CHANGES IN GLYCOGEN PHOSPHORYLASE ACTIVITY AND GLYCOGEN LEVELS OF MOUSE CEREBRAL CORTEX DURING CONVULSIONS INDUCED BY HOMOCYSTEINE

Glycogen phosphorylase activity and glycogen levels were investigated in the cerebral cortex of mice of two different strains under the influence of homocysteine. Control levels of glycogen and total phosphorylase activity (i. e. activity in the presence of 1 mM-AMP) were higher in the inbred strain A, whereas a higher proportion of phosphorylase in its active form (activity without 5′-AMP) was obtained in the ICR strain (probably due to slower fixation of brain in this strain). Changes occurring after the administration of homocysteine were similar in both strains. With the onset of first clonic seizures a marked increase of phosphorylase a occurred (increase 99 per cent in strain A and 46.5 per cent in ICR, respectively). During the latter phase of tonic seizures active phosphorylase a did not significantly differ from control values. Five minutes after the end of a tonic seizure, i. e. when partial recovery could already be observed, a marked decrease of active phosphorylase a in comparison with control values, was evident (decrease against control values of 45.5 per cent in strain A and 30.5 per cent in ICR, respectively). The total phosphorylase activity was not affected in strain A, whereas a slight increase during clonic seizures was seen in the ICR strain. In accordance with the enhanced activation of phosphorylase at the onset of clonic seizures, a marked decrease in glycogen levels (35-50 per cent) was observed in both strains of mice. This decrease persisted even during the 5 min recovery period. When seizures were prevented by Na phenobarbital or glycine, the activation of phosphorylase was either completely prevented (by a non-anaesthetic dose of phenobarbital) or reduced (by glycine). The present results have demonstrated that changes in glycogen metabolism occurring during homocysteine seizures differ distinctly from those previously found during seizures induced by methionine sulphoximine, a substance structurally related to homocysteine.     

Ontogeny of susceptibility to the convulsant, Ro 5-4864, and its relationship to audiogenic seizure susceptibility in inbred mice

The postnatal development of susceptibility to the convulsant effects of Ro5-4864 (4'-chlorodiazepam) was characterized in two inbred mouse strains (DBA/2J and BALB/c ByJ) which as adults differ markedly in their response to this convulsant. Onset of susceptibility to a dose of Ro5-4864 which caused a high frequency of clonic seizures in adults was observed at 10 days of age in DBA/2 mice, but not until 35 days in BALB/c By mice. At 14 days of age an abrupt increase in susceptibility to Ro5-4864-induced tonic seizures was found in DBA/2 but not BALB/c By mice. Both the peak of tonic seizure susceptibility (21 days) and the time course of its subsequent age-dependent decline closely paralleled the change in audiogenic seizure susceptibility in the DBA/2 strain. PK11195 (40 mg/kg) blocked Ro5-4864 (25 mg/kg)-induced, age-dependent tonic seizures but had no effect on clonic seizure induction in the same mice. These observations establish that both the susceptibility to Ro5-4864 in adult mice and the postnatal time course for development of susceptibility to this convulsant are inherently different in these two strains of mice. The lack of coincidence between the developmental onset of susceptibility to Ro5-4864-induced seizures and the onset of supersensitivity to Ro5-4864-induced tonic seizures during the period of peak audiogenic seizure susceptibility in DBA/2 mice implies that more than one neurochemical mechanism is involved in the ability of Ro5-4864 to induce seizures in this strain. However, the blockade of Ro5-4864-induced tonic seizures by PK11195 suggests that peripheral type benzodiazepine receptors may mediate this effect.     

The convulsive effects of dopamine sulfate conjugates in rat brain

The administration of 40 μg or more of dopamine sulfate conjugate, the predominant form of dopamine in the peripheral nervous system, into the left lateral ventricle of Sprague Dawley rat led to seizures. The severe and generalized convulsions with clonic extension of forelimbs and hindlimbs occurred within 2–6 minutes of the injection, and lasted for 10–20 minutes. No convulsion was observed when dopamine, norepinephrine, nitrocatechol sulfate or a hydrolyzed solution of dopamine sulfate conjugate were similarly injected. The dopamine sulfate- induced seizures were not blocked by pretreatment of rats with phenoxybenzamine, metoclopramide or haloperidol but were reduced by propranolol and suppressed by diazepam. Dopamine sulfate conjugates which were recently detected in discrete areas of rat brain and in human cerebrospinal fluid may thus have certain function in the brain different from that of free dopamine.     

