levels between the control group and the 48 hr withdrawal group. The changes of 5-HT level in the hypothalamus were similar to those in the striatum. These results suggest that the pharmacological actions of PCP and tolerance development to PCP may be related to the functional changes of serotonergic neuronal activity.     

Acute and chronic effects of citalopram on postsynaptic 5-hydroxytryptamine(1A) receptor-mediated feedback: a microdialysis study in the amygdala

Microdialysis was used to assess the involvement of postsynaptic 5-hydroxytryptamine(1A) (5-HT(1A)) receptors in the regulation of extracellular 5-HT in the amygdala. Local infusion of the 5-HT(1A) receptor agonist flesinoxan (0.3, 1, 3 microM) for 30 min into the amygdala maximally decreased 5-HT to 50% of basal level. Systemic administration of citalopram (10 micromol/kg) increased 5-HT to 175% of basal level. Local infusion of 1 microM of the 5-HT(1A) receptor antagonist WAY 100.635 into the amygdala augmented the effect of citalopram to more than 500% of basal 5-HT level. 5-HT(1A) receptor responsiveness after chronic citalopram treatment was determined in two ways. First, by local infusion of 1 microM flesinoxan for 30 min into the amygdala, which showed a significant 63% reduction in response (area under the concentration-time curve; AUC) for the citalopram group compared to the saline group. Second, by systemic administration of citalopram (10 micromol/kg), which increased 5-HT to 350% of basal level. The effect was larger than in untreated animals, but more important, local infusion of 1 microM WAY 100.635 into the amygdala now failed to augment the effect of citalopram. Both the flesinoxan and WAY 100.635 data suggest an involvement of postsynaptic 5-HT(1A) receptor-mediated feedback in the amygdala, which diminishes following chronic citalopram treatment.     

Halogenated aromatic amino acid 3,5-dibromo-<Emphasis Type="SmallCaps">d</Emphasis>-tyrosine produces beneficial effects in experimental stroke and seizures

The effects of the halogenated aromatic amino acid 3,5-dibromo-d-tyrosine (3,5-DBr-d-Tyr) were studied in rat models of stroke and epileptic seizures caused by middle cerebral artery occlusion (MCAo) through respective intracerebral injection of endothelin-1 (ET-1) and intraperitoneal (i.p.) injection of pentylenetetrazole (PTZ). 3,5-DBr-d-Tyr was administered as three bolus injections (30 or 90 mg/kg, i.p.) starting at 30, 90, and 180 min after ET-1 administration or as a single bolus (30 mg/kg, i.p.) 15 min prior to PTZ administration. Neurological deficits and infarct volume were estimated 3 days after ET-1 administration and seizure score was assessed during the first 20 min after PTZ administration. The safety of 3,5-DBr-d-Tyr was evaluated in control animals using telemetry to measure cardiovascular parameters and immunostaining to assess the level of activated caspase-3. 3,5-DBr-d-Tyr significantly improved neurological function and reduced infarct volume in the brain even when the treatment was initiated 3 h after the onset of MCAo. 3,5-DBr-d-Tyr significantly depressed PTZ-induced seizures. 3,5-DBr-d-Tyr did not cause significant changes in arterial blood pressure, heart rate and spontaneous locomotor activity, nor did it increase the number of activated caspase-3 positive cells in the brain. We conclude that 3,5-DBr-d-Tyr, by alleviating the deleterious effects of MCAo and PTZ in rats with no obvious intrinsic effects on cardiovascular parameters and neurodegeneration, exhibits promising potential as a novel therapeutic direction for stroke and seizures.     

Correlation between brain glycogen and convulsive state in mice submitted to methionine sulfoximine

It is now well established that in epileptic patients, hypometabolic foci appear during interictal periods. The meaning and the mechanism of such an hypometabolism are as yet unclear. The aim of the present investigation was to look for a putative relationship between glucose metabolism in the brain and the genesis of seizures in mice using administration of the convulsant, methionine sulfoximine. Besides its epileptic action, methionine sulfoximine is a powerful glycogenic agent. We analyzed the epileptogenic and glycogenic effects of methionine sulfoximine in two inbred mouse strains with different susceptibility towards the convulsant. CBA/J mice displayed high response to methionine sulfoximine. The tonic convulsions appeared 5-6 h after MSO administration, without brain glycogen content variations during the preconvulsive period. These mice died of status epilepticus during the first seizure(s). Conversely, C57BL/6J mice displayed low response to MSO. The tonic and clonic seizures appeared 8 to 14 h after MSO administration with only 2% mortality. The seizures were preceded by an increase in brain glycogen content during the preconvulsive period. Moreover, during seizures, C57BL/6J mice were able to mobilize this accumulated brain glycogen, that returned to high value after seizures. The epileptic and glycogenic responses of the parental strains were also observed in mice of the F2 generation. The F2 mice that convulsed early (16%) did not utilize their small increase in brain glycogen content, and resembled CBA/J mice; while the F2 mice that seized tardily (24%) increased their brain glycogen content before convulsion, utilized it during convulsions, and resembled C57BL/6J mice. Sixty percent of the F2 mice presented an intermediate pattern in epileptogenic responses to the convulsant. These data suggest a possible genetic link between the two MSO effects, epileptiform seizures and increase in brain glycogen content. The increase in brain glycogen content and the capability of its mobilization during seizures could delay the seizure's onset and could be considered a "resistance factor" against the seizures.