Experimental limbic seizure status epilepticus and focus resection in cats

Status epilepticus is a neurological emergency and refractory one often resulted in neurological damage or death. Since the basic mechanisms of status epilepticus was not fully understood, a surgical treatment was not attempted until now. In the present study, a surgical resection of the epileptic focus was made in experimentally induced limbic status epilepticus and influences of the surgery upon status epilepticus was discussed. Limbic status epilepticus was induced by means of kainic acid (KA) microinjection into unilateral amygdala in cats and effects of focus resection upon limbic seizure status were studied. Ten adult cats were stereotaxically operated on under pentobarbital anesthesia. Bipolar electrodes were placed in bilateral amygdala and hippocampus. An injection cannula, designed for kainic acid injection, was placed in the left amygdala. The cats were then divided into two groups. Group A (5 cats) received 0.5 microgram of KA injection into the amygdala resulted in mild limbic status. Two of them were controls and 3 of them received amygdalotomy after induction of the limbic seizure status. Group B (5 cats) received 2.0 micrograms KA injection resulted in severe limbic status. Moreover, independent spontaneous seizure activities were observed in the ipsilateral hippocampus. Two of them were controls and 3 of them were operated on. After amygdalotomy, limbic seizure stopped in the operated cats of Group A. In the operated cats of Group B, repeated seizures in the epileptogenic focus (amygdala) was completely suppressed, however, spontaneous seizures of the ipsilateral hippocampus persisted even after the surgery.(ABSTRACT TRUNCATED AT 250 WORDS)     

Limbic seizure and ibotenic acid-induced lesions of substantia innominata in cats

The substantia innominata (SI) contains a lot of cholinergic neurons and mainly project their fibers to the cerebral cortex and to the amygdala. Degenerative lesions were made in the bilateral SI and influences of these lesions upon kainic acid-induced limbic seizure were studied. Eleven adult cats were stereotaxically implanted and 2.5 micrograms of ibotenic acid (IBO) was injected into the bilateral SI in 6 cats (IBO group) and 1 microliter of phosphate buffer (PB) in 5 cats (PB group). All animals were given freedom at least 8 days to recover from the operation. Kainic acid microinjection was made into the left amygdala and electroclinical observation was done. In PB group, the limbic status was elicited and these seizures persisted for about 3 days after the KA injection. Seizures were subsided but interictal discharges were observed at the injected site of the amygdala. Then, limbic seizures reappeared within 10 days and a slowly progressive development of limbic seizure was observed. These seizures developed further. Occasionally, these limbic seizures successively developed and secondarily generalized seizures occurred once or twice a week. Otherwise, their clinical behaviors were normal during the interictal periods. In IBO group, the limbic status were elicited and lasted for about 3 days after the KA injection. Although interictal discharges reappeared at the injected site of the amygdala, successive development of the limbic seizure was not observed. The secondarily generalized seizure never occurred in the IBO group. Histopathological studies revealed circumscribed degenerative changes in the bilateral SI. The KA microinjection into the amygdala resulted stereotyped amygdaloid degenerative lesions in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Amygdaloid lesion increases the toxicity of intrahippocampal kainic acid injection and reduces the late occurrence of spontaneous recurrent seizures in rats

Spontaneous recurrent seizures (SRS) following intrahippocampal kainic acid (KA) injection have been described in a previous paper from our laboratory. The SRSs are clinically similar to the seizures induced by kindling the amygdala and we suggested that the amygdala plays a role in initiating the SRSs. Accordingly, the present paper examines the effect of amygdaloid lesions on intrahippocampal KA-treated rats. There were short- and long-term effects. (1) Short-term: the toxicity of KA was increased in lesioned animals. Status epilepticus followed by death of the animals was evoked with half of the dose required to cause the same effect in intact rats. Moreover, a gross haematuria was encountered 6–12 h after KA injection. This was not observed in non-lesioned rats even following the highest KA doses. (2) Long-term: amygdaloid lesions delayed the occurrence of the SRSs, reduced their incidence and modified their expression. In lesioned animals seizures has began with a period of tonic immobility with no sign of the masticatory movements seen in intact animals. Histological examination of the KA-induced lesions did not show any major differences between lesioned and intact animals. It is suggested that the short-term effects are due to an unspecific effect on homeostatic mechanisms, whereas the long-term ones reflect a specific involvement of the amygdala in the late appearing seizures.     