Anticonvulsant effects of some inhibitory neurotransmitter amino acids

The anticonvulsive effects of GABA, taurine, and glycine were investigated on several chemically-induced and genetic seizure models. Intravenous injections of either GABA, taurine, or glycine provided protection against 3-mercaptopropionic acid (MPA)-induced convulsions in adult Swiss mice. GABA was partially effective against isonicotinic acid hydrazide and was without effect against bicuculline-induced convulsions bProlonged administration of glycine prevented MPA-induced convulsions but not electrically induced seizures or seizures induced by strychnine or metrazol.Intragastric glycine protected young audiogenic seizure-susceptible DBA/2 mice against all three phases of sound-induced convulsions (wild running, clonic and tonic seizure), but GABA and taurine provided little or no protection. With increase of glycine, the cerebral levels of glutamine and serine also increased, but that of glutamic acid decreased. The endogenous glutamic and glycine levels were slightly higher in the brains of the audiogenic seizure-susceptible DBA/2 mice than in that of the resistant BALB/Cy strain.     

Inhibition of electroshock-induced seizures by cholecystokinin-related peptides in mice

The effects of several doses of cholecystokinin octapeptide sulphate ester (CCK-8-SE) and nonsulphated cholecystokinin octapeptide (CCK-8-NS), and two CCK-related peptide analogues Ac-Thr5-caerulein, and nonsulphated Ac-Thr5-caerulein were investigated on electroshock-(ES)-induced seizures after intraperitoneal administration in mice. As parameters, the duration of the tonic and clonic phase of the fit, and those of postictal coma and behavioural depression were measured. CCK-8-SE decreased the duration of the clonic phase; its highest dose, 3.2 mumol/kg, shortened the coma. CCK-8-NS antagonized only slightly the clonic phase of seizure. Ac-Thr5-caerulein did not influence ES-induced seizures in any dose, only increased the duration of behavioural depression. Similarly to CCK-8-NS, the nonsulphated form of Ac-Thr5-caerulein inhibited selectively the clonic phase of seizures. The reference drugs, diazepam and phenobarbital, antagonized dose-dependently and most effectively the tonic phase of ES-induced seizures, but in much higher doses than did the CCK-related peptides. Besides, diazepam increased and phenobarbital decreased the duration of postictal coma. The results showed that the tested CCK-related peptides inhibit prevalently the clonic phase of ES-induced seizures after peripheral administration.     

Role of NMDA and AMPA glutamate receptors in the mechanism of korazol-induced convulsions in mice

The potency of mono- and dikationic derivatives of adamantane and phenylcyclohexyl to prevent seizures induced in mice by intraperitoneal administration of 80 mg/kg pentylenetetrazol (corazol), was studied. Monocationic derivatives of phenylcyclohexyl, being the selective channel blockers of NMDA glutamate receptors, as well memantine and MK-801 in micromolar concentrations, prevented both clonic and tonic components of corazol-induced convulsions. Their dicatonic derivatives which are channel blockers of NMDA and AMPA types of glutamate receptors, failed to prevent clonic seizures but at submicromolar concentrations prevented the tonic extensions provoked by corazol. Evidently, convulsive action of corazol originating from suppression of GABA-ergic inhibition is realized through activation of glutamergic synaptic transmission, and NMDA receptors are mainly involved in genesis of clonic seizures whereas activation of AMPA receptors is important for the tonic component of the corazol-induced syndrome.     

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.     

Brain Adrenoceptor Binding Sites in Mice Susceptible (DBA/2J) and Resistant (C57 Bl/6) to Audiogenic Seizures

We have examined if the age-related susceptibility of DBA/2J mice to audiogenic seizures is the result of an abnormality in the number or sensitivity of brain adrenoceptors. The binding of alpha 1-, alpha 2-, and beta-adrenoceptor ligands to membranes prepared from whole brain or regions of brain of DBA/2J mice was measured at various ages, corresponding to the periods before, during, and after the maximal sensitivity to audiogenic seizures. For comparison, we have studied concurrently age-matched C57 Bl/6 mice, a strain resistant to audiogenic seizures at all ages. There was no difference in the binding of alpha 2- or beta-adrenoceptor ligands to whole brain membranes between the two strains of mice at any age. The maximal number of alpha 1-adrenoceptor binding sites was lower in whole brains of DBA/2J mice than of C57 Bl/6 mice at all ages studied except 13-15 days of age. The differences were small (maximally 17%) but were statistically significant at 21-23 days of age, the time of maximal sensitivity of DBA/2J mice to audiogenic seizures. No difference between the two strains was found in the number or affinity of alpha 1- or alpha 2-adrenoceptor binding sites at any age in any of the brain regions studied. The age-related susceptibility of DBA/2J mice to audiogenic seizures is not the result of an abnormality in number or sensitivity of alpha 2- or beta-adrenoceptor binding sites, but a reduced number of alpha 1-adrenoceptor binding sites may be involved.     

Long lasting effect of a single audiogenic seizure on GABA turnover rates and steady-state levels

GABA turnover rates (TOR) and steady-state levels (SSL) were determined, 16–18 h after a single acoustic stimulation, in 15 brain areas of 3 mouse sublines. Each subline differs in its response to an acoustic stimulation (Rb1 mice are clonic-tonic seizure-prone, Rb2: clonic seizure-prone, Rb3: seizure-resistant). TOR and SSL were compared to those of unstimulated control mice and to those of repeatedly stimulated mice of the same subline. Following a single acoustic stimulation long-lasting alterations of GABA metabolism, mainly large alterations of GABA TOR, are observed. Most of the effects elicited after repeated stimulations, either on SSL or TOR, are not those of the last stimulation and repeated seizures (and/or stimulations) strengthen the effect of a single one. It appears that, for each of the Rb sublines, a specific and quite simple profile of the alterations of GABA metabolism in response to a single or repeated audiogenic seizures (and/or stimulations) can be given. The global analysis through the correlation of GABA TOR and SSL gives an indication that the alterations of the parameters of the correlation observed are to be allocated to the audiogenic seizures. Furthermore the tonic and clonic components of the audiogenic seizures can be distinguished.     

Role of the brain-stem reticular formation in tonic-clonic seizures: lesion and pharmacological studies

Bilateral lesions of the pontine tegmentum involving the superior cerebellar peduncles and the nucleus reticularis pontis oralis have been shown to attenuate the tonic components of maximal seizures induced by electroshock, sound stimulation (audiogenic), or pentylenetetrazol, although having no effect on clonus in three separate seizure models. The pontine tegmental lesion also abolishes the clonus of minimal audiogenic seizures that have a motor pattern different from that of other clonic models, and are believed to originate in the brain stem. The preponderant suppression of tonus by the pontine tegmental lesion as well as the inhibition of clonus in audiogenic seizures is strikingly similar to the effects of phenytoin in these same seizure models. The findings presented are consistent with the hypothesis that the pontine reticular formation (RF) plays a key role in the generation and/or expression of tonic convulsions. Additional findings are presented that suggest that serotonin may attenuate the tonic components of maximal electroshock seizures by an action on the brain stem. Thus, it seems likely that pontine tegmental lesions as well as antiepileptic drugs and neurotransmitters with preferential effects on tonic seizures act on a common neural substrate that appears to include the brain-stem RF.     