Zonisamide: Electrophysiological and Metabolic Changes in Kainic Acid-Induced Limbic Seizures in Rats

Summary: We studied the pharmacological mechanism of zonisamide (ZNS) using an electrophysiological and autoradiographical method in a limbic seizure model in rats. Limbic seizure status epilepticus was induced by a unilateral microinjection of kainic acid (KA) into the amygdala. Initially, observed seizures were limited to the side of the injected amygdala and then propagated to bilateral sensorimotor cortex. Eighty minutes after injection, secondarily generalized seizure status epilepticus was induced, with each seizure lasting ∼30 s and recurring every 5 min. ZNS 100 mg/kg was administered intravenously (i.v.) during the generalized seizure. Forty minutes after ZNS administration, epileptic activity was observed only at the KA-injected amygdalar site and spikes were not observed in the bilateral sensorimotor cortex. We studied local cerebral glucose utilization (LCGU) after ZNS or saline administration using an autoradiographical method in the same limbic seizure preparation. In the ZNS group, LCGU decreased in the ipsilateral sensorimotor cortex and hippocampus, whereas in the controls LCGU increased in these structures. On the other hand, ZNS did not suppress the epileptic activity of the primary focus and no decrease in LCGU was observed in the KA-injected amygdala. ZNS inhibited seizure propagation from the epileptogenic focus but did not suppress the epileptic activity of the focus. Our results suggest that ZNS is effective for the treatment of secondarily generalized seizure.     

Spontaneous secondarily generalized seizures induced by a single microinjection of kainic acid into unilateral amygdala in cats

Electrographic and clinical observations were made for 6 months after the injection of kainic acid (KA) solution (1 microgram in 1 microliter of phosphate buffer solution) through a chronically implanted cannula into a unilateral amygdala of freely moving and non-anesthetized cats. The control group (phosphate buffer group) showed no change during the observation period. After the injection of kainic acid, focal status epilepticus in the limbic system was observed for 3 days. Cats recovered clinically but persistent IIDs were observed at the injected site of the amygdala. These IIDs increased in amplitude and frequency and began to trigger spontaneous amygdaloid seizures. Secondary epileptogenic foci were then established in the contralateral amygdala, and amygdaloid seizures began to occur alternatively on both sides and finally trigger frequent limbic seizures from 20 to 40 days after KA injection. Spontaneous secondarily generalized seizures developed about 30 days after KA injection and occurred once or twice a week thereafter. The animals were completely normal in their behavior during the interictal phase. This is an excellent model of experimental epilepsy for the investigation of the mechanism of limbic seizure development and further study using this model will provide informations useful for the therapy of temporal lobe epilepsy in man.     

Complex partial status epilepticus induced by a microinjection of kainic acid into unilateral amygdala in dogs and its brain damage

OBJECTIVE: In order to investigate kainic acid (KA)-induced amygdaloid seizure and seizure-induced brain damage in dogs, and to compare these findings with that in other species, a KA-induced seizure model in dogs was produced. MATERIAL AND METHODS: Normal beagle dogs were used. A Teflon cannula for KA injection was inserted into the left amygdala, and cortical or depth electrodes were positioned. One week after surgery, 1.5 microg of KA was microinjected into the left amygdala. EEGs and the behavior of the animals were monitored for 2 months after KA injection. In addition, neuron-specific enolase levels in the cerebrospinal fluid (CSF-NSE) were measured intermittently. At 2 months after the injection, histopathological studies were performed. RESULTS: KA-treated dogs showed limbic seizures that started from the left amygdala within 30 min after injection. The seizures developed into complex partial status epilepticus (CPSE), and started independently from the bilateral amygdala during the CPSE. The CPSE lasted for 1-3 days, and the animals showed no spontaneous seizures during the 2-month observation period. A significant increase in CSF-NSE was observed immediately after CPSE. Histopathologically, extensive necrosis, which formed large cavity lesions, was observed around the bilateral amygdala. SUMMARY: A microinjection of KA into unilateral amygdala in dogs induced CPSE. The seizures elicited independently from bilateral amygdala, and bilateral limbic structures suffered extensive injury. In addition, CSF-NSE was demonstrated as a useful marker of acute neuronal damage.     