Antiepileptic effects of ghrelin on pentylenetetrazole-induced seizures in rats

It is well known that neuropeptide Y (NPY) and gamma-aminobutyric acid (GABA) exert antiepileptic effects in animal models. It has recently been shown that ghrelin neurons increase the activities of GABA and NPY in the brain. Therefore it can be said that ghrelin is an antiepileptic agent. In this study we aimed to investigate the antiepileptic effect of ghrelin in an acute experimental epilepsy model in pentylenetetrazole (PTZ) injected rats. Adult male Wistar albino rats were divided into a control group and four experimental groups with seven rats in each group. In order to generate epileptic seizures, PTZ (50mg/kg) was injected intraperitoneally. The experimental groups received intraperitoneal injections of ghrelin at doses of 20, 40, 60 and 80microg/kg 30min before PTZ injection. After PTZ injection, the latencies were separated into three components: first myoclonic jerk, generalized clonic seizures and tonic generalized extension. The injection of 50mg/kg PTZ-induced epileptic seizures in the control group. The onset times of the three characteristic behavioral changes were significantly delayed and the duration of tonic generalized extension was diminished by dose-dependent ghrelin administration. Our results demonstrated that ghrelin suppresses the onset time of PTZ-induced seizures. In the light of our current knowledge, it seems that ghrelin may be considered as an antiepileptic drug.     

Angiotensin peptides modulatory system: how is it implicated in the control of seizure susceptibility?

Accumulated studies support the concept that angiotensin peptides, ANG II, ANG III, and ANG IV act as neurotransmitters or neuromodulators in specific neuronal pathways in the brain stem, the hypothalamus, and the forebrain. They have been implicated in the regulation of several physiological processes, particularly in excitable brain structures that express high concentration of their receptors. With the help of pharmacological approaches it was shown that angiotensin peptides appear to be anticonvulsant in a variety of experimental seizure models. Thus, ANG II increases the threshold for pentylenetetrazol (PTZ)-, bicuculline-and picrotoxin-induced seizures in mice. It also attenuates the intensity of clonic seizures evoked by PTZ and 3-mercaptopropionic acid and is effective in the maximal electroshock test. Furthermore, ANG II, ANG III, and ANG IV protect against the clonic convulsions in the PTZ kindling model of epilepsy in mice. From the accumulated results it could be assumed that the angiotensin peptides appear to realize their effects acting directly on their receptors (AT(1), AT(2) and AT(4)) and through close interaction with different neurotransmitter/neuromodulator systems as dopamine (DA)-, gamma-aminobutyric acid (GABA)-and adenosine. This may contribute to a new potential use of angiotensin drugs either alone or in combination with other neuroprotective agents acting through the above mentioned systems, thus providing a more rational strategy for the treatment of neurodegenerative disorders such as epilepsy.     

Modulation of benzodiazepine by lysine and pipecolic acid on pentylenetetrazol-induced seizures

L-lysine, an essential amino acid for man and animals, and its metabolite pipecolic acid (PA) have been studied for their effects on pentylenetetrazol (PTZ)-induced seizures in mice. L-Lysine or L-PA i.p. significantly increased clonic and tonic latencies in a dose-dependent manner against 90 mg/kg PTZ-induced seizures. L-Lysine but not L-PA enhanced the anticonvulsant effect of diazepam (DZ) (0.2 mg/kg). L-PA (0.1 mmol/kg) i.c.v. showed a slight decrease in clonic latency; it did not enhance the antiseizure activity of DZ; it caused seizures at 0.6 mmol/kg. D-PA (0.1 mmol/kg) i.c.v. displayed an opposite effect compared to its L-isomer. The anticonvulsant effect of L-lysine in terms of increase in seizure latency and survival was even more amplified when tested with a submaximal PTZ concentration (65 mg/kg). L-Lysine showed an enhancement of specific 3H-flunitrazepam (FZ) binding to mouse brain membranes both in vitro and in vivo. The possibility of L-lysine acting as a modulator for the GABA/benzodiazepine receptors was demonstrated. Since L-PA showed enhancement of 3H-FZ binding only in vitro but not in vivo, the anticonvulsant effect of L-PA may not be linked to the GABA/benzodiazepine receptor.     

Alteration of neurotensin receptors in MPTP-treated mice.

We examined the sequential changes in neurotensin receptors in the striatum and substantia nigra of mouse brains lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by receptor autoradiography, in comparison with the alterations in dopamine uptake sites. The mice received four intraperitoneal injections of MPTP (10 mg/kg) at 1-h intervals and then the brains were analyzed at 6 h and 1, 3, 7, and 21 days after the treatments. [3H]Neurotensin and [3H]mazindol were used to label neurotensin receptors and dopamine uptake sites, respectively. [3H]Neurotensin binding was significantly decreased in the striatum from 6 h to 21 days after MPTP treatment. In the substantia nigra, pars reticulata also showed a significant decrease in [3H]neurotensin binding from 3 to 21 days post-MPTP treatment. However, no significant change in [3H]neurotensin binding was observed in the pars compacta even after 21 days. On the other hand, [3H]mazindol binding was markedly decreased in the striatum and substantia nigra from 6 h to 21 days after MPTP treatment. These results indicate that neurotoxin MPTP can produce a severe decrease in neurotensin receptors and dopamine uptake sites in the striatum and substantia nigra of mice. Thus, our findings provide evidence that the dysfunction in neurotensin receptors may be involved in the degenerative processes causing Parkinson's disease.     

Elemental anomalies in the hippocampal formation after repetitive electrical stimulation: an X-ray fluorescence microscopy study

Our previous studies carried out on the pilocarpine model of seizures showed that highly resolved elemental analysis might be very helpful in the investigation of processes involved in the pathogenesis of epilepsy, such as excitotoxicity or mossy fiber sprouting. In this study, the changes in elemental composition that occurred in the hippocampal formation in the electrical kindling model of seizures were examined to determine the mechanisms responsible for the phenomenon of kindling and spontaneous seizure activity that may occur in this animal model. X-ray fluorescence microscopy was applied for topographic and quantitative analysis of selected elements in tissues taken from rats subjected to repetitive transauricular electroshocks (ES) and controls (N). The detailed comparisons were carried out for sectors 1 and 3 of the Ammon’s horn (CA1 and CA3, respectively), the dentate gyrus (DG) and hilus of DG. The obtained results showed only one statistically significant difference between ES and N groups, namely a higher level of Fe was noticed in CA3 region in the kindled animals. However, further analysis of correlations between the elemental levels and quantitative parameters describing electroshock-induced tonic and clonic seizures showed that the areal densities of some elements (Ca, Cu, Zn) strongly depended on the progress of kindling process. The areal density of Cu in CA1 decreased with the cumulative (totaled over 21 stimulation days) intensity and duration of electroshock-induced tonic seizures while Zn level in the hilus of DG was positively correlated with the duration and intensity of both tonic and clonic seizures.     

Protective effects of long-term probiotic mixture supplementation against pentylenetetrazole-induced seizures,inflammation and oxidative stress in rats

Emerging evidence indicates that dysbiosis of gut microbiota plays an important role in epilepsy, although the underlying mechanisms remain unclear due to the complex nature of both microbial composition and pathophysiology of epilepsy. We investigated effects of long-term probiotics supplementation on epileptic seizures, and inflammatory and oxidant/antioxidant biomarkers in a pentylenetetrazole(PTZ)-induced seizure model in rats.Male Wistar weaner-rats were divided into four groups. The first two groups received 1 ml/day saline solution, while the other groups received 0.05 mg/1ml/day vehicle or 109cfu/1ml/day probiotic-mixture, respectively, for 60 days by gavage. Seizure was induced by a single convulsive dose of PTZ. Seizures were evaluated using Racine's scale. Concentrations of pro-inflammatory cytokines in plasma and brain tissue were determined using ELISA, while oxidant/antioxidant biomarkers were measured using an automated-colorimetric method.Probiotics supplementation exhibited anticonvulsant effects against PTZ-induced seizures by retarding onset-times of both myoclonic-jerk and generalized tonic–clonic seizure, and by shortening duration of generalized tonic–clonic seizure. Additionally, it alleviated PTZ-induced increases in levels of pro-inflammatory cytokines IL-1β, IL-6, and IL-17A, but not of IFNγ, in plasma and brain tissue. Moreover, it restored PTZinduced fluctuations in levels of oxidants TOS and disulfide, and of antioxidants native thiol and total thiol.Our findings suggest that long-term probiotics supplementation exhibits protective effects against epileptic seizures, and alleviates (neuro)inflammation and oxidative stress related to pathophysiology of epilepsy. A probiotic-rich diet provided from childhood may provide prophylaxis against epileptic seizures, especially in susceptible individuals, as the neonate diet represents a fundamental extrinsic factor in establishing gut microbiota.     