Damage induced by systemic kainic acid in rats is dependent upon seizure activity--a behavioral and morphological study

Kainic acid (KA) was injected intraperitoneally into rats at a dose (9 mg/kg) which produced status epilepticus in approximately 50% of the animals. Rats were categorized into groups that displayed status epilepticus, partial seizures or no effect in the 4 hr following kainic acid injection. Behavioral and morphological changes were characterized for each group. Rats that were not affected by kainic acid were indistinguishable from a saline-injected control group. When sacrificed 4 hr after treatment, rats displaying partial seizures showed morphological changes similar to, but less severe than, those exhibiting status epilepticus. Additional groups were tested and sacrificed 7 days (d) after treatment. Rats from the limited seizure group showed little behavioral or morphological response, while animals from the status epilepticus group had marked behavioral deficits and severe lesions. The tissue damage and its distribution were similar to lesions observed after seizures induced by other convulsants, and in spontaneously epileptic dogs. These results suggest that the extent of damage resulting from systemic administration of KA is dependent on the extent of seizure activity, which may in turn be related to the influence of kainic acid and other excitatory amino acids on the limbic system.     

Ibotenic acid-induced limbic seizures and neuronal degeneration

Electrographic and clinical observations were made as long as 2 months after the injection of ibotenic acid (IBO) solution (50 micrograms in 1 microliter of phosphate buffer solution) through a chronically implanted cannula into unilateral amygdala of freely moving and non-anesthetized cats. The control group (phosphate buffer group) showed no change during the observation period. About 30 to 60 minutes after the injection of IBO, focal amygdaloid seizures occurred and propagated to the adjacent limbic structures. Clinically, attention and ipsilateral mydriasis were observed. The seizures occurred only 2 to 5 times and ceased within 4 hours. Cats became electroclinically normal afterwards. Histopathological examination revealed a small necrosis at the injected site of the amygdala. Remarkable pyknosis and gliosis were noted around the necrosis. Remote lesions such as neuronal cell loss and pyknosis were observed in the ipsilateral pyramidal cell layer of the hippocampus. But these changes were mild and not so severe as compared to our previous report of kainic acid microinjection in cats. Authors emphasized that IBO should be an excellent tool for lesion making and also suggested that an aseptic manipulation was essential in the lesion study in cats.     

Rapid hippocampal kindling following intraamygdaloid injection of quisqualic acid in cats

Quisqualic acid (QA) is a potent neuroexcitant and a heterocyclic analogue of glutamate as is kainic acid. Twenty micrograms of QA in unilateral lateral amygdaloid nucleus of cats produced a transient limbic status epilepticus lasting 20-30 hours. Over 14 days after recovery from the limbic status, the animals received daily electrical stimulation to the ipsilateral hippocampus at the intensity of afterdischarge threshold which was determined before the injection of QA. These stimulations resulted in secondarily generalized convulsive seizures in all animals within 4 to 12 days. Spontaneous secondarily generalized seizures were confirmed in two cats after completion of the hippocampal kindling. This rapid completion of the kindling process is interesting phenomenon in contrast to the report that the hippocampal kindling took nearly 60 days. This rapid completion of the kindling effect is considered to be due to the transfer effect (Goddard, 1975) established in the ipsilateral hippocampus by severe bombardments from the amygdala stimulated by the injection of QA as the primary focus. In addition, the pathological changes in the amygdala and hippocampus on the injected side might be related to the rapid kindling process of the ipsilateral hippocampus as the irritable foci.     