mGlu5 receptor deletion does not confer seizure protection to mice

Metabotropic glutamate mGlu5 receptors have been implicated in the regulation of seizures and have been suggested as a target against which discovery of novel anticonvulsants may be possible. However, the experimental literature is not consistent in reporting anticonvulsant efficacy of mGlu5 receptor antagonists. Additional assessment of this target was approached in the present study by comparing convulsions in wild-type (WT) and mGlu5 receptor null (knockout or KO) mice. Chemically induced seizures induced by a variety of mechanisms including pentylenetetrazole, N-methyl-d-aspartic acid (NMDA), cocaine, kainic acid, aminophylline, 4-aminopyridine, strychnine, and nicotine did not differentially increase clonic, clonic/tonic, or lethality in WT vs. mGlu5 receptor KO mice. The mGlu5 receptor antagonist 3-[(2-Methyl-1,3-thiazol-4-yl) ethynyl]-pyridine (MTEP) did not significantly prevent seizures induced by NMDA; in contrast, the uncompetitive NMDA receptor antagonist, dizocilpine, significantly prevented NMDA-induced seizures and lethality in both WT and KO mice. The present findings do not support the idea that mGlu5 receptors play as important a role in seizure control as previously speculated.     

Anticonvulsant activity of topiramate and phenytoin in a rat model of ischemia-induced epilepsy

Topiramate, a structurally novel anticonvulsant, and phenytoin were evaluated in a rat model of ischemia-induced epilepsy. In this model a transient global cerebral ischemia is induced by cardiac compression. By precisely controlling the experimental conditions the procedure causes reproducible neurological deficits that include audiogenic epileptic seizures. The seizures can be broadly separated into three types reflecting the degree of severity: wild running, clonic seizures, and tonic extension seizures of the forelimbs and hindlimbs. Topiramate and phenytoin blocked all three types of seizures. Calculated ED₅₀ values for topiramate 1 hr after oral administration were 8.2, 13.0 and 36.1 mg/kg for blockade of tonic extension seizures, clonic seizures and wild running, respectively. Corresponding ED₅₀ values for phenytoin were 5.0, 10.8 and 20.7 mg/kg. These results support the concept that the anticonvulsant activity of these drugs is due primarily to an ability to block the spread of seizures.     

Thioperamide, a selective histamine H3 receptor antagonist, protects against PTZ-induced seizures in mice

The effect of selective histamine H3-receptor antagonist thioperamide was studied on PTZ-induced seizures in mice. Thioperamide significantly protected clonic seizures induced by PTZ in a dose-dependent manner. The effect of thioperamide was completely countered by pretreatment with R (alpha)-methylhistamine (RAMH), a selective H3-receptor agonist suggesting that the observed effect of thioperamide was elicited by histamine H3-receptors. RAMH alone did not significantly modify PTZ seizures. The findings are consistent with a role for the histaminergic neuronal system in seizures and suggest that H3-receptors may play an important role in modulating clonic seizures induced by PTZ in mice.     

Pentylenetetrazole kindling in rats: whether neurodegeneration is associated with manifestations of seizure activity?

Structural changes in neurons and oxidative stress in hippocampus were studied in rats "tolerant" (TR) and susceptible (SR) to tonic and clonic seizures in pentylenetetrazole (PTZ) kindling. The number of normal neurons was significantly decreased in CA1 subfield of TR hippocampus after 11 injections of PTZ, while in SR neuronal cell loss was evident in CA1 and fascia dentata. In both groups, neuronal cell loss was accompanied by increase in damaged neuron number in CA4 subfield. After 21 injections of PTZ, the decrease in normal neuron number was revealed in CA1 subfield of both TR and SR, while the number of damaged neurons was above the control level in hippocampal subfields CA1 and CA4 in TR only. Glutathione level was decreased in hippocampus of both TR and SR as compared with control rats. Thus, rats tolerant to PTZ-induced convulsions demonstrated oxidative stress and neurodegeneration in hippocampus. The results suggest that, in PTZ kindling model, oxidative damage of neurons resulting in neurodegeneration in hippocampus is not directly related to the convulsive activity.