Hypothermia reduces brain edema, spontaneous recurrent seizure attack, and learning memory deficits in the kainic acid treated rats

Aims: It is unknown whether hypothermia can disrupt the progress of epileptogenesis. The present study aimed to determine the effect of hypothermia on brain edema and epileptogenesis and to establish whether brain edema is associated with epileptogenesis after severe status epilepticus (SE). Methodology: Rats were injected with a single dose of Kainic acid (KA) to produce either chronic epileptic rats (rats with spontaneous recurrent seizure, SRS) or rats without spontaneous recurrent seizure (no‐SRS rats). A second KA injection was used to induce SE in SRS rats and in no‐SRS rats. The number of SRS was counted and the brain edema induced by SE was assessed by brain water content measurement. The cognitive function was assessed by the radial‐arm maze (RAM) test. Results: A second KA injection resulted in brain edema that was more severe in SRS rats than in no‐SRS rats. After second injection of KA, hypothermia treatment attenuated the KA induced brain edema and reduced the SRS attack in SRS rats. Additionally cognitive function was better in hypothermia‐treated SRS rats than in nomothermia treated SRS rats 1 month after the second KA injection. Conclusions: Hypothermia treatment immediately after SE not only exhibited protective effects against the chronic spontaneous recurrent convulsant seizures but also improved cognitive function. These antiepileptogenic properties of hypothermia may be related to its attenuating effect on brain edema induced by SE. They therefore suggest that brain edema may be involved in the progress of epileptogenesis.     

Effects of thyrotropin-releasing hormone (TRH) on status epilepticus in rats

Recent studies have demonstrated that intramuscular administration of thyrotropin-releasing hormone (TRH) or its analogue improves various clinical aspects of intractable epilepsy such as Lennox-Gastaut syndrome, West syndrome, and myoclonus epilepsy. Other clinical studies reported efficient property of intravenous TRH against status epilepticus. However, it is also true that intravenous TRH produces epileptic seizures in patients with epilepsy or organic brain damage. Thus, the utility of intravenous TRH for the treatment of status epilepticus seems to be equivocal. To further explore the problem in this regard, we examined the effect of TRH on limbic status epilepticus in rats. Thirty-eight male Wistar rats weighing 180-220g were used. Status epilepticus was induced by intracerebral injection of a combination of 200 micrograms of dibutyryl-cAMP (db-cAMP) and 67.2ng of ethylenediaminetetraacetic acid (EDTA) into the amygdala (AM) through an implanted cannula. 30 min later, TRH or vehicle (distilled water) was administered intravenously (i.v.) or intracerebroventricularly (i.c.v.). Although 3 mg/kg of TRH (n = 9), when injected i.v., did not alter the pattern of electroclinical ictal responses induced by db-cAMP/EDTA, 25 mg/kg (n = 5) and 50 mg/kg (n = 5) of TRH significantly exaggerated EEG and/or behavioral ictal seizures, beginning immediately after the injection and lasting for more than 30 min. With 50 mg/kg of TRH, the exaggerated seizure patterns were followed by marked suppression of electroclinical seizures. 50 micrograms of i.c.v. TRH (n = 5), like higher doses of i.v. TRH, caused a slight, but not a significant, build up of electroclinical ictal seizures, beginning immediately after the injection and lasting for about 30 min.(ABSTRACT TRUNCATED AT 250 WORDS)     

Limbic seizures without brain damage after injection of low doses of kainic acid into the amygdala of freely moving rats

Kainic acid (KA, 8-15 ng) was injected into the amygdala of conscious freely moving rats via chronically implanted fused silica cannulas. At 15-25 min after the injection, most rats suffered a limbic seizure attack of short duration, consisting of mastication, forelimb clonus, and raising on hind limbs, behaviorally indistinguishable from kindled seizures. Typically, the attack was followed by stereotypies, intense exploration, and by 1 or 2 more attacks. About 60 min after the injection, most rats appeared normal again and histopathological changes in their brains did not exceed those seen in vehicle-injected rats. In 3 cases, however, recurrent seizures culminated in behavioral status epilepticus 60-90 min after the injection. The status epilepticus was stopped by i.p. injection of diazepam (10 mg/kg) after a duration of 10 min (1 case) and 30 min (2 cases), respectively. After 10 min status epilepticus, we observed marginal neuronal damage with slight gliosis in both hippocampi (CA3 and CA1); after 30 min, hippocampal histopathology was more pronounced, with additional necrosis of the ipsilateral piriform cortex. After 0.8 microgram KA, a hundredfold higher dose, the incidence of limbic seizures during the first 40 min was not significantly higher (9/12) than after the lower KA doses (13/19). However, a significantly higher proportion of rats exhibited long-lasting seizure activity, associated with confluent destruction of CA3 pyramidal cells and additional seizure-related brain damage. Our results show that limbic motor seizures do not inevitably lead to histopathological changes in the brain, provided they do not culminate in a state of permanent seizure activity.     

Behavioral and Histopathological Analysis of Domoic Acid Administration in Marmosets

Summary:  Purpose: To induce status epilepticus (SE) followed by the subsequent onset of spontaneous recurrent seizures, thus characterizing a new model of temporal lobe epilepsy in a nonhuman primate.
Methods: Male and female marmosets ( Callithrix jacchus ) (n = 18), ages between 2 and 8 years, were injected with domoic acid (0.5–4 mg/kg, i.p.) or saline, and behaviorally assessed with regard to the presence of acutely induced seizures and for ≤6 months for spontaneous seizures. Injection of doses ranging from 3.5 to 4 mg/kg either did not induce SE or resulted in fatal SE. Even a 5-min SE duration (SE blockade resulting from diazepam injection) proved lethal to marmosets within 1 h of domoate administration, regardless of intensive care and monitoring of the animals. Animals injected with doses ranging from 0.5 to 3 mg/kg that developed only a few minor convulsive signs were allowed a 6-month survival period for the assessment of spontaneous epileptic events. At the end of the experiment, 6-month period, or acute intoxication associated with SE induction, animals were deeply anesthetized and had their brains subjected to histologic processing for Nissl and delta-FosB.
Results: For the animals injected with domoate that did not develop SE (i.e., those that survived), we could not detect any behavioral signs of spontaneous epileptic seizures in the 6-month observation period, and only minor indications of neuropathologic changes (i.e., neuronal death) over Nissl-stained sections, as well as some small changes in the staining for delta-FosB in a few of the animals.
Conclusions: Systemic administration of domoic acid to marmosets is not effective for the generation of a model of chronic temporal lobe epilepsy. Administration of domoic acid at doses that do not lead to SE also did not lead to the development of temporal lobe epilepsy or clear-cut behavioral changes over a 6-month period.     

Effect of diphenylhydantoin on a developed epileptogenic focus in cats with split cerebral hemispheres]

The purpose of this work was to assess the effects of DPH on a developed epileptogenic focus in cats with split cerebral hemispheres. The investigations were carried out on 12 cats with a chronic epileptogenic focus produced by means of aluminum method in the right motor area. In all cats the epileptogenic focus was found in EEG. All animals received DPH in daily doses of 8-15 mg/kg. In 2 cats they appeared before beginning of treatment. One of these cats died after 3 days from status epilepticus, the other survived status epilepticus and died after 42 days of DPH administration with signs of intoxication. In 3 cats clinical seizures developed during DPH treatment after 30.84 and 210 days. DPH was given during from 171 to 314 days. Clinical seizures appeared in these cats only sporadically and the animals were sacrificed after completion of investigations. In 7 out of 12 cats clinical seizures failed to develop despite presence of bioelectrically active epileptogenic seizures in the right motor area. Administration of DPH in cats with developed epileptogenic focus failed to prevent clinical seizures. In cats with seizures their control was limited by drug toxicity. In all animals toxic effects were observed although the serum DPH level was in the range 8-20 mug/ml.     

Epileptogenic properties of quisqualic acid: microinjection into the unilateral amygdala in cats

The present studies demonstrated that the microinjection of quisqualic acid (QA) into unilateral amygdala in chronically implanted cats resulted in various types of limbic seizures in accordance with injected doses. The epileptogenic potency of QA in the induction of epileptic seizures was lower then that of kainic acid (KA), which has also been demonstrated in our previous studies. Electroencephalographic changes and clinical manifestations of QA-induced epilepsy were less prominent as compared with those of KA-induced epilepsy. Five micrograms of QA resulted in pure amygdaloid seizures. The moderate dose administration of QA (15 micrograms) was suitable to observe limbic status. Both doses of QA elicited similar characteristic epileptic patterns on EEG, which was quite distinguishable from those of KA. In pathological study, mild degeneration of hippocampal pyramidal cell layer was observed in the cases injected 15 micrograms of QA. These electro-clinical and pathological features are interesting in similarities to those of human complex partial seizures, mesial temporal sclerosis. In conclusion, the strict dose dependency of QA in the production of limbic seizures is a valid advantage for an experimental model of a complex partial epilepsy in man.     

A gliotoxin model of occipital seizures in rats

PURPOSE: Intracortical microinjection of fluorocitrate, a reversible inhibitor of glial tricarboxylic acid (TCA), results in impaired glial metabolism and epileptic seizures. To determine the potential contribution of epileptic activities to the metabolic properties of fluorocitrate, we investigated the seizure-inducing property of fluorocitrate at different doses. METHODS: Twenty-seven male Sprague Dawley rats (250-400g) were studied with chronically implanted electrodes and cannulae in the occipital cortices. A week after surgery, awake behaving rats were injected with 0.2microl solution containing various concentrations of fluorocitrate or saline in the right occipital cortex; two sham-treated animals did not receive an injection. EEG was recorded with implanted electrodes. Thionin staining was used to verify injection sites. Twenty rats underwent immunohistochemistry for glial fibrilary acidic protein (GFAP) and neuronal nuclear-specific antigen (NeuN) 48h after the injections. RESULTS: Seizures developed within an hour of injection in all the rats that received > or =0.8nmol fluorocitrate and 2 of 4 rats that received 0.4nmol fluorocitrate. Five of 12 animals that received > or =1.2nmol fluorocitrate experienced status epilepticus. There was a significant increase in GFAP staining at the injection site in doses > or =0.8nmol fluorocitrate. There was only mild neuronal loss revealed by NeuN staining at the injection site in the animals that had received 1.6nmol flourocitrate. CONCLUSION: This study shows that fluorocitrate results in focal epileptic seizures with secondary generalization in a dose-dependent manner, including low doses of this agent previously used for studies of brain metabolism.     

Nerve Growth Factor and Basic Fibroblast Growth Factor Protect Cholinergic Neurons Against Quinolinic Acid Excitotoxicity in Rat Neostriatum

In the present work we have characterized a possible mechanism leading to the early survival of neostriatal cholinergic neurons after quinolinic acid injection. Different doses of quinolinic acid were injected in rat neostriatum and two different parameters were analysed 7 days after the lesion: choline acetyltransferase (ChAT) activity and nerve growth factor (NGF) levels. We have observed that ChAT activity decreased (until 68 nmol quinolinic acid) and NGF levels increased (until 34 nmol quinolinic acid) in a dose-dependent manner. In order to characterize the time-course of the lesion on NGF levels and ChAT activity, and the possible protective effect of NGF and basic fibroblast growth factor (bFGF) on cholinergic neurons, we have used the quinolinic acid dose (68 nmol) at which the first decrease of ChAT activity was observed. ChAT activity and NGF levels showed different patterns of response to quinolinic acid injection, since the maximal effect was reached at 1 day for ChAT activity and at 2 days for NGF levels. NGF or bFGF simultaneously injected with quinolinic acid (68 nmol) completely prevented the decrease in ChAT activity in a dose-dependent manner but NGF was more effective than bFGF. Furthermore, differences observed in ChAT activity after NGF but not bFGF treatment were correlated with changes in the number of ChAT immunoreactive cells. Finally, we have also observed that, although bFGF alone was not able to modify NGF levels, bFGF simultaneously injected with quinolinic acid produced an increase of NGF levels higher than that observed after quinolinic acid injection alone. Our results show that NGF and bFGF protect striatal cholinergic neurons against quinolinic acid injury, and bFGF is able to potentiate the increase of NGF after the lesion, suggesting a cooperative action between different trophic factors in neuronal protection after excitotoxic injury. Thus, administration of trophic factors may be relevant in the prevention and treatment of neurodegenerative disorders, such as Huntington's disease.     

Acute effect of penicillin G on feline models of focal epilepsy

Penicillin is well known as a potent convulsive agent. A cortical topical, intracerebral or systemic administration of penicillin produces abnormal and paroxysmal activity which may lead to seizure, and has been used in the investigation of the mechanisms of epilepsy. This is a report on the studies of an acute effect of potassium penicillin G on two models of experimental focal epilepsy: a) amygdaloid kindling model, and b) kainic acid-induced limbic seizure model. Twelve adult cats for amygdaloid kindling model (kindling group), six for KA-induced limbic seizure model (KA group) and four for a control group were prepared for this study. In kindling group, after completion of kindling procedure, 40-60 X 10(4) unit/kg of potassium penicillin G (PC), dissolved in sterilized normal saline, was injected intraperitoneally during an interictal period. In KA group, 1 micrograms of KA was injected into the left amygdala. Limbic seizures occurred frequently during the initial 5 hours but subsided completely within 3 days. After a latent period, spontaneous secondarily generalized convulsion occurred from 30 to 60 days after KA injection. The cats were completely normal in their behavior during the interictal period. During the interictal stage after the first generalized convulsion has been observed, 15-20 X 10(4) unit/kg of PC was injected intraperitoneally. In the control group, 40-60 X 10(4) unit/kg was injected intraperitoneally. Electroclinical observations were continued until 5 hours after PC injection in three groups. In the control group, no cats developed generalized convulsion. In the kindling group, 4 of 12 cats developed focal amygdaloid seizures with secondary generalization by nearly the identical doses required in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Kainic acid-induced substantia nigra seizure in rats: behavior, EEG and metabolism

RATIONALE: In order to clarify the role of substantia nigra pars reticulata (SNr) upon the development of epileptic seizure, kainic acid (KA) was injected into a unilateral SNr. MATERIALS AND METHODS: Wistar rats weighing 250-350 g were used. A stainless-steel cannula and depth electrode were inserted stereotaxically into the left substantia nigra pars reticulata (SNr). At 7 days after surgery, 1.0 microg of KA was injected into the left SNr. Experiment 1: In eight rats, behavior and electroencephalograms (EEG) were continuously recorded for about 30 h, and intermittently monitored following 1 month. Experiment 2: Two hours after KA injection into SNr, rats demonstrated status epilepticus. Then, 100 microCi/kg of [(14)C]2-deoxyglucose (2-DG) was intravenously injected in seven rats, and the rats were processed for autoradiographic study. RESULTS: Changes in behavior and EEG: On EEG, a secondary generalized seizure status was observed at about 70 min after KA injection. In video, limbic seizure manifestations such as salivation were observed as a initial symptom and followed by rolling and generalized tonic seizures. [(14)C]deoxyglucose autoradiographic study demonstrated increased local cerebral glucose metabolism in the medial and lateral septal nucleus, substantia nigra, hippocampus, parietal cortex, piriform cortex, medial and lateral geniculate nucleus, anterodorsal, lateral and ventral nucleus of the thalamus, amygdala and midbrain reticular formation. SUMMARY: The result suggested that the substantia nigra played an important role in the secondary generalization in the substantia nigra seizure model due to the decreased function of the GABAergic projection system induced by an excessive epileptic excitation of SNr.     

Repeated systemic administration of the nutraceutical alpha-linolenic acid exerts neuroprotective efficacy,an antidepressant effect and improves cognitive performance when given after soman exposure

Exposure to nerve agents results in severe seizures or status epilepticus caused by the inhibition of acetylcholinesterase, a critical enzyme that breaks down acetylcholine to terminate neurotransmission. Prolonged seizures cause brain damage and can lead to long-term consequences. Current countermeasures are only modestly effective against the brain damage supporting interest in the evaluation of new and efficacious therapies. The nutraceutical alpha-linolenic acid (LIN) is an essential omega-3 polyunsaturated fatty acid that has a wide safety margin. Previous work showed that a single intravenous injection of alpha-linolenic acid (500 nmol/kg) administered before or after soman significantly protected against soman-induced brain damage when analyzed 24 h after exposure. Here, we show that administration of three intravenous injections of alpha-linolenic acid over a 7 day period after soman significantly improved motor performance on the rotarod, enhanced memory retention, exerted an anti-depressant-like activity and increased animal survival. This dosing schedule significantly reduced soman-induced neuronal degeneration in four major vulnerable brain regions up to 21 days. Taken together, alpha-linolenic acid reduces the profound behavioral deficits induced by soman possibly by decreasing neuronal cell death, and increases animal survival